Shock. 2022 May 1;57(5):694-702. doi: 10.1097/SHK.0000000000001893. Epub 2022 Jan 20.

ABSTRACT

Sepsis-associated encephalopathy (SAE) often manifests in severe diffuse cerebral dysfunction due to an aberrant systemic immune response to infection. The underlying pathophysiology of SAE is not entirely understood but is likely a multifactorial process that involves disruption in cell death mechanism. Ferroptosis is a novel form of programmed cell death characterized by iron accumulation and lipid peroxidation, leading to inflammatory cascade and glutamate release. We hypothesized that ferroptosis is involved in the glutamate-mediated excitotoxic neuron injury during the uncontrolled neural inflammatory process of SAE. Inhibiting ferroptosis with ferrostatin-1 (Fer-1) could alleviate glutamate excitotoxicity and reduce neuron death of SAE, potentially improving prognosis. We found that in the cecal ligation and puncture (CLP) sepsis model, ferroptosis occurred increasingly in the cerebrum, characterized by glutathione-dependent antioxidant enzyme glutathione peroxidase 4 (GPX4) inactivation, transferrin upregulation, mitochondria shrink and malondialdehyde (MDA) increased. Fer-1 treatment downregulated cerebral ferroptosis and alleviated glutamate excitotoxicity via dampening system xc-(SXC) and glutamate receptor N-methyl-D-asperate receptor subunit 2. Combined with an observed reduction in calcium transporter PLCG and PLCB activation, these processes ultimately protected the integrities of synapses and neurons during SAE. Fer-1 treatment also rescued sepsis-induced nuclear autophagy and improved the behaviors of tail suspension test and novel object recognition test in septic mice. Conclusively, our results suggested that inhibition of ferroptosis could attenuate glutamate excitotoxicity and SAE outcomes.

PMID:35066511 | DOI:10.1097/SHK.0000000000001893

Comp Biochem Physiol C Toxicol Pharmacol. 2022 Jan;251:109210. doi: 10.1016/j.cbpc.2021.109210. Epub 2021 Oct 8.

ABSTRACT

Cadmium (Cd) can adversely affect aquatic life, altering reproductive and molting processes in crustaceans. The objective of this study was to evaluate the influence of Cd on reproduction and molting in the crab Callinectes danae. Adult females were obtained from environments with different levels of pollution: low (LC), medium (MC), and high contaminated (HC) areas. Animals from LC, MC, and HC areas were exposed to 0, 0.5, and 2 mg L^-1 of CdCl₂ for 3 h. Cd bioaccumulation, oxidative stress (evaluated by antioxidant enzymes activity), and lipid peroxidation (LPX) were analyzed in mature ovaries (stage II), gills, and hepatopancreas. The expression levels of crustacean hyperglycemic hormone (CHH) and molt-inhibiting hormone (MIH) genes were quantified in the eyestalks, while 17β-estradiol (E2) and melatonin concentration were measured in the hemolymph. Cd bioaccumulated mainly in the hepatopancreas and gills, with increased E2, LPX, and antioxidant enzymes in HC compared to the LC region. Decreased CHH and MIH transcripts were observed in the animals from HC regions compared to LC and MC areas. Physiological differences were recorded, especially for bioaccumulation, oxidative stress, and hormone levels, in animals sampled in HC areas compared to LC and MC regions. In conclusion, the physiological damage triggered by Cd could be reduced due to higher levels of melatonin and antioxidant enzymes in HC areas.

PMID:34628057 | DOI:10.1016/j.cbpc.2021.109210

Exp Cell Res. 2021 Nov 15;408(2):112840. doi: 10.1016/j.yexcr.2021.112840. Epub 2021 Oct 9.

ABSTRACT

Alzheimer's disease (AD) is a devastating neurodegenerative condition with significant socio-economic impact that is exacerbated by the rapid increase in population aging, particularly impacting already burdened health care systems of poorly resourced countries. Accumulation of the amyloid-β (Aβ) peptide, generated through amyloid precursor protein (APP) processing, manifesting in senile plaques, is a well-established neuropathological feature. Aβ plays a key role in driving synaptic dysfunction, neuronal cell loss, glial cell activation and oxidative stress associated with the pathogenesis of AD. Thus, the enhanced clearance of Aβ peptide though modulation of the mechanisms that regulate intracellular Aβ metabolism and clearance during AD progression have received major attention. Autophagy, a lysosome-based major proteolytic pathway, plays a crucial role in intracellular protein quality control and has been shown to contribute to the clearance of Aβ peptide. However, to what extent autophagy activity remains upregulated and functional in the process of increasing Aβ neurotoxicity is largely unclear. Here, we investigated the extent of neuronal toxicity in vitro by characterising autophagic flux, the expression profile of key amyloidogenic proteins, and proteins associated with prominent subtypes of the autophagy pathway to dissect the interplay between the engagement of proteolytic pathways and cell death onset in the context of APP overexpression. Moreover, we assessed the neuroprotective effects of a caloric restriction regime in vivo on the modulation of autophagy in specific brain regions. Our results reveal that autophagy is upregulated in the presence of high levels of APP and Aβ and remains heightened and functional despite concomitant apoptosis induction, suggestive of a mismatch between autophagy cargo generation and clearance capacity. These findings were confirmed when implementing a prolonged intermittent fasting (IF) intervention in a model of paraquat-induced neuronal toxicity, where markers of autophagic activity were increased, while apoptosis onset and lipid peroxidation were robustly decreased in brain regions associated with neurodegeneration. This work highlights that especially caloric restriction mimetics and controlled prolonged IF may indeed be a highly promising therapeutic strategy at all stages of AD-associated pathology progression, for a cell-inherent and cell specific augmentation of Aβ clearance through the powerful engagement of autophagy and thereby robustly contributing to neuronal protection.

PMID:34624324 | DOI:10.1016/j.yexcr.2021.112840

Neurochem Res. 2022 Feb;47(2):279-294. doi: 10.1007/s11064-021-03442-7. Epub 2021 Sep 4.

ABSTRACT

Studies have shown that diabetes is associated with the occurrence of neurodegenerative diseases and cognitive decline. However, there is currently no effective treatment for diabetes-induced cognitive dysfunction. The superior efficacy of liraglutide (LIRA) for cognitive impairment and numerous neurodegenerative diseases has been widely demonstrated. This study determined the effects of LIRA on diabetic cognitive impairment and on the levels of oxidative stress, lipid peroxidation, iron metabolism and ferroptosis in the hippocampus. Mice were injected daily with liraglutide (200 μg/kg/d) for 5 weeks. LIRA could repair damaged neurons and synapses, and it increased the protein expression levels of PSD 95, SYN, and BDNF. Furthermore, LIRA significantly decreased oxidative stress and lipid peroxidation levels by downregulating the production of ROS and MDA and upregulating SOD and GSH-Px in the serum and hippocampus, and the upregulation of SOD2 expression was also proven. The decreased levels of TfR1 and the upregulation of FPN1 and FTH proteins observed in the LIRA-treated db/db group were shown to reduce iron overload in the hippocampus, whereas the increased expression of Mtft and decreased expression of Mfrn in the mitochondria indicated that mitochondrial iron overload was ameliorated. Finally, LIRA was shown to prevent ferroptosis in the hippocampus by elevating the expression of GPX4 and SLC7A11 and suppressing the excessive amount of ACSL4; simultaneously, the damage to the mitochondria observed by TEM was also repaired. For the first time, we proved in the T2DM model that ferroptosis occurs in the hippocampus, which may play a role in diabetic cognitive impairment. LIRA can reduce oxidative stress, lipid peroxidation and iron overload in diabetic cognitive disorders and further inhibit ferroptosis, thereby weakening the damage to hippocampal neurons and synaptic plasticity and ultimately restoring cognitive function.

PMID:34480710 | DOI:10.1007/s11064-021-03442-7

Epilepsy Res. 2021 Oct;176:106722. doi: 10.1016/j.eplepsyres.2021.106722. Epub 2021 Jul 12.

ABSTRACT

Epilepsy is a neurological disorder which is characterized by brain hyper-excitability and manifests as seizure. Due to its complicated pathogenesis, treatment for epilepsy still remains a huge challenge for neurology in the whole world. MciroRNA-134 (miR-134) is one kind of miRNAs which was firstly found abundant in synapses. In this study, we tried to unveil the role of inhibiting MciroRNA-134-5p (miR-134-5p) in excitotoxicity induced by kainic acid (KA) in the hippocampal neurons (HT22) cells. The results showed that treatment of KA increased the expression of miR-134-5p significantly and caused marked neuron excitotoxicity, evidenced by risen cell death rate, higher LDH release and aggravated cell viability. After suppressing miR-134-5p expression via transfecting HT22 cells with miR-134-5p antisense (Anti-134), cell viability was promoted obviously, along with decreased LDH release and cell death rate. In addition, KA-induced lipid peroxidation, cytochrome c release and mitochondrial ROS generation were also attenuated by Anti-134. The level of Sirtuin 3 (Sirt3) and its downstream antioxidant enzymes, such as mitochondrial superoxide dismutase 2 (SOD2), isocitrate dehydrogenase 2 (IDH2) and glutathione peroxidase (GSH-Px), were significantly higher in Anti-134 group compared with the control and scramble group. After inhibiting Sirt3 expression with SiRNA targeting Sirt3 (Si-Sirt3) and 3-(1H-1,2,3-triazol-4-yl) pyridine (3-TYP), the positive role of Anti-134 was apparently reversed. In conclusion, this research highly suggests that inhibition of miR-134-5p could protect neurons from KA-induced excitotoxicity through Sirt3-mediated preservation of mitochondrial function.

PMID:34273723 | DOI:10.1016/j.eplepsyres.2021.106722

Antioxidants (Basel). 2021 Jun 1;10(6):892. doi: 10.3390/antiox10060892.

ABSTRACT

Dysregulated glutamate signaling, leading to neuronal excitotoxicity and death, has been associated with neurodegenerative pathologies. 17β-estradiol (E2) is a human steroid hormone having a role in reproduction, sexual maturation, brain health and biological activities. The study aimed to explain the neuroprotective role of E2 against glutamate-induced ROS production, MAP kinase-dependent neuroinflammation, synaptic dysfunction and neurodegeneration in the cortex and hippocampus of postnatal day 7 rat brain. Biochemical and immunofluorescence analyses were applied. Our results showed that a single subcutaneous injection of glutamate (10 mg/kg) induced brain oxidative stress after 4 h by disturbing the homeostasis of glutathione (GSH) and revealed an upsurge in ROS and LPO levels and downregulated the expression of Nrf2 and HO-1 antioxidant protein. The glutamate-exposed P7 pups illustrated increased phosphorylation of stress-activated c-Jun N-terminal kinase (JNK) and p38 kinase (p38) and downregulated expression of P-Erk1/2. This was accompanied by pathological neuroinflammation as revealed by enhanced gliosis with upregulated expression of GFAP and Iba-1, and the activation of proinflammatory cytokines (TNF-α) in glutamate-injected P7 pups. Moreover, exogenous glutamate also reduced the expression of synaptic markers (PSD-95, SYP) and induced apoptotic neurodegeneration in the cortical and hippocampal regions by dysregulating the expression of Bax, Bcl-2 and caspase-3 in the developing rat brain. On the contrary, co-treatment of E2 (10 mg/kg) with glutamate significantly abrogated brain neuroinflammation, neurodegeneration and synapse loss by alleviating brain oxidative stress by upregulating the Nrf2/HO-1 antioxidant pathway and by deactivating pro-apoptotic P-JNK/P-p38 and activation of pro-survival P-Erk1/2 MAP kinase pathways. In brief, the data demonstrate the neuroprotective role of E2 against glutamate excitotoxicity-induced neurodegeneration. The study also encourages future studies investigating if E2 may be a potent neuroprotective and neurotherapeutic agent in different neurodegenerative diseases.

