Oxidative Damage In Brain Research Articles

Long-Term Effects of Perinatal Exposure to a Glyphosate-Based Herbicide on Melatonin Levels and Oxidative Brain Damage in Adult Male Rats.

Concerns have been raised regarding the potential adverse health effects of the ubiquitous herbicide glyphosate. Here, we investigated long-term effects of developmental exposure to a glyphosate-based herbicide (GBH) by analyzing serum melatonin levels and cellular changes in the striatum of adult male rats (90 days old). Pregnant and lactating rats were exposed to 3% GBH (0.36% glyphosate) through drinking water from gestational day 5 to postnatal day 15. The offspring showed reduced serum melatonin levels (43%) at the adult age compared with the control group. The perinatal exposure to GBH also induced long-term oxidative stress-related changes in the striatum demonstrated by increased lipid peroxidation (45%) and DNA/RNA oxidation (39%) together with increased protein levels of the antioxidant enzymes, superoxide dismutase (SOD1, 24%), glutamate-cysteine ligase (GCLC, 58%), and glutathione peroxidase 1 (GPx1, 31%). Moreover, perinatal GBH exposure significantly increased the total number of neurons (20%) and tyrosine hydroxylase (TH)-positive neurons (38%) in the adult striatum. Mechanistic in vitro studies with primary rat pinealocytes exposed to 50 µM glyphosate demonstrated a decreased melatonin secretion partially through activation of metabotropic glutamate receptor 3 (mGluR3), while higher glyphosate levels (100 or 500 µM) also reduced the pinealocyte viability. Since decreased levels of the important antioxidant and neuroprotector melatonin have been associated with an increased risk of developing neurodegenerative disorders, this demonstrates the need to consider the melatonin hormone system as a central endocrine-related target of glyphosate and other environmental contaminants.

Exposure to Polystyrene Nanoplastics Led to Learning and Memory Deficits in Zebrafish by Inducing Oxidative Damage and Aggravating Brain Aging.

Nanoplastics (NPs) may pass through the blood-brain barrier, giving rise to serious concerns about their potential toxicity to the brain. In this study, the effects of NPs exposure on learning and memory, the primary cognitive functions of the brain, are assessed in zebrafish with classic T-maze exploration tasks. Additionally, to reveal potential affecting mechanisms, the impacts of NPs exposure on brain aging, oxidative damage, energy provision, and the cell cycle are evaluated. The results demonstrate that NP-exposed zebrafish takes significantly longer for their first entry and spends markedly less time in the reward zone in the T-maze task, indicating the occurrence of learning and memory deficits. Moreover, higher levels of aging markers (β-galactosidase and lipofuscin) are detected in the brains of NP-exposed fish. Along with the accumulation of reactive free radicals, NP-exposed zebrafish suffer significant levels of brain oxidative damage. Furthermore, lower levels of Adenosine triphosphate (ATP) and cyclin-dependent kinase 2 and higher levels of p53 are observed in the brains of NP-exposed zebrafish, suggesting that NPs exposure also results in a shortage of energy supply and an arrestment of the cell cycle. These findings suggest that NPs exposure may pose a severe threat to brain health, which deserves closer attention.

Single and Combined Effects of Chlorpyrifos and Glyphosate on the Brain of Common Carp: Based on Biochemical and Molecular Perspective.

Chlorpyrifos (CPF) and glyphosate (GLY) are the most widely used organophosphate insecticide and herbicide worldwide, respectively; co-occurrence of CPF and GLY in aquatic environments occurs where they inevitably have potential hazards