Stress In Synaptosomes Research Articles

Amelioration of Phytanic Acid-Induced Neurotoxicity by Nutraceuticals: Mechanistic Insights.

Phytanic acid (PA) (3,7,11,15-tetramethylhexadecanoic acid) is a methyl-branched fatty acid that enters the body through food consumption, primarily through red meat, dairy products, and fatty marine foods. The metabolic byproduct of phytol is PA, which is then oxidized by the ruminal microbiota and some marine species. The first methyl group at the 3-position prevents the β-oxidation of branched-chain fatty acid (BCFA). Instead, α-oxidation of PA results in the production of pristanic acid (2,10,14-tetramethylpentadecanoic acid) with CO2. This fatty acid (FA) builds up in individuals with certain peroxisomal disorders and is historically linked to neurological impairment. It also causes oxidative stress in synaptosomes, as demonstrated by an increase in the production of reactive oxygen species (ROS), which is a sign of oxidative stress. This review concludes that the nutraceuticals (melatonin, piperine, quercetin, curcumin, resveratrol, epigallocatechin-3-gallate (EGCG), coenzyme Q10, ω-3 FA) can reduce oxidative stress and enhanced the activity of mitochondria. Furthermore, the use of nutraceuticals completely reversed the neurotoxic effects of PA on NO level and membrane potential. Additionally, the review further emphasizes the urgent need for more research into dairy-derived BCFAs and their impact on human health.

Phytanic acid induced neurological alterations in rat brain synaptosomes and its attenuation by melatonin

Phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) (Phyt) is a saturated branched chain fatty acid which originates after the breakdown of chlorophyll molecule, phytol. It plays an important role in a variety of metabolic disorders with peroxisomal impairments. The aim of our investigation was to evaluate the adverse effects of Phyt on synaptic functions by using synaptosomal preparation of rat brain as an in vitro model and the possible protective role of melatonin against Phyt-induced neurotoxicity. Melatonin is an antioxidant, secreted by the pineal gland. Melatonin and its metabolites have neuroprotective effects on cellular stress, by reducing reactive oxygen species (ROS) and reactive nitrogen species (RNS). In the present investigation, synaptosomes prepared from rat brain were co-treated with melatonin (10μM) and Phyt (50μM) for 2h. Co-treatment of Phyt with melatonin significantly restored the altered levels of protein carbonyl (PC) contents and lipid peroxidation (LPO). It also replenished the Phyt-induced alterations on the levels of non-enzymatic antioxidant defence reduced glutathione (GSH), enzymatic antioxidants such as catalase (CAT) and superoxide dismutase (SOD) and synaptosomal integral enzymes such as AChE, Na+, K+-ATPase and MAO. We observed that Phyt induced oxidative stress in synaptosomes as indicated by an elevation in the generation of ROS and melatonin was able to inhibit the elevated ROS generation. Moreover, the neurotoxic effects elicited by Phyt on NO level and membrane potential were totally prevented by the treatment of melatonin. The results of our investigation emphasize the potential use of melatonin as a nutraceutical and mitigatory agent against Phyt-induced oxidative stress.

Synaptosomal and mitochondrial oxidative damage followed by behavioral impairments in streptozotocin induced diabetes mellitus: restoration by Malvastrum tricuspidatum.

Synaptosomal and mitochondrial impairments in the brain of diabetic individual manifest metabolicrisk factorsthat most likely affect the brain functions. Diabetes is associated with the structural and functional alterations of the brain and neuronal loss leading to cognitive and other behavioral impairments, thus reducing the quality of life. The biochemical mechanisms underlying the diabetes-associated behavioral decline are poorly understood. In the present study, we examined the effects of hyperglycemia on the oxidative stress and behavioral functions in streptozotocin-induced diabetic mice. Our results showed the increase in oxidative stress in synaptosomes and brain mitochondria marked by an increase in lipid peroxidation and protein carbonyl content and decline in reduced glutathione in mice treated with streptozotocin. The oxidative damage in synaptosomes and brain mitochondria further caused impairment in locomotor and memory behavioral functions. Furthermore, we examined the protective effects of plant extract derived from Malvastrum tricuspidatum against STZ induced oxidative stress and behavioural impairments. For the first time we showed that this plant extract attenuate synaptosomal and mitochondrial oxidative stress and behavioral impairments in mice treated with streptozotocin. We suggest that streptozotocin caused impairments in synaptosomes and brain mitochondria and altered behavioral functions via increase in the oxidative stress and decrease in the antioxidant defense system. These impairments in synaptosomes and brain mitochondria and alterations in behavioral functions are significantly prevented by supplementation of Malvastrum tricuspidatum extract.