PMID:34206065 | PMC:PMC8229583 | DOI:10.3390/antiox10060892

Brain Res. 2021 Sep 15;1767:147449. doi: 10.1016/j.brainres.2021.147449. Epub 2021 Mar 24.

ABSTRACT

Alzheimer disease (AD) is the most frequent form of dementia in the elderly. It is characterized by the deterioration of memory and learning. The histopathological hallmarks of AD include the presence of extracellular deposits of amyloid beta peptide, intracellular neurofibrillary tangles, neuron and synapse loss, in the brain, including the hippocampus. Accumulation of Aβ peptide causes an increase in intracellular reactive oxygen species (ROS) and free radicals associated to a deficient antioxidant defense system. Besides oxidative stress and cognitive deficit, AD patients show alterations in their circadian rhythms. The objective of this work was to investigate the effects of an intracerebroventricular injection of amyloid beta peptide Aβ(1-42) aggregates on temporal patterns of protein oxidation, antioxidant enzymes and clock factors in the rat hippocampus. Four-month-old male Holtzman rats divided into the groups control (CO) and Aβ-injected (Aβ), were maintained under 12 h-light12h-dark conditions and received water and food ad-libitum. Hippocampus samples were isolated every 6 h during a 24 h period. Our results showed daily patterns of protein carbonyls, catalase (CAT) and glutathione peroxidase (GPx) expression and activity, as well as Rorα and Rev-erbß mRNA, in the rat hippocampus. Interestingly, an intracerebroventricular injection of Aβ aggregates modified daily oscillation of protein carbonyls levels, phase-shifted daily rhythms of clock genes and had a differential effect on the daily expression and activity of CAT and GPx. Thus, Aβ aggregates might affect clock-mediated transcriptional regulation of antioxidant enzymes, by affecting the formation of BMAL1:CLOCK heterodimer, probably, as a consequence of the alteration of the redox state observed in rats injected with Aβ.

PMID:33771518 | DOI:10.1016/j.brainres.2021.147449

Food Chem Toxicol. 2021 May;151:112114. doi: 10.1016/j.fct.2021.112114. Epub 2021 Mar 13.

ABSTRACT

Ferroptosis is a novel form of cell death that involves in the pathophysiological process of diverse brain diseases. However, how arsenite induces ferroptosis in the neuronal cells remains unsolved. In this study, by using in vitro and in vivo models, we demonstrated that arsenite was able to trigger ferroptosis in the neuronal cells. Exposure of arsenite for 6 months at 0.5, 5 and 50 mg/L arsenite via drinking water significantly reduced the number of neurons and caused the pathological changes in the mitochondria of hippocampus. Treatment of arsenite elevated the contents of lipid peroxidation products, disrupted the iron homeostasis, altered the expressions of ferroptosis-related proteins in the hippocampus and PC-12 cells. The results also showed that arsenite significantly decreased the expressions of ferritin and NCOA4, but sharply enhanced the level of autophagy marker LC3B, suggesting the activation of ferritinophagy by arsenite. Co-treatment of arsenite with ferroptosis inhibitor ferrostatin-1, or autophagy inhibitors 3-MA and BafA1, all remarkably attenuated the cytotoxic effects of arsenite. These findings not only present a novel mechanism that arsenite triggers ferroptosis in the neuronal cells via activation of ferritinophagy, but also indicate that regulating ferritinophagy to control iron level may provide a clue for prevention against arsenite neurotoxicity.

PMID:33722599 | DOI:10.1016/j.fct.2021.112114

Life Sci. 2021 May 15;273:119300. doi: 10.1016/j.lfs.2021.119300. Epub 2021 Mar 2.

ABSTRACT

AIMS: Plasma hyperlipidemia is a protective factor in amyotrophic lateral sclerosis (ALS) while cholesterol-lowering drugs aggravate the pathology. We hypothesize that this phenomenon can be linked with membrane lipid alterations in the neuromuscular junctions (NMJs) occurring before motor neuron loss.

METHODS: Neurotransmitter release in parallel with lipid membrane properties in diaphragm NMJs of SOD1G93A (mSOD) mice at nine weeks of age (pre-onset stage) were assessed.

KEY FINDINGS: Despite on slight changes in spontaneous and evoked quantum release of acetylcholine, extracellular levels of choline at resting conditions, an indicator of non-quantum release, were significantly increased in mSOD mice. The use of lipid-sensitive fluorescent probes points to lipid raft disruption in the NMJs of mSOD mice. However, content of cholesterol, a key raft component was unchanged implying another pathway responsible for the loss of raft integrity. In the mSOD mice we found marked increase in levels of raft-destabilizing lipid ceramide. This was accompanied by enhanced ability to uptake of exogenous ceramide in NMJs. Acute and chronic administration of 25-hydroxycholesterol, whose levels increase due to hypercholesterolemia, recovered early alterations in membrane properties. Furthermore, chronic treatment with 25-hydroxycholesterol prevented increase in ceramide and extracellular choline levels as well as suppressed lipid peroxidation of NMJ membranes and fragmentation of end plates.

SIGNIFICANCE: Thus, lipid raft disruption likely due to ceramide accumulation could be early event in ALS which may trigger neuromuscular abnormalities. Cholesterol derivative 25-hydroxycholesterol may serve as a molecule restoring the membrane and functional properties of NMJs at the early stage.

PMID:33662433 | DOI:10.1016/j.lfs.2021.119300

J Musculoskelet Neuronal Interact. 2020 Dec 1;20(4):570-578.

ABSTRACT

OBJECTIVES: evaluate the effects that whole-body vibration (WBV) causes on the neuromuscular junctions and oxidative stress of the soleus muscle of obese Wistar rats.

METHODS: 32 male Wistar rats were used, 16 of which were obesity induced by monosodium glutamate, randomized into four groups: control (GC), control with WBV (GCP), obese (GO) and obese with WBV (GOP). At the 70 days old, the training on WBV was started, performed 3 times a week, during 8 consecutive weeks. At the 130 days old, the animals were euthanized and the soleus muscles were collected.

RESULTS: Regarding the analysis of the neuromuscular junctions, the obese groups had lower mean size when compared to the control groups. On the other hand, the WBV presented higher averages when compared to the groups that did not perform the training. Regarding the oxidative stress, for the lipid peroxidation there was a significant difference between obese and non-obese animals, however, there was no difference between the animals WBV and those who did not.

CONCLUSION: WBV promotes beneficial changes such as increased measurements of the structures of the neuromuscular junctions, but is not able to promote changes in the concentration of the cholinesterase enzyme in the synaptic cleft.

PMID:33265086 | PMC:PMC7716688

Curr Neurovasc Res. 2020;17(4):510-517. doi: 10.2174/1567202617999200831152233.

ABSTRACT

BACKGROUND: Hypoxic-ischemic encephalopathy (HIE) is a major cause of pediatric and adult mortality and morbidity. Unfortunately, to date, no effective treatment has been identified. In the striatum, neuronal injury is analogous to the cellular mechanism of necrosis observed during NMethyl- D-Aspartate (NMDA) excitotoxicity. Adenosine acts as a neuromodulator in the central nervous system, the role of which relies mostly on controlling excitatory glutamatergic synapses.

OBJECTIVE: To examine the effect of pretreatment of SCH58261, an adenosine 2A (A2A) receptor antagonist and modulator of NMDA receptor function, following hypoxic-ischemia (HI) on sodium- potassium ATPase (Na+, K+-ATPase) activity and oxidative stress.

METHODS: Piglets (4-7 days old) were subjected to 30 min hypoxia and 7 min of airway occlusion producing asphyxic cardiac arrest. Groups were divided into four categories: HI samples were divided into HI-vehicle group (n = 5) and HI-A2A group (n = 5). Sham controls were divided into Sham vehicle (n = 5) and Sham A2A (n = 5) groups. Vehicle groups were pretreated with 0.9% saline, whereas A2A animals were pretreated with SCH58261 10 min prior to intervention. Striatum samples were collected 3 h post-arrest. Sodium-potassium ATPase (Na+, K+-ATPase) activity, malondialdehyde (MDA) + 4-hydroxyalkenals (4-HDA) and glutathione (GSH) levels were compared.

RESULTS: Pretreatment with SCH58261 significantly attenuated the decrease in Na+, K+-ATPase, decreased MDA+4-HDA levels and increased GSH in the HI-A2A group when compared to HIvehicle.

CONCLUSION: A2A receptor activation may contribute to neuronal injury in newborn striatum after HI in association with decreased Na+, K+-ATPase activity and increased oxidative stress.

PMID:32867657 | DOI:10.2174/1567202617999200831152233

Free Radic Biol Med. 2020 Aug 1;155:19-28. doi: 10.1016/j.freeradbiomed.2020.05.017. Epub 2020 May 21.

ABSTRACT

Cd²⁺ is one of the most widespread environmental pollutants and its accumulation in central and peripheral nervous systems leads to neurotoxicity as well as aggravation of common neurodegenerative diseases. Mechanism of the Cd²⁺ toxicity is far from being resolved. Here, using microelectrode recordings of postsynaptic responses and fluorescent redox indicators we studied the effect of Cd²⁺ in the submicromolar range on timing of neurotransmitter release and oxidative status in two functionally different compartments of the same frog motor nerve terminal. Cd²⁺ (0.1-1 μM) acting as typical voltage-gated Ca²⁺channel (VGCC) antagonist decreased neurotransmitter release in both distal and proximal parts of the nerve terminal, but in contrast to the VGCC blockers Cd²⁺(0.1-0.5 μM) desynchronized the release selectively in the distal region. The latter action of Cd²⁺ was completely prevented by inhibitor of NADPH-oxidase and antioxidants, including mitochondrial specific, as well as redox-sensitive TRPV1 channel blocker. Cd²⁺ markedly increased levels of mitochondrial reactive oxygen species (ROS) in both the distal and proximal compartments of the nerve terminal, which was associated with lipid peroxidation mainly in the distal region. Zn²⁺, whose transport systems translocate Cd²⁺, markedly enhanced the effects of Cd²⁺ on both the mitochondrial ROS levels and timing of neurotransmitter release. Furthermore, in the presence of Zn²⁺ ions, Cd²⁺ also desynchronized the neurotransmitter release in the proximal region. Thus, in synapses Cd²⁺ at very low concentrations can increase mitochondrial ROS, lipid peroxidation and disturb the timing of neurotransmitter release via a ROS/TRPV-dependent mechanism. Desynchronization of neurotransmitter release and synaptic oxidative stress could be early events in Cd²⁺ neurotoxicity.

PMID:32445865 | DOI:10.1016/j.freeradbiomed.2020.05.017

Exp Neurol. 2020 Aug;330:113322. doi: 10.1016/j.expneurol.2020.113322. Epub 2020 Apr 20.

ABSTRACT

Traumatic brain injury (TBI) results in mitochondrial dysfunction and induction of lipid peroxidation (LP). Lipid peroxidation-derived neurotoxic aldehydes such as 4-HNE and acrolein bind to mitochondrial proteins, inducing additional oxidative damage and further exacerbating mitochondrial dysfunction and LP. Mitochondria are heterogeneous, consisting of both synaptic and non-synaptic populations, with synaptic mitochondria being more vulnerable to injury-dependent consequences. The goal of these studies was to explore the hypothesis that interrupting secondary oxidative damage following TBI using phenelzine (PZ), an aldehyde scavenger, would preferentially protect synaptic mitochondria against LP-mediated damage in a dose- and time-dependent manner. Male Sprague-Dawley rats received a severe (2.2 mm) controlled cortical impact (CCI)-TBI. PZ (3-30 mg/kg) was administered subcutaneously (subQ) at different times post-injury. We found PZ treatment preserves both synaptic and non-synaptic mitochondrial bioenergetics at 24 h and that this protection is partially maintained out to 72 h post-injury using various dosing regimens. The results from these studies indicate that the therapeutic window for the first dose of PZ is likely within the first hour after injury, and the window for administration of the second dose seems to fall between 12 and 24 h. Administration of PZ was able to significantly improve mitochondrial respiration compared to vehicle-treated animals across various states of respiration for both the non-synaptic and synaptic mitochondria. The synaptic mitochondria appear to respond more robustly to PZ treatment than the non-synaptic, and further experimentation will need to be done to further understand these effects in the context of TBI.

PMID:32325157 | PMC:PMC7418938 | DOI:10.1016/j.expneurol.2020.113322

Antioxidants (Basel). 2020 Jan 27;9(2):112. doi: 10.3390/antiox9020112.

ABSTRACT

Noise-induced hearing loss (NIHL) is primarily caused by damage to cochlear hair cells, associated with synaptopathy. The novel cell-penetrating peptide GV1001, an antitumor agent, also has antioxidant and anti-inflammatory effects, and is otoprotective in a murine model of kanamycin-induced ototoxicity. Here, we explored whether GV1001 attenuated NIHL, and the underlying mechanism at play. We established an NIHL model by exposing 4- to 6-week-old C57/BL6 mice to white noise at 120 dB SPL for 2 h, resulting in a significant permanent threshold shift (PTS). We then subcutaneously injected saline (control), GV1001, or dexamethasone immediately after cessation of PTS-noise exposure and evaluated the threshold shifts, structural damages to outer hair cells (OHCs), and ribbon synapses. We also verified whether GV1001 attenuates oxidative stress at the level of lipid peroxidation or protein nitration in OHCs 1 h after exposure to white noise at 120 dB SPL. GV1001-treated mice exhibited significantly less hearing threshold shifts over 2 weeks and preserved OHCs and ribbon synapses compared with controls. Similarly, dexamethasone-treated mice showed comparable protection against NIHL. Importantly, GV1001 markedly attenuated oxidative stress in OHCs. Our findings suggest that GV1001 may protect against NIHL by lowering oxidative stress and may serve as preventive or adjuvant treatment.

PMID:32012778 | PMC:PMC7070461 | DOI:10.3390/antiox9020112

Arq Neuropsiquiatr. 2019 Dec;77(12):881-887. doi: 10.1590/0004-282X20190184.

ABSTRACT

OBJECTIVE: Induction of long-term potentiation (LTP) increases the storage capacity of synapses in the hippocampal dentate gyrus (DG). Irisin is a myokine generated from FNDC5 (a gene precursor) during exercise.

METHODS: Although intra-cornu ammonis 1 administration of irisin fortifies LTP in mice with Alzheimer's disease, the effects of intra-DG injection of irisin on the LTP in rats remains to be elucidated in vivo. In this study, male Wistar rats were randomly divided into a control group (saline), irisin (0.5, 1, and 1.5 μg/rat), and dimethyl sulfoxide (DMSO).

RESULTS: After treatment, the population spike (PS) amplitude and slope of excitatory postsynaptic potentials (EPSP) were measured in the DG of rats in vivo. Moreover, following completion of the experiments, the stimulating and recording sites in the hippocampus were confirmed histologically from brain sections. Furthermore, biochemical assays like malondialdehyde (MDA), total antioxidant capacity (TAC), and total oxidant status (TOS) were evaluated (the antioxidant markers were analyzed in the plasma).

CONCLUSION: Our results suggest that all doses of irisin (0.5, 1, 1.5 μg/rat) caused an increase in the EPSP slope and PS amplitude when compared with the control group. In addition, the results obtained showed that irisin decreased TOS and MDA levels while increasing TAC levels as a marker of lipid peroxidation in plasma. The present report provides direct evidence that irisin affects the activity-dependent synaptic plasticity in the dentate gyrus.

PMID:31939585 | DOI:10.1590/0004-282X20190184

Ecotoxicol Environ Saf. 2019 Dec 15;185:109686. doi: 10.1016/j.ecoenv.2019.109686. Epub 2019 Sep 20.

ABSTRACT

Gestational exposure to PM_2.5 is a worldwide environmental issue associated with long-lasting behavior abnormalities and neurodevelopmental impairments in the hippocampus of offspring. PM_2.5 may induce hippocampus injury and lead to autism-like behavior such as social communication deficits and stereotyped repetitive behavior in children through neuroinflammation and neurodegeneration. Here, we investigated the preventive effect of B-vitamin on PM_2.5-induced deleterious effects by focusing on anti-inflammation, antioxidant, synaptic remodeling and neurodevelopment. Pregnant mice were randomly divided into three groups including control group (mice subject to PBS only), model group (mice subject to both 30 μL PM_2.5 of 3.456 μg/μL and 10 mL/(kg·d) PBS), and intervention group (mice subject to both 30 μL PM_2.5 of 3.456 μg/μL and 10 mL/(kg·d) B-vitamin supplementation (folic acid, vitamin B6 and vitamin B12 with concentrations at 0.06, 1.14 and 0.02 mg/mL, respectively)). In the current study B-vitamin significantly alleviated neurobehavioral impairment reflected in reduced social communication disorders, stereotyped repetitive behavior, along with learning and spatial memory impairment in PM_2.5-stimulated mice offspring. Next, B-vitamin corrected synaptic loss and reduced mitochondrial damage in hippocampus of mice offspring, demonstrated by normalized synapse quantity, synaptic cleft, postsynaptic density (PSD) thickness and length of synaptic active area. Furthermore, significantly down-regulated expression of pro-inflammatory cytokines including NF-κB, TNF-α and IL-1β, and lipid peroxidation were found. We observed elevated levels of oxidant-related genes (SOD, GSH and GSH-Px). Moreover, decreased cleaved caspase-3 and TUNEL-positive cells suggested inhibited PM_2.5-induced apoptosis by B-vitamin. Furthermore, B-vitamin increased neurogenesis by increasing EdU-positive cells in the subgranular zone (SGZ) of offspring. Collectively, our results suggest that B-vitamin supplementation exerts preventive effect on autism-like behavior and neurodevelopmental impairment in hippocampus of mice offspring gestationally exposed to PM_2.5, to which alleviated mitochondrial damage, increased anti-inflammatory and antioxidant capacity and synaptic efficiency, reduced neuronal apoptosis and improved hippocampal neurogenesis may contribute.

PMID:31546205 | DOI:10.1016/j.ecoenv.2019.109686

Eur Biophys J. 2019 Oct;48(7):593-598. doi: 10.1007/s00249-019-01388-x. Epub 2019 Jul 6.

ABSTRACT

Cell membrane nanotubes, variously referred to as tunneling nanotubes and cytonemes, are currently the focus of much interest. They are of ancient origin, as indicated by their opportunistic use for cell invasion by pathogens, including bacteria and virus, and by their employment in bacterial networking. They play a significant role in cancer invasion and in the explanation of glioblastoma resistance to treatment. Their structure and properties have been investigated with optical tweezers. They have been detected in vivo. Their role in the immune system was early verified. Very recently, it was shown that they share many properties with nerve synapses, including the roles of glutamate and Ca ions. Similar features have also been observed in primitive plants. These results support the conjecture that, besides their roles in immunology, developmental biology and cancer, cell membrane nanotubes are the ancestors of the nervous system.

PMID:31280337 | DOI:10.1007/s00249-019-01388-x

Int J Dev Neurosci. 2019 Jun;75:1-12. doi: 10.1016/j.ijdevneu.2019.03.004. Epub 2019 Apr 1.

ABSTRACT

Enhanced levels of homocysteine during pregnancy induce oxidative stress and contribute to many age-related diseases. In this study, we analyzed age-dependent synaptic modifications in developing neuromuscular synapses of rats with prenatal hyperhomocysteinemia (hHCY). One of the main findings indicate that the intensity and the timing of transmitter release in synapses of neonatal (P6 and P10) hHCY rats acquired features of matured synaptic transmission of adult rats. The amplitude and frequency of miniature end-plate currents (MEPCs) and evoked transmitter release were higher in neonatal hHCY animals compared to the control group. Analysis of the kinetics of neurotransmitter release demonstrated more synchronized release in neonatal rats with hHCY. At the same time lower release probability was observed in adults with hHCY. Spontaneous transmitter release in neonates with hHCY was inhibited by hydrogen peroxide (H₂O₂) whereas in controls this oxidant was effective only in adult animals indicating a higher susceptibility of motor nerve terminals to oxidative stress. The morphology and the intensity of endocytosis of synaptic vesicles in motor nerve endings was assessed using the fluorescence dye FM 1-43. Adult-like synapses were found in neonates with hHCY which were characterized by a larger area of presynaptic terminals compared to controls. No difference in the intensity of FM 1-43 fluorescence was observed between two groups of animals. Prenatal hHCY resulted in reduced muscle strength assessed by the Paw Grip Endurance test. Using biochemical assays we found an increased level of H₂O₂ and lipid peroxidation products in the diaphragm muscles of hHCY rats. This was associated with a lowered activity of superoxide dismutase and glutathione peroxidase. Our data indicate that prenatal hHCY induces oxidative stress and apparent faster functional and morphological "maturation" of motor synapses. Our results uncover synaptic mechanisms of disrupted muscle function observed in hHCY conditions which may contribute to the pathogenesis of motor neuronal diseases associated with enhanced level of homocysteine.