Treatment with Dehydroepiandrosterone Prevents Oxidative Stress Induced by 3-Nitropropionic Acid in Synaptosomes

This study evaluates the antioxidative effect of dehydroepiandrosterone (DHEA) treatment on 3-nitropropionic acid (3-NPA)-induced oxidative stress in striatal and brain cortex synaptosomes. The oxidative derangement was confirmed by a high level of lipid peroxidation products and protein carbonyls, as well as by an enhanced superoxide dismutase activity (p < 0.001). These changes were partially prevented by DHEA. Moreover, 3-NPA induced a drop in succinate dehydrogenase activity, while DHEA treatment restored the succinate dehydrogenase activity. These results show that DHEA reduces oxidative stress in synaptosomes isolated from the brain of 3-NPA-treated rats, and they suggest this neurosteroid may protect mitochondrial and maintain synaptic integrity against damage induced by this acid.

In vivo protection of synaptosomes from oxidative stress mediated by Fe 2+/H 2O 2 or 2,2-azobis-(2-amidinopropane) dihydrochloride by the glutathione mimetic tricyclodecan-9-yl-xanthogenate

D609 (tricyclodecan-9-yl-xanthogenate) is a phosphatidylcholine-specific phospholipase C inhibitor that also has been reported to protect rodents against oxidative damage caused by lethal doses of ionizing radiation. We previously showed that D609 mimics glutathione. D609 has a free thiol group, which upon oxidation forms a disulfide. The resulting dixanthate is a substrate for glutathione reductase, regenerating D609. Recent studies from our laboratory have also shown that D609 reduces the Alzheimer amyloid β-peptide (1-42)-induced oxidative stress and cytotoxicity in neuronal cell culture. The present study was undertaken to test the hypothesis that D609 would provide neuroprotection against free radical oxidative stress in vivo. Synaptosomes isolated from gerbils, previously injected intraperitoneally (ip) with D609, were treated with the oxidants Fe 2+/H 2O 2 or 2,2-azobis-(2-amidinopropane) dihydrochloride (AAPH), which produce free radicals. Synaptosomes isolated from the gerbils ip injected with D609 and treated with Fe 2+/H 2O 2 or AAPH showed significant reduction in reactive oxygen species, levels of protein carbonyl, protein-bound hydroxynonenal (a lipid peroxidation product), and 3-nitrotyrosine (another marker of protein oxidation formed by reaction of tyrosine residues with peroxynitrite) compared to oxidative stress in synaptosomes isolated from gerbils that were injected with saline, but treated with Fe 2+/H 2O 2 or AAPH. These results are discussed with reference to the potential use of this brain-accessible glutathione mimetic in the treatment of oxidative stress-related neurodegenerative disorders.

Effect of nicotine on 3-nitropropionic acid-induced oxidative stress in synaptosomes

In this paper, the effect of nicotine on the oxidative changes produced by 3-nitropropionic acid (20 mg/kg i.p./day for 4 days) in striatal and cortical synaptosomes of Wistar rats was studied. The effects of 3-nitropropionic acid were evaluated as changes in the quantity of protein carbonyl groups, lipid peroxidation products, superoxide distumase activity and reduced succinate dehydrogenase activity. All changes were prevented by the pre-injection of nicotine (1.5 mg/kg i.p./day), beginning 4 days before and continuing for 4 days after the first injection of 3-nitropropionic acid. These findings indicate that: (i) 3-nitropropionic acid induces a state of oxidative stress in cortical and striatal synaptosomes and (ii) nicotine prevents oxidative stress induced by 3-nitropropinonic acid. In conclusion, the results show the ability of nicotine to modify neural response to 3-nitropropionic acid with the protective mechanism likely involving the antioxidative processes of nicotine.