PMID:30946975 | DOI:10.1016/j.ijdevneu.2019.03.004

PLoS One. 2019 Mar 22;14(3):e0213663. doi: 10.1371/journal.pone.0213663. eCollection 2019.

ABSTRACT

Parkinson's Disease (PD) is a neurodegenerative disease for which there currently is no cure. Aggregation of the pre-synaptic protein α-synuclein (aSN) into oligomers (αSOs) is believed to play a key role in PD pathology, but little is known about αSO formation in vivo and how they induce neurodegeneration. Both the naturally occurring polyunsaturated fatty acid docosahexaenoic acid (DHA) and the lipid peroxidation product 4-hydroxynonenal (HNE), strongly upregulated during ROS conditions, stimulate the formation of αSOs, highlighting a potential role in PD. Yet, insight into αSOs structure and biological effects is still limited as most oligomer preparations studied to date are heterogeneous in composition. Here we have aggregated aSN in the presence of HNE and DHA and purified the αSOs using size exclusion chromatography. Both compounds stimulate formation of spherical αSOs containing anti-parallel β-sheet structure which have the same shape as unmodified αSOs though ca. 2-fold larger. Furthermore, the yield and stabilities of these oligomers are significantly higher than for unmodified aSN. Both modified and unmodified αSOs permeabilize synthetic vesicles, show high co-localisation with glutamatergic synapses and decrease Long Term Potentiation (LTP), in line with the reported synaptotoxic effects of αSOs. We conclude that DHA- and HNE-αSOs are convenient models for pathogenic disease-associated αSOs in PD.

PMID:30901378 | PMC:PMC6430514 | DOI:10.1371/journal.pone.0213663

Mol Neurobiol. 2019 Sep;56(9):6293-6309. doi: 10.1007/s12035-019-1512-7. Epub 2019 Feb 12.

ABSTRACT

Hesperetin is a bioactive flavonoid in the body, produced from hesperidin. No comprehensive studies have shown its protective effects in neurodegenerative disorders. Here, we hypothesized that hesperetin may protect the mice brain against Aβ-induced neurodegeneration. Twenty-four hours after intracerebroventricular injection of Aβ1-42, the treated group was injected hesperetin. For in vitro experiments, HT22 and BV-2 cells were used. Immunoblot, immunofluorescence, and behavioral analyses were used to evaluate the different parameters. Our results indicated that hesperetin significantly attenuated oxidative stress, as assessed by the expression of Nrf2/HO-1 and LPO and ROS assays, in the hippocampus, cortex, and in vitro HT22 cells. Similarly, activated glial cells were regulated by hesperetin, as assessed by the expression of GFAP and Iba-1. Moreover, the expression of TLR4, p-NF-κB, and downstream targets was analyzed; the results showed that hesperetin reinstated the expression of these markers. The effects of hesperetin were further confirmed by using specific TLR4 and p-NF-κB inhibitors in BV-2 cells. Next, we evaluated Aβ pathology in the cortex, hippocampus, and HT22 cells, showing that hesperetin significantly reduced the Aβ pathology. Furthermore, the antiapoptotic effects of hesperetin were assessed, which showed strong antiapoptotic effects. Overall, the neuroprotective effect of hesperetin was found to be a multipotent effect, involving the inhibition of oxidative stress, neuroinflammation, apoptotic cell death, and cognitive consolidation. Given antioxidant, anti-inflammatory, and antiapoptotic potentials against Aβ-induced neurodegeneration and memory impairment, hesperetin may be a promising therapeutic agent for Alzheimer's disease-like neurological disorders.

PMID:30756299 | DOI:10.1007/s12035-019-1512-7

J Neuroimmune Pharmacol. 2019 Jun;14(2):278-294. doi: 10.1007/s11481-018-9824-3. Epub 2018 Nov 27.

ABSTRACT

Cognitive decline and memory impairment induced by oxidative brain damage are the critical pathological hallmarks of Alzheimer's disease (AD). Based on the potential neuroprotective effects of melatonin, we here explored the possible underlying mechanisms of the protective effect of melatonin against scopolamine-induced oxidative stress-mediated c-Jun N-terminal kinase (JNK) activation, which ultimately results in synaptic dysfunction, neuroinflammation, and neurodegeneration. According to our findings, scopolamine administration resulted in LPO and ROS generation and decreased the protein levels of antioxidant proteins such as Nrf2 and HO-1; however, melatonin co-treatment mitigated the generation of oxidant factors while improving antioxidant protein levels. Similarly, melatonin ameliorated oxidative stress-mediated JNK activation, enhanced Akt/ERK/CREB signaling, promoted cell survival and proliferation, and promoted memory processes. Immunofluorescence and western blot analysis indicated that melatonin reduced activated gliosis via attenuation of Iba-1 and GFAP. We also found that scopolamine promoted neuronal loss by inducing Bax, Pro-Caspase-3, and Caspase-3 and reducing the levels of the antiapoptotic protein Bcl-2. In contrast, melatonin significantly decreased the levels of apoptotic markers and increased neuronal survival. We further found that scopolamine disrupted synaptic integrity and, conversely, that melatonin enhanced synaptic integrity as indicated by Syntaxin, PSD-95, and SNAP-23 expression levels. Furthermore, melatonin ameliorated scopolamine-induced impairments in spatial learning behavior and memory formation. On the whole, our findings revealed that melatonin attenuated scopolamine-induced synaptic dysfunction and memory impairments by ameliorating oxidative brain damage, stress kinase expression, neuroinflammation, and neurodegeneration. Graphical Abstract The proposed schematic diagram showing the neuroprotective effect of melatonin against scopolamine-induced oxidative stress-mediated synaptic dysfunction, memory impairment neuroinflammation and neurodegeneration.

PMID:30478761 | DOI:10.1007/s11481-018-9824-3

Neuroscience. 2018 Aug 21;386:265-283. doi: 10.1016/j.neuroscience.2018.06.028. Epub 2018 Jun 28.

ABSTRACT

Traumatic brain injury (TBI) results in mitochondrial dysfunction and induction of lipid peroxidation (LP). Lipid peroxidation-derived neurotoxic aldehydes such as 4-HNE and acrolein bind to mitochondrial proteins, inducing additional oxidative damage and further exacerbating mitochondrial dysfunction and LP. Mitochondria are heterogeneous, consisting of both synaptic and non-synaptic populations. Synaptic mitochondria are reported to be more vulnerable to injury; however, this is the first study to characterize the temporal profile of synaptic and non-synaptic mitochondria following TBI, including investigation of respiratory dysfunction and oxidative damage to mitochondrial proteins between 3 and 120 h following injury. These results indicate that synaptic mitochondria are indeed the more vulnerable population, showing both more rapid and severe impairments than non-synaptic mitochondria. By 24 h, synaptic respiration is significantly impaired compared to synaptic sham, whereas non-synaptic respiration does not decline significantly until 48 h. Decreases in respiration are associated with increases in oxidative damage to synaptic and non-synaptic mitochondrial proteins at 48 h and 72 h, respectively. These results indicate that the therapeutic window for mitochondria-targeted pharmacological neuroprotectants to prevent respiratory dysfunction is shorter for the more vulnerable synaptic mitochondria than for the non-synaptic population.

PMID:29960045 | DOI:10.1016/j.neuroscience.2018.06.028

Biochim Biophys Acta Mol Basis Dis. 2018 Sep;1864(9 Pt B):3060-3068. doi: 10.1016/j.bbadis.2018.06.020. Epub 2018 Jun 27.

ABSTRACT

Parkinson's disease (PD) and other synucleinopathies are characterized by accumulation of misfolded aggregates of α-synuclein (α-syn). The normal function of α-syn is still under investigation, but it has been generally linked to synaptic plasticity, neurotransmitter release and the maintenance of the synaptic pool. α-Syn localizes at synaptic terminals where it can bind to synaptic vesicles as well as to other cellular membranes. It has become clear that these interactions have an impact on both α-syn functional role and its propensity to aggregate. In this study, we investigated the aggregation process of α-syn covalently modified with 4-hydroxy-2-nonenal (HNE). HNE is a product of lipid peroxidation and has been implicated in the pathogenesis of different neurodegenerative diseases by modifying the kinetics of soluble toxic oligomers. Although HNE-modified α-syn has been reported to assemble into stable oligomers, we found that slightly acidic conditions promoted further protein aggregation. Lipid vesicles delayed the aggregation process in a concentration-dependent manner, an effect that was observed only when they were added at the beginning of the aggregation process. Co-aggregation of lipid vesicles with HNE-modified α-syn also induced cytotoxic effects on differentiated SHSY-5Y cells. Under conditions in which the aggregation process was delayed cell viability was reduced. By exploring the behavior and potential cytotoxic effects of HNE-α-syn under acidic conditions in relation to protein-lipid interactions our study gives a framework to examine a possible pathway leading from a physiological setting to the pathological outcome of PD.

PMID:29960040 | DOI:10.1016/j.bbadis.2018.06.020

CNS Neurol Disord Drug Targets. 2018;17(9):689-695. doi: 10.2174/1871527317666180627120501.

ABSTRACT

BACKGROUND & OBJECTIVE: Traumatic Brain Injury (TBI) is one of the major causes of mortality and morbidity worldwide. It represents mild, moderate and severe effects of physical assault to brain which may cause sequential, primary or secondary ramifications. Primary injury can be due to the first physical hit, blow or jolt to one of the brain compartments. The primary injury is then followed by secondary injury which leads to biochemical, cellular, and physiological changes like blood brain barrier disruption, inflammation, excitotoxicity, necrosis, apoptosis, mitochondrial dysfunction and generation of oxidative stress. Apart from this, there is also an immediate increase in glutamate at the synapses following severe TBI. Excessive glutamate at synapses in turn activates corresponding NMDA and AMPA receptors that facilitate excessive calcium influx into the neuronal cells. This leads to the generation of oxidative stress which further leads to mitochondrial dysfunction, lipid peroxidation and oxidation of proteins and DNA. As a consequence, neuronal cell death takes place and ultimately people start facing some serious disabilies.

CONCLUSION: In the present review we provide extensive overview of the role of reactive oxygen species (ROS)-induced oxidative stress and its fatal effects on brain after TBI.

PMID:29952272 | DOI:10.2174/1871527317666180627120501

Hum Mol Genet. 2018 Jul 15;27(14):2502-2516. doi: 10.1093/hmg/ddy154.