Protective effect of melatonin on 3‐nitropropionic acid‐induced oxidative stress in synaptosomes in an animal model of Huntington's disease

The effect of melatonin (1 mg/kg BW i.p./day) on the oxidative changes produced by 3-nitropropionic acid (20 mg/kg BW/day for 4 days) in rat striatal and cortical synaptosomes was investigated. The effects of 3-nitropropionic acid were evaluated as changes in the quantity of lipid peroxidation products, protein carbonyl groups and superoxide dismutase and succinate dehydrogenase activities. 3-Nitropropionic acid caused a rise in lipid peroxidation levels and protein carbonyls content whereas it induced a reduction in the activity of succinate dehydrogenase and triggered an enhancement in superoxide dismutase activity. These changes were prevented by previous administration of melatonin. Our results reveal: (i) 3-nitropropionic acid induces a status of oxidative stress in some brain regions of the Wistar rat; (ii) melatonin prevents the deleterious effects induced by the acid. In conclusion, the results show the ability of melatonin to modify the neural response to 3-nitropropionic acid with the protective mechanism likely involving the antioxidative processes of melatonin.

Effect of glucocorticoids on 3-nitropropionic acid-induced oxidative stress in synaptosomes

The present study with rat striatal and cortical synaptosomes evaluated the effect of dexamethasone (300 μg/kg i.p./day) with and without simultaneous adrenalectomy on the oxidative stress induced by 3-nitropropionic acid (20 mg/kg/day for 4 days). Adrenalectomy enhanced the oxidative stress induced by 3-nitropropionic acid. These changes were prevented by previous and simultaneous administration of dexamethasone. Adrenalectomy alone induced oxidative stress with decreases in succinate dehydrogenase activity. Our results revealed that adrenal glucocorticoids, and especially dexamethasone (synthetic glucocorticoid), have a protective effect against oxidative stress induced by 3-nitropropionic acid in some brain regions of the Wistar rat.

Enhanced depolarization-evoked calcium signal and reduced [ATP]/[ADP] ratio are unrelated events induced by oxidative stress in synaptosomes.

Oxidative insult elicited by hydrogen peroxide (H2O2) was previously shown to increase the basal intracellular Ca2+ concentration in synaptosomes. In the present study, the effect of H2O2 on the depolarization-evoked [Ca2+] signal was investigated. Pretreatment of synaptosomes with H2O2 (0.1-1 mM) augmented the [Ca2+] rise elicited by high K+ depolarization with essentially two alterations, the sudden sharp rise of [Ca2+]i due to K+ depolarization is enhanced and, instead of a decrease to a stable plateau, a slow, steady rise of [Ca2+]i follows the peak [Ca2+]i. H2O2 in the same concentration range lowered the ATP level and the [ATP]/[ADP] ratio. When carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone (FCCP) (1 microM) or rotenone (2 microM)/oligomycin (10 microM) was applied initially to block mitochondrial ATP production, the lowered [ATP]/[ADP] ratio was further reduced by subsequent addition of 0.5 mM H2O2. The decline of the [ATP]/[ADP] ratio was parallel with but could not explain the enhanced K+-evoked [Ca2+]i signal, indicated by experiments in which the [ATP]/[ADP] ratio was decreased by FCCP (0.1 microM) or rotenone (2 microM) to a similar value as by H2O2 without causing any alteration in the [Ca2+]i signal. These results indicate that H2O2-evoked oxidative stress, in its early phase, gives rise to a complex dysfunction in the Ca2+ homeostasis and, parallel with it, to an impaired energy status.