ABSTRACT

The purpose of our study was to determine the toxic effects of hippocampal mutant APP (mAPP) and amyloid beta (Aβ) in human mAPP complementary DNA (cDNA) transfected with primary mouse hippocampal neurons (HT22). Hippocampal tissues are the best source of studying learning and memory functions in patients with Alzheimer's disease (AD) and healthy controls. However, investigating immortalized hippocampal neurons that express AD proteins provide an excellent opportunity for drug testing. Using quantitative reverse transcriptase-polymerase chain reaction, immunoblotting & immunofluorescence and transmission electron microscopy, we assessed messenger RNA (mRNA) and protein levels of synaptic, autophagy, mitophagy, mitochondrial dynamics, biogenesis, dendritic protein MAP2 and assessed mitochondrial number and length in mAPP-HT22 cells that express Swedish/Indiana mutations. Mitochondrial function was assessed by measuring the levels of hydrogen peroxide, lipid peroxidation, cytochrome c oxidase activity and mitochondrial adenosine triphosphate. Increased levels of mRNA and protein levels of mitochondrial fission genes, Drp1 and Fis1 and decreased levels fusion (Mfn1, Mfn2 and Opa1) biogenesis (PGC1α, NRF1, NRF2 & TFAM), autophagy (ATG5 & LC3BI, LC3BII), mitophagy (PINK1 & TERT, BCL2 & BNIPBL), synaptic (synaptophysin & PSD95) and dendritic (MAP2) genes were found in mAPP-HT22 cells relative to WT-HT22 cells. Cell survival was significantly reduced mAPP-HT22 cells. GTPase-Drp1 enzymatic activity was increased in mAPP-HT22 cells. Transmission electron microscopy revealed significantly increased mitochondrial numbers and reduced mitochondrial length in mAPP-HT22 cells. These findings suggest that hippocampal accumulation of mAPP and Aβ is responsible for abnormal mitochondrial dynamics and defective biogenesis, reduced MAP2, autophagy, mitophagy and synaptic proteins & reduced dendritic spines and mitochondrial structural and functional changes in mAPP hippocampal cells. These observations strongly suggest that accumulation of mAPP and Aβ causes mitochondrial, synaptic and autophagy/mitophagy abnormalities in hippocampal neurons, leading to neuronal dysfunction.

PMID:29701781 | PMC:PMC6031001 | DOI:10.1093/hmg/ddy154

Mol Neurobiol. 2018 Dec;55(12):9220-9233. doi: 10.1007/s12035-018-1059-z. Epub 2018 Apr 14.

ABSTRACT

Amyotrophic lateral sclerosis (ALS) is an adult-onset fatal neurodegenerative disease characterized by muscle wasting, weakness, and spasticity due to a progressive degeneration of cortical, brainstem, and spinal motor neurons. The etiopathological causes are still largely obscure, although astrocytes definitely play a role in neuronal damage. Several mechanisms have been proposed to concur to neurodegeneration in ALS, including mitochondrial dysfunction. We have previously shown profound modifications of glutamate release and presynaptic plasticity in the spinal cord of the SOD1^G93A mouse model of ALS. In this work, we characterized, for the first time, the aerobic metabolism in two specific compartments actively involved in neurotransmission (i.e. the presynaptic district, using purified synaptosomes, and the perisynaptic astrocyte processes, using purified gliosomes) in SOD1^G93A mice at different stages of the disease. ATP/AMP ratio was lower in synaptosomes isolated from the spinal cord, but not from other brain areas, of SOD1^G93A vs. control mice. The energy impairment was linked to altered oxidative phosphorylation (OxPhos) and increment of lipid peroxidation. These metabolic dysfunctions were present during disease progression, starting at the very pre-symptomatic stages, and did not depend on a different number of mitochondria or a different expression of OxPhos proteins. Conversely, gliosomes showed a reduction of the ATP/AMP ratio only at the late stages of the disease and an increment of oxidative stress also in the absence of a significant decrement in OxPhos activity. Data suggest that the presynaptic neuronal moiety plays a pivotal role for synaptic energy metabolism dysfunctions in ALS. Changes in the perisynaptic compartment seem subordinated to neuronal damage.

PMID:29656361 | DOI:10.1007/s12035-018-1059-z

Neurobiol Aging. 2018 Jun;66:165-176. doi: 10.1016/j.neurobiolaging.2018.02.024. Epub 2018 Mar 5.

ABSTRACT

Alzheimer's disease (AD) involves progressive deposition of amyloid β-peptide (Aβ), synapse loss, and neuronal death, which occur in brain regions critical for learning and memory. Considerable evidence suggests that lipid peroxidation contributes to synaptic dysfunction and neuronal degeneration, both upstream and downstream of Aβ pathology. Recent findings suggest that lipid peroxidation can be inhibited by replacement of polyunsaturated fatty acids (PUFA) with isotope-reinforced (deuterated) PUFA (D-PUFA), and that D-PUFA can protect neurons in experimental models of Parkinson's disease. Here, we determined whether dietary D-PUFA would ameliorate Aβ pathology and/or cognitive deficits in a mouse model of AD (amyloid precursor protein/presenilin 1 double mutant transgenic mice). The D-PUFA diet did not ameliorate spatial learning and memory deficits in the AD mice. Compared to mice fed an hydrogenated-PUFA control diet, those fed D-PUFA for 5 months exhibited high levels of incorporation of deuterium into arachidonic acid and docosahexaenoic acid, and reduced concentrations of lipid peroxidation products (F2 isoprostanes and neuroprostanes), in the brain tissues. Concentrations of Aβ40 and Aβ38 in the hippocampus were significantly lower, with a trend to reduced concentrations of Aβ42, in mice fed D-PUFA compared to those fed hydrogenated-PUFA. We conclude that a D-PUFA diet reduces the brain tissue concentrations of both arachidonic acid and docosahexaenoic acid oxidation products, as well as the concentration of Aβs.

PMID:29579687 | PMC:PMC5924637 | DOI:10.1016/j.neurobiolaging.2018.02.024

Arch Physiol Biochem. 2018 Dec;124(5):442-447. doi: 10.1080/13813455.2017.1420666. Epub 2017 Dec 25.

ABSTRACT

In this study we aimed to investigate whether reduced BDNF levels aggravate the susceptibility of the brain to hazardous effects of high fat diet. For this purpose, we fed BDNF heterozygous mice and wild type littermates with normal and high fat diet for 16 weeks. Concentrations of two synaptic proteins (SNAP-25 and PSD-95) and oxidative stress parameters (MDA, SOD, CAT) were evaluated in the cortex after diet period. Interestingly, body weights of BDNF heterozygous groups fed with control diet were higher than their littermates and heterozygous mice fed with HFD were the heaviest in all experimental groups. MDA levels were significantly elevated in both HFD groups (wild type and BDNF(+/-)). Synaptic markers PSD-95 and SNAP-25 markedly decreased in BDNF(+/-) group fed with HFD compared to other groups. In conclusion, we suggest that endogenous BDNF has an important and possibly protective role in diet-induced changes in the cortex.

PMID:29277119 | DOI:10.1080/13813455.2017.1420666

Int J Mol Sci. 2017 Nov 23;18(12):2504. doi: 10.3390/ijms18122504.

ABSTRACT

Alzheimer's disease (AD) is a neurodegenerative disorder representing the major cause of dementia. It is characterized by memory loss, and cognitive and behavioral decline. In particular, the hallmarks of the pathology are amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs), formed by aggregated hyperphosphorylated tau protein. Oxidative stress plays a main role in AD, and it is involved in initiation and progression of AD. It is well known that Aβ induced oxidative stress, promoting reactive oxygen species (ROS) production and consequently lipid peroxidation, protein oxidation, tau hyperphosphorylation, results in toxic effects on synapses and neurons. In turn, oxidative stress can increase Aβ production. For these reasons, the administration of an antioxidant therapy in AD patients was suggested. The term vitamin E includes different fat-soluble compounds, divided into tocopherols and tocotrienols, that possess antioxidant action. α-Tocopherol is the most studied, but some studies suggested that tocotrienols may have different health promoting capacities. In this review, we focused our attention on the effects of vitamin E supplementation in AD animal models and AD patients or older population. Experimental models showed that vitamin E supplementation, by decreasing oxidative stress, may be a good strategy to improve cognitive and memory deficits. Furthermore, the combination of vitamin E with other antioxidant or anti-inflammatory compounds may increase its efficacy. However, even if some trials have evidenced some benefits, the effects of vitamin E in AD patients are still under debate.

PMID:29168797 | PMC:PMC5751107 | DOI:10.3390/ijms18122504

Exp Gerontol. 2018 Jan;101:80-94. doi: 10.1016/j.exger.2017.11.003. Epub 2017 Nov 13.

ABSTRACT

Synapses loss during aging has been related to decreased neuronal excitability and reduced electrophysiological activity in the nervous system, as well as to increased brain damage. Those physiological and biochemical alterations have been related to the oxidative stress increase associated with old age. The main substrate of lipid peroxidation (LPX) in the central and peripheral nervous systems are the myelin sheaths, and their damage generates a delayed nerve conduction velocity. However, studies in which the neural conduction velocity is related to changes in the redox state are still lacking. Therefore, our aim was to correlate the sensory neural pathways delay in healthy geriatric Rhesus monkeys (Macaca mulatta) with the oxidative stress associated with physiological aging. Twenty-four monkeys were divided into four groups according to age and gender. Auditory, visual, and somatosensory evoked potentials were obtained. Superoxide dismutase, catalase, and glutathione peroxidase enzymatic activity, as well as LPX, were determined from blood samples. Our results showed significant differences between the older and younger age groups in all neural generators of the different sensory pathways evaluated, along with an increase in LPX and the antioxidant enzymatic activities. It suggests that, even though the enzymatic activity was found to be higher in older monkeys, probably as a compensatory effect, it was not enough to avoid LPX damage and the declined electric activity associated with age.

PMID:29146475 | DOI:10.1016/j.exger.2017.11.003

Cell Rep. 2017 Nov 14;21(7):1757-1769. doi: 10.1016/j.celrep.2017.10.066.

ABSTRACT

The lateral habenula (LHb) is a brain structure that participates in cognitive and emotional processing and has been implicated in several mental disorders. Although one of the largest inputs to the LHb originates in the lateral preoptic area (LPO), little is known about how the LPO participates in the regulation of LHb function. Here, we provide evidence that the LPO exerts bivalent control over the LHb through the convergent transmission of LPO glutamate and γ-aminobutyric acid (GABA) onto single LHb neurons. In vivo, both LPO-glutamatergic and LPO-GABAergic inputs to the LHb are activated by aversive stimuli, and their predictive cues yet produce opposing behaviors when stimulated independently. These results support a model wherein the balanced response of converging LPO-glutamate and LPO-GABA are necessary for a normal response to noxious stimuli, and an imbalance in LPO→LHb glutamate or GABA results in the type of aberrant processing that may underlie mental disorders.

PMID:29141211 | PMC:PMC5699228 | DOI:10.1016/j.celrep.2017.10.066

Mol Neurobiol. 2018 Jul;55(7):5868-5878. doi: 10.1007/s12035-017-0804-z. Epub 2017 Nov 3.

ABSTRACT

S-Adenosylmethionine (AdoMet) concentrations are highly elevated in tissues and biological fluids of patients affected by S-adenosylhomocysteine hydrolase deficiency, who are clinically characterized by cerebral symptoms whose pathogenesis is still unknown. In the present work, we investigated the effects of AdoMet on redox homeostasis and on the activity of Na⁺, K⁺-ATPase in the cerebral cortex of young rats. AdoMet caused lipid peroxidation (increase of malondialdehyde concentrations) and protein oxidation (increase of carbonyl formation and decrease of sulfhydryl content). AdoMet also reduced the antioxidant defenses (reduced glutathione, GSH) and Na⁺, K⁺-ATPase activity. Furthermore, AdoMet-induced lipid peroxidation was fully prevented by the antioxidants trolox, melatonin, and resveratrol, and the decrease of GSH concentrations was abolished by trolox, suggesting the involvement of reactive oxygen species in these effects. In this context, AdoMet induced reactive oxygen (increase of 2',7'-dichloroflurescein-DCFH oxidation) but not nitrogen (nitrate and nitrite levels) species generation. Finally, the decrease of Na⁺, K⁺-ATPase activity provoked by AdoMet was totally prevented by trolox, implying a possible oxidation of cysteine groups of the enzyme that are critical for its function and highly susceptible to oxidative attack. It is also noted that adenosine and methionine did not alter the parameters evaluated, suggesting selective effects of AdoMet. Our data strongly indicate that disturbance of redox homeostasis caused by a major metabolite (AdoMet) accumulating in S-adenosylhomocysteine hydrolase deficiency may represent a deleterious mechanism of brain damage in this disease. Finally, reduction of Na⁺, K⁺-ATPase activity provoked by AdoMet may lead to impaired neurotransmission, but disturbance of this system should be better clarified in future studies.

PMID:29101646 | DOI:10.1007/s12035-017-0804-z

Hum Mol Genet. 2018 Jan 1;27(1):30-40. doi: 10.1093/hmg/ddx381.

ABSTRACT

The purpose of our study was to understand the toxic effects of hippocampal phosphorylated tau in tau mice. Using rotarod and Morris water maze (MWM) tests, immunoblotting and immunofluorescence, Golgi-Cox staining and transmission electron microscopy, we assessed cognitive behavior, measured protein levels of mitochondrial dynamics, MAP2, total and phosphorylated tau, and quantified dendritic spines and mitochondrial number and length in 12-month-old tau mice with P301L mutation. Mitochondrial function was assessed by measuring the levels of H2O2, lipid peroxidation, cytochrome oxidase activity and mitochondrial ATP. MWM and rotarod tests revealed that hippocampal learning and memory and motor learning and coordination were impaired in tau mice relative to wild-type (WT) mice. Increased levels of mitochondrial fission proteins, Drp1 and Fis1 and decreased levels of mitochondrial fusion proteins, Mfn1, Mfn2 and Opa1 were found in 12-month-old tau mice relative to age-matched WT mice, indicating that the presence of abnormal mitochondrial dynamics in tau mice. Decreased levels of dendritic protein, MAP2 and increased levels of total and phosphorylated tau proteins were found in tau mice relative to WT mice. Mitochondrial function was defective. Golgi-Cox staining analysis revealed that dendritic spines are significantly reduced. Transmission electron microscopy revealed significantly increased mitochondrial numbers and reduced mitochondrial length in tau mice. These findings suggest that hippocampal accumulation of phosphorylated tau is responsible for abnormal mitochondrial dynamics and reducing dendritic protein MAP2 and dendritic spines and hippocampal based learning and memory impairments, and mitochondrial structural and functional changes in tau mice. Based on these observations, we propose that reduced hippocampal phosphorylated tau is an important therapeutic strategy for AD and other tauopathies.

PMID:29040533 | PMC:PMC5886218 | DOI:10.1093/hmg/ddx381

Synapse. 2017 Oct;71(10):e21990. doi: 10.1002/syn.21990. Epub 2017 Aug 2.

ABSTRACT

Alzheimer's disease (AD) is the most common cause of dementia and one of the most important causes of morbidity and mortality among the aging population. AD diagnosis is made post-mortem, and the two pathologic hallmarks, particularly evident in the end stages of the illness, are amyloid plaques and neurofibrillary tangles. Currently, there is no curative treatment for AD. Additionally, there is a strong relation between oxidative stress, metabolic syndrome, and AD. The high levels of circulating lipids and glucose imbalances amplify lipid peroxidation that gradually diminishes the antioxidant systems, causing high levels of oxidative metabolism that affects cell structure, leading to neuronal damage. Accumulating evidence suggests that AD is closely related to a dysfunction of both insulin signaling and glucose metabolism in the brain, leading to an insulin-resistant brain state. Four drugs are currently used for this pathology: Three FDA-approved cholinesterase inhibitors and one NMDA receptor antagonist. However, wide varieties of antioxidants are promissory to delay or prevent the symptoms of AD and may help in treating the disease. Therefore, therapeutic efforts to achieve attenuation of oxidative stress could be beneficial in AD treatment, attenuating Aβ-induced neurotoxicity and improve neurological outcomes in AD. The term inflammaging characterizes a widely accepted paradigm that aging is accompanied by a low-grade chronic up-regulation of certain pro-inflammatory responses in the absence of overt infection, and is a highly significant risk factor for both morbidity and mortality in the elderly.

PMID:28650104 | DOI:10.1002/syn.21990

J Neurosci. 2017 May 24;37(21):5263-5273. doi: 10.1523/JNEUROSCI.3981-16.2017.

ABSTRACT

We previously found that Mertk and its ligand Gas6, astrocytic genes involved in phagocytosis, are upregulated after acute sleep deprivation. These results suggested that astrocytes may engage in phagocytic activity during extended wake, but direct evidence was lacking. Studies in humans and rodents also found that sleep loss increases peripheral markers of inflammation, but whether these changes are associated with neuroinflammation and/or activation of microglia, the brain's resident innate immune cells, was unknown. Here we used serial block-face scanning electron microscopy to obtain 3D volume measurements of synapses and surrounding astrocytic processes in mouse frontal cortex after 6-8 h of sleep, spontaneous wake, or sleep deprivation (SD) and after chronic (∼5 d) sleep restriction (CSR). Astrocytic phagocytosis, mainly of presynaptic components of large synapses, increased after both acute and chronic sleep loss relative to sleep and wake. MERTK expression and lipid peroxidation in synaptoneurosomes also increased to a similar extent after short and long sleep loss, suggesting that astrocytic phagocytosis may represent the brain's response to the increase in synaptic activity associated with prolonged wake, clearing worn components of heavily used synapses. Using confocal microscopy, we then found that CSR but not SD mice show morphological signs of microglial activation and enhanced microglial phagocytosis of synaptic elements, without obvious signs of neuroinflammation in the CSF. Because low-level sustained microglia activation can lead to abnormal responses to a secondary insult, these results suggest that chronic sleep loss, through microglia priming, may predispose the brain to further damage.SIGNIFICANCE STATEMENT We find that astrocytic phagocytosis of synaptic elements, mostly of presynaptic origin and in large synapses, is upregulated already after a few hours of sleep deprivation and shows a further significant increase after prolonged and severe sleep loss, suggesting that it may promote the housekeeping of heavily used and strong synapses in response to the increased neuronal activity of extended wake. By contrast, chronic sleep restriction but not acute sleep loss activates microglia, promotes their phagocytic activity, and does so in the absence of overt signs of neuroinflammation, suggesting that like many other stressors, extended sleep disruption may lead to a state of sustained microglia activation, perhaps increasing the brain's susceptibility to other forms of damage.

PMID:28539349 | PMC:PMC5456108 | DOI:10.1523/JNEUROSCI.3981-16.2017

Neurotox Res. 2017 Aug;32(2):276-290. doi: 10.1007/s12640-017-9735-8. Epub 2017 Apr 20.

ABSTRACT

Tissue accumulation of α-ketoadipic (KAA) and α-aminoadipic (AAA) acids is the biochemical hallmark of α-ketoadipic aciduria. This inborn error of metabolism is currently considered a biochemical phenotype with uncertain clinical significance. Considering that KAA and AAA are structurally similar to α-ketoglutarate and glutamate, respectively, we investigated the in vitro effects of these compounds on glutamatergic neurotransmission in the brain of adolescent rats. Bioenergetics and redox homeostasis were also investigated because they represent fundamental systems for brain development and functioning. We first observed that AAA significantly decreased glutamate uptake, whereas glutamate dehydrogenase activity was markedly inhibited by KAA in a competitive fashion. In addition, AAA and more markedly KAA induced generation of reactive oxygen and nitrogen species (increase of 2',7'-dichloroflurescein (DCFH) oxidation and nitrite/nitrate levels), lipid peroxidation (increase of malondialdehyde concentrations), and protein oxidation (increase of carbonyl formation and decrease of sulfhydryl content), besides decreasing the antioxidant defenses (reduced glutathione (GSH)) and aconitase activity. Furthermore, KAA-induced lipid peroxidation and GSH decrease were prevented by the antioxidants α-tocopherol, melatonin, and resveratrol, suggesting the involvement of reactive species in these effects. Noteworthy, the classical inhibitor of NMDA glutamate receptors MK-801 was not able to prevent KAA-induced and AAA-induced oxidative stress, determined by DCFH oxidation and GSH levels, making unlikely a secondary induction of oxidative stress through overstimulation of glutamate receptors. In contrast, KAA and AAA did not significantly change brain bioenergetic parameters. We speculate that disturbance of glutamatergic neurotransmission and redox homeostasis by KAA and AAA may play a role in those cases of α-ketoadipic aciduria that display neurological symptoms.

PMID:28429309 | DOI:10.1007/s12640-017-9735-8

Oncotarget. 2016 Nov 1;7(44):71817-71832. doi: 10.18632/oncotarget.12376.

ABSTRACT

Accruing data indicate that radiation-induced consequences resemble pathologies of neurodegenerative diseases such as Alzheimer´s. The aim of this study was to elucidate the effect on hippocampus of chronic low-dose-rate radiation exposure (1 mGy/day or 20 mGy/day) given over 300 days with cumulative doses of 0.3 Gy and 6.0 Gy, respectively. ApoE deficient mutant C57Bl/6 mouse was used as an Alzheimer´s model. Using mass spectrometry, a marked alteration in the phosphoproteome was found at both dose rates. The radiation-induced changes in the phosphoproteome were associated with the control of synaptic plasticity, calcium-dependent signalling and brain metabolism. An inhibition of CREB signalling was found at both dose rates whereas Rac1-Cofilin signalling was found activated only at the lower dose rate. Similarly, the reduction in the number of activated microglia in the molecular layer of hippocampus that paralleled with reduced levels of TNFα expression and lipid peroxidation was significant only at the lower dose rate. Adult neurogenesis, investigated by Ki67, GFAP and NeuN staining, and cell death (activated caspase-3) were not influenced at any dose or dose rate. This study shows that several molecular targets induced by chronic low-dose-rate radiation overlap with those of Alzheimer´s pathology. It may suggest that ionising radiation functions as a contributing risk factor to this neurodegenerative disease.

PMID:27708245 | PMC:PMC5342125 | DOI:10.18632/oncotarget.12376

Mol Neurobiol. 2017 Oct;54(8):5815-5828. doi: 10.1007/s12035-016-0129-3. Epub 2016 Sep 22.

ABSTRACT

Autophagy is a catabolic process involved in the continuous removal of toxic protein aggregates and cellular organelles to maintain the homeostasis and functional integrity of cells. The mechanistic understanding of autophagy mediated neuroprotection during the development of neurodegenerative disorders remains elusive. Here, we investigated the potential role of rapamycin-induced activation of autophagy and PI3K/Akt1/mTOR/CREB pathway(s) in the neuroprotection of amyloid-beta (Aβ1-42)-insulted hippocampal neurons in rat model of Alzheimer's disease (AD) like phenotypes. A single intra-hippocampal injection of Aβ1-42 impaired redox balance and markedly induced synaptic dysfunction, neurotransmission dysfunction, and cognitive deficit, and suppressed pro-survival signaling in the adult rats. Rapamycin administration caused a significant reduction of mTOR complex 1 phosphorylation at Ser2481 and a significant increase in levels of autophagy markers such as microtubule-associated protein-1 light chain-3 (LC3), beclin-1, sequestosome-1/p62, unc-51-like kinase 1 (ULK1). In addition, rapamycin induced the activation of autophagy that further activated p-PI3K, p-Akt1 (Ser473), and p-CREB (Ser183) expression in Aβ1-42-treated rats. The activated autophagy markedly reversed Aβ1-42-induced impaired redox homeostasis by decreasing the levels of prooxidants-ROS generation, intracellular Ca²⁺ flux and LPO, and increasing the levels of antioxidants-SOD, catalase, and GSH. The activated autophagy also provided significant neuroprotection against Aβ1-42-induced synaptic dysfunction by increasing the expression of synapsin-I, synaptophysin, and PSD95; and neurotransmission dysfunction by increasing the levels of CHRM2, DAD2 receptor, NMDA receptor, and AMPA receptor; and ultimately improved cognitive ability in rats. Wortmannin administration significantly reduced the expression of autophagy markers, p-PI3K, p-Akt1, and p-CREB, as well as the autophagy mediated neuroprotective effect. Our study demonstrate that autophagy can be an integrated part of pro-survival (PI3K/Akt1/mTOR/CREB) signaling and autophagic activation restores the oxidative defense mechanism(s), neurodegenerative damages, and maintains the integrity of synapse and neurotransmission in rat model of AD.

PMID:27660271 | DOI:10.1007/s12035-016-0129-3

J Investig Med. 2016 Dec;64(8):1220-1234. doi: 10.1136/jim-2016-000240. Epub 2016 Aug 12.

ABSTRACT

The purpose of our study was to investigate the protective effects of a natural product-'curcumin'- in Alzheimer's disease (AD)-like neurons. Although much research has been done in AD, very little has been reported on the effects of curcumin on mitochondrial biogenesis, dynamics, function and synaptic activities. Therefore, the present study investigated the protective effects against amyloid β (Aβ) induced mitochondrial and synaptic toxicities. Using human neuroblastoma (SHSY5Y) cells, curcumin and Aβ, we studied the protective effects of curcumin against Aβ. Further, we also studied preventive (curcumin+Aβ) and intervention (Aβ+curcumin) effects of curcumin against Aβ in SHSY5Y cells. Using real time RT-PCR, immunoblotting and immunofluorescence analysis, we measured mRNA and protein levels of mitochondrial dynamics, mitochondrial biogenesis and synaptic genes. We also assessed mitochondrial function by measuring hydrogen peroxide, lipid peroxidation, cytochrome oxidase activity and mitochondrial ATP. Cell viability was studied using the MTT assay. Aβ was found to impair mitochondrial dynamics, reduce mitochondrial biogenesis and decrease synaptic activity and mitochondrial function. In contrast, curcumin enhanced mitochondrial fusion activity and reduced fission machinery, and increased biogenesis and synaptic proteins. Mitochondrial function and cell viability were elevated in curcumin treated cells. Interestingly, curcumin pre- and post-treated cells incubated with Aβ showed reduced mitochondrial dysfunction, and maintained cell viability and mitochondrial dynamics, mitochondrial biogenesis and synaptic activity. Further, the protective effects of curcumin were stronger in pretreated SHSY5Y cells than in post-treated cells, indicating that curcumin works better in prevention than treatment in AD-like neurons. Our findings suggest that curcumin is a promising drug molecule to treat AD patients.

PMID:27521081 | PMC:PMC5256118 | DOI:10.1136/jim-2016-000240

Neurobiol Aging. 2016 Jun;42:1-12. doi: 10.1016/j.neurobiolaging.2016.02.030. Epub 2016 Mar 8.

ABSTRACT

Neuritic amyloid plaques and neurofibrillary tangles are hallmarks of Alzheimer's disease (AD) and are major components used for the clinical diagnosis of this disorder. However, many individuals with no cognitive impairment (NCI) also present at autopsy with high levels of these AD pathologic hallmarks. In this study, we evaluated 15 autopsy cases from NCI individuals with high levels of AD-like pathology (high pathology no cognitive impairment) and compared them to age- and postmortem-matched cohorts of individuals with amnestic mild cognitive impairment and NCI cases with low AD-like pathology (low pathology no cognitive impairment [LPNCI]). Individuals classified as high pathology no cognitive impairment or amnestic mild cognitive impairment had a significant loss of both presynaptic and postsynaptic proteins in the hippocampus compared with those in the LPNCI cohort. In addition, these 2 groups had a significant increase in 3 different markers of oxidative stress compared with that in the LPNCI group. The changes in levels of synaptic proteins are strongly associated with levels of oxidative stress. These data suggest that cognitively older subjects without dementia but with increased levels of AD-like pathology may represent a very early preclinical stage of AD.

PMID:27143416 | PMC:PMC4857887 | DOI:10.1016/j.neurobiolaging.2016.02.030

Epilepsy Res. 2016 Feb;120:13-8. doi: 10.1016/j.eplepsyres.2015.11.021. Epub 2015 Dec 3.

ABSTRACT

Because the ketogenic diet (KD) was affecting expression of energy metabolism- related genes in hippocampus and because lipid membrane peroxidation and its associated autophagy stress were also found to be involved in energy depletion, we hypothesized that KD might exert its neuroprotective action via lipid membrane peroxidation and autophagic signaling. Here, we tested this hypothesis by examining the long-term expression of lipid membrane peroxidation-related cPLA2 and clusterin, its downstream autophagy marker Beclin-1, LC3 and p62, as well as its execution molecule Cathepsin-E following neonatal seizures and chronic KD treatment. On postnatal day 9 (P9), 48 Sprague-Dawley rats were randomly assigned to two groups: flurothyl-induced recurrent seizures group and control group. On P28, they were further randomly divided into the seizure group without ketogenic diet (RS+ND), seizure plus ketogenic diet (RS+KD), the control group without ketogenic diet (NS+ND), and the control plus ketogenic diet (NS+KD). Morris water maze test was performed during P37-P43. Then mossy fiber sprouting and the protein levels were detected by Timm staining and Western blot analysis, respectively. Flurothyl-induced RS+ND rats show a long-term lower amount of cPLA2 and LC3II/I, and higher amount of clusterin, Beclin-1, p62 and Cathepsin-E which are in parallel with hippocampal mossy fiber sprouting and cognitive deficits. Furthermore, chronic KD treatment (RS+KD) is effective in restoring these molecular, neuropathological and cognitive changes. The results imply that a lipid membrane peroxidation and autophagy-associated pathway is involved in the aberrant hippocampal mossy fiber sprouting and cognitive deficits following neonatal seizures, which might be a potential target of KD for the treatment of neonatal seizure-induced brain damage.

PMID:26709877 | DOI:10.1016/j.eplepsyres.2015.11.021

Mol Neurobiol. 2016 Dec;53(10):7200-7212. doi: 10.1007/s12035-015-9627-y. Epub 2015 Dec 19.

ABSTRACT

Inadequate oxygen availability-for instance at high altitudes-leads to hippocampal neurodegeneration and memory impairment. Although oxidative stress is one factor, the mechanism underlying the effects of hypobaric hypoxia (HH) are unclear, and effective strategies for preventing the resultant damage to the brain are limited. In the present study, we demonstrate that ingesting dihydromyricetin (DM) protects against memory impairment in adult rats subjected to HH for 7 days, equivalent to an altitude of 5000 m above sea level. Moreover, DM treatment stimulated mitochondrial biogenesis and improved mitochondrial morphology and function, suppressed the generation of reactive oxygen species, and reduced lipid peroxidation in the hippocampus. In HT-22 cells exposed to hypoxic conditions, the neuroprotective effects of DM were shown to be exerted via attenuation of oxidative stress through sirtuin 3-induced forkhead box O3 deacetylation.

PMID:26687185 | DOI:10.1007/s12035-015-9627-y

Exp Neurol. 2016 Jan;275 Pt 1(0 1):126-32. doi: 10.1016/j.expneurol.2015.10.002. Epub 2015 Oct 22.

ABSTRACT

A high calorie diet (HCD) can impair hippocampal synaptic plasticity and cognitive function in animal models. Mitochondrial thioredoxin 2 (TRX-2) is critical for maintaining intracellular redox status, but whether it can protect against HCD-induced impairment of synaptic plasticity is unknown. We found that levels of TRX-2 are reduced in the hippocampus of wild type mice maintained for 8 months on a HCD, and that the mice on the HCD exhibit impaired hippocampal synaptic plasticity (long-term potentiation at CA1 synapses) and cognitive function (novel object recognition). Transgenic mice overexpressing human TRX-2 (hTRX-2) exhibit increased resistance to diquat-induced oxidative stress in peripheral tissues. However, neither the HCD nor hTRX-2 overexpression affected levels of lipid peroxidation products (F2 isoprostanes) in the hippocampus, and hTRX-2 transgenic mice were not protected against the adverse effects of the HCD on hippocampal synaptic plasticity and cognitive function. Our findings indicate that TRX-2 overexpression does not mitigate adverse effects of a HCD on synaptic plasticity, and also suggest that oxidative stress may not be a pivotal factor in the impairment of synaptic plasticity and cognitive function caused by HCDs.

PMID:26476179 | PMC:PMC4688172 | DOI:10.1016/j.expneurol.2015.10.002

J Enzyme Inhib Med Chem. 2016 Dec;31(6):1095-101. doi: 10.3109/14756366.2015.1094470. Epub 2015 Oct 9.

ABSTRACT

Caffeic acid phenethyl ester (CAPE) is an active component of honeybee propolis extracts. Carbonic anhydrases (CAs, EC 4.2.1.1) are widespread and intensively studied metalloenzymes present in higher vertebrates including humans as many diverse isoforms. Acetylcholinesterase (AChE) is responsible for acetyl choline (ACh) hydrolysis and plays a fundamental role in nerve impulse transmission by terminating the action of the ACh neurotransmitter at cholinergic synapses and neuromuscular junctions. Butyrylcholinesterase (BChE) is another enzyme abundantly present in the liver and released into blood in a soluble form. Lactoperoxidase (LPO) is an enzyme involved in fighting pathogenic microorganisms whereas glutathione S-transferases (GSTs) are dimeric proteins present both in prokaryotic and eukaryotic organisms and involved in cellular detoxification mechanisms. In the present study, the inhibition effect of CAPE on human carbonic anhydrase (hCA) isoforms I, II, IX, and XII, AChE, BChE, LPO, and GST was evaluated. CAPE inhibited these enzymes with Kis in the range between micromolar to picomolar. The best inhibitory effect was observed against AChE and BChE.

PMID:26453427 | DOI:10.3109/14756366.2015.1094470

Eur Neuropsychopharmacol. 2015 Nov;25(11):2170-82. doi: 10.1016/j.euroneuro.2015.03.018. Epub 2015 Apr 10.

ABSTRACT

Dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs) and cdc2-like kinases (CLKs) are implicated in the onset and progression of Down syndrome (DS) and Alzheimer's disease (AD). DYRK1A has emerged as a possible link between amyloid-β (Aβ) and Tau, the major pathological proteins in AD. We here assessed the neuroprotective potential of a novel inhibitor of DYRKs/CLKs. The Leucettine L41, acting preferentially on DYRK1A, was tested in Aβ25-35-treated mice, a nontransgenic model of AD-like toxicity. We co-injected intracerebroventricularly oligomeric Aβ25-35 peptide and L41 in Swiss male mice. After 7 days, they were submitted to behavioral tests addressing spatial and non-spatial, short- and long-term memories. The oxidative stress, apoptotic markers, kinases involved in Tau phosphorylation, and synaptic integrity were analyzed by Western blot and ELISA in the hippocampus. L41, tested at 0.4, 1.2, 4 µg, prevented the Aβ25-35-induced memory deficits in the Y-maze, passive avoidance and water-maze tests, with the most active dose being 4 µg. The inhibitor prevented the Aβ25-35-induced oxidative stress, as revealed by measures of lipid peroxidation levels and reactive oxygen species accumulation, and abolished Aβ25-35-induced expression of pro-apoptotic markers. L41 prevented the Aβ25-35-induced decrease of AKT activation and increase of glycogen synthase kinase-3β (GSK-3β) activation, resulting in a decrease of Tau phosphorylation. Finally, L41 restored Aβ25-35-reduced levels of synaptic markers. The novel DYRK1A-preferential inhibitor L41 therefore prevented Aβ25-35-induced memory impairments and neurotoxicity in the mouse hippocampus. These in vivo data highlighted particularly DYRK1A as a major kinase involved in Aβ pathology and suggested therapeutic developments for DYRK1A inhibitors in AD.

PMID:26381812 | DOI:10.1016/j.euroneuro.2015.03.018

Synapse. 2015 Sep;69(9):421-33. doi: 10.1002/syn.21832. Epub 2015 Jun 30.

ABSTRACT

A high calorie intake can induce the appearance of the metabolic syndrome (MS), which is a serious public health problem because it affects glucose levels and triglycerides in the blood. Recently, it has been suggested that MS can cause complications in the brain, since chronic hyperglycemia and insulin resistance are risk factors for triggering neuronal death by inducing a state of oxidative stress and inflammatory response that affect cognitive processes. This process, however, is not clear. In this study, we evaluated the effect of the consumption of a high-calorie diet (HCD) on both neurodegeneration and spatial memory impairment in rats. Our results demonstrated that HCD (90 day consumption) induces an alteration of the main energy metabolism markers, indicating the development of MS in rats. Moreover, an impairment of spatial memory was observed. Subsequently, the brains of these animals showed activation of an inflammatory response (increase in reactive astrocytes and interleukin1-β as well as tumor necrosis factor-α) and oxidative stress (reactive oxygen species and lipid peroxidation), causing a reduction in the number of neurons in the temporal cortex and hippocampus. Altogether, these results suggest that a HCD promotes the development of MS and contributes to the development of a neurodegenerative process and cognitive failure. In this regard, it is important to understand the relationship between MS and neuronal damage in order to prevent the onset of neurodegenerative disorders.

PMID:26073877 | DOI:10.1002/syn.21832

Mol Brain. 2015 Apr 25;8:27. doi: 10.1186/s13041-015-0117-y.

ABSTRACT

BACKGROUND: The study of late-onset/age-related Alzheimer's disease (AD)(sporadic AD, 95% of AD cases) has been hampered by a paucity of animal models. Oxidative stress is considered a causative factor in late onset/age-related AD, and aldehyde dehydrogenase 2 (ALDH2) is important for the catabolism of toxic aldehydes associated with oxidative stress. One such toxic aldehyde, the lipid peroxidation product 4-hydroxynonenal (HNE), accumulates in AD brain and is associated with AD pathology. Given this linkage, we hypothesized that in mice lacking ALDH2, there would be increases in HNE and the appearance of AD-like pathological changes.

RESULTS: Changes in relevant AD markers in Aldh2 (-/-) mice and their wildtype littermates were assessed over a 1 year period. Marked increases in HNE adducts arise in hippocampi from Aldh2 (-/-) mice, as well as age-related increases in amyloid-beta, p-tau, and activated caspases. Also observed were age-related decreases in pGSK3β, PSD95, synaptophysin, CREB and pCREB. Age-related memory deficits in the novel object recognition and Y maze tasks begin at 3.5-4 months and are maximal at 6.5-7 months. There was decreased performance in the Morris Water Maze task in 6 month old Aldh2 (-/-) mice. These mice exhibited endothelial dysfunction, increased amyloid-beta in cerebral microvessels, decreases in carbachol-induced pCREB and pERK formation in hippocampal slices, and brain atrophy. These AD-associated pathological changes are rarely observed as a constellation in current AD animal models.

CONCLUSIONS: We believe that this new model of age-related cognitive impairment will provide new insight into the pathogenesis and molecular/cellular mechanisms driving neurodegenerative diseases of aging such as AD, and will prove useful for assessing the efficacy of therapeutic agents for improving memory and for slowing, preventing, or reversing AD progression.

PMID:25910195 | PMC:PMC4409701 | DOI:10.1186/s13041-015-0117-y

Cell Mol Neurobiol. 2015 Aug;35(6):797-806. doi: 10.1007/s10571-015-0173-y. Epub 2015 Mar 13.

ABSTRACT

Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is an inborn error of metabolism caused by a defect in the transport of ornithine (Orn) into mitochondrial matrix leading to accumulation of Orn, homocitrulline (Hcit), and ammonia. Affected patients present a variable clinical symptomatology, frequently associated with cerebellar symptoms whose pathogenesis is poorly known. Although in vitro studies reported induction of oxidative stress by the metabolites accumulating in HHH syndrome, so far no report evaluated the in vivo effects of these compounds on redox homeostasis in cerebellum. Therefore, the present work was carried out to investigate the in vivo effects of intracerebellar administration of Orn and Hcit on antioxidant defenses (reduced glutathione concentrations and the activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glucose-6-phosphate dehydrogenase), lipid oxidation (malondialdehyde concentrations), as well as on the activity of synaptic Na(+), K(+)-ATPase, an enzyme highly vulnerable to free radical attack, in the cerebellum of adolescent rats. Orn significantly increased malondialdehyde levels and the activities of all antioxidant enzymes, and reduced Na(+), K(+)-ATPase activity. In contrast, glutathione concentrations were not changed by Orn treatment. Furthermore, intracerebellar administration of Hcit was not able to alter any of these parameters. The present data show for the first time that Orn provokes in vivo lipid oxidative damage, activation of the enzymatic antioxidant defense system, and reduction of the activity of a crucial enzyme involved in neurotransmission. It is presumed that these pathomechanisms may contribute at least partly to explain the neuropathology of cerebellum abnormalities and the ataxia observed in patients with HHH syndrome.

PMID:25772141 | DOI:10.1007/s10571-015-0173-y

Redox Biol. 2015;4:308-20. doi: 10.1016/j.redox.2015.01.013. Epub 2015 Jan 20.

ABSTRACT

Oxidative stress plays a major part in the pathogenesis of drug-induced liver injury. Yet, overcoming it with other xenobiotics impose additional risks. In this study, we consider the use of natural-occurring and purified Vitamin E analogs as hepatoprotective agents. Vitamin E is well-known for its intrinsic antioxidant property even though the differential effect of specific analogs of tocopherol (TP) and tocotrienol (T3) is still not ascertained. This study investigates the protective effect of T3 analogs (α-, δ-, γ-) in comparison with α-TP followed by assessing the underlying mechanisms of the cytoprotective T3 analog(s) in two xenobiotics-induced liver injury models using (1) acetaminophen (APAP)- and (2) hydrogen peroxide (H2O2). Both α-TP and α-T3 exerted cytoprotective effects while only lower concentration of γ-T3 was effective in inhibiting both toxicants induced injury. α-TP/α-T3 protected hepatocytes from APAP and H2O2-induced liver injury through arresting free radicals and inhibiting oxidative stress (inhibition of reactive oxygen species, lipid peroxidation and mitochondrial permeability transition). There was also demonstrable inhibition of the apoptotic pathway (inhibition of caspse-3 activity and overexpression of Bcl-XL), accompanied with an induction of liver regeneration (PCNA and NF-kB). The cellular uptake of α-T3 was higher than α-TP at the same treatment dosage after 24h. Overall, α-T3 seems to be a more potent hepatoprotective analog among the tocotrienols and α-TP at the same in vitro treatment dosage. In summary, these results suggest that α-TP/α-T3 elicit hepatoprotective effects against toxicants-induced damage mainly through activation of antioxidant responses at an early stage to prevent the exacerbation of injury.

PMID:25637740 | PMC:PMC4803800 | DOI:10.1016/j.redox.2015.01.013

Synapse. 2015 Mar;69(3):128-38. doi: 10.1002/syn.21793. Epub 2015 Jan 10.

ABSTRACT

Mitochondrial dysfunctions have been implicated in the progression of Huntington's disease (HD). To date, several free radical scavengers have been tested in experimental HD, but only a few have shown promise. Although most antioxidants rapidly reduce ROS but in the process they are oxidized, which limits their ability to protect. Therefore, in the present study we employed a potent recycling antioxidant, 4-hydroxy tempo (4-HT), because it can reinstate its reduced state even after its oxidation during scavenging of ROS. Female Wistar rats were administered 3-nitropropionic acid (3-NP) and/or 4-HT for 21 days, after which animals were subjected to biochemical and behavioral assessments. Our results showed that 4-HT treatment significantly attenuated the 3-NP induced decrease in the activities of mitochondrial electron transport chain enzymes. In addition, 4-HT administration restored the increased nitrite and lipid peroxidation levels. Apart from this, 4-HT also attenuated the 3-NP induced decrease in superoxide dismutase and catalase activities. Further, 4-HT administration resulted in significant improvement in 3-NP induced cognitive and motor impairments. Taken together, the results of the study demonstrate that 4-HT is beneficial in 3-NP induced model of HD and thus could be a potential therapeutic agent in management of this disease.

PMID:25482019 | DOI:10.1002/syn.21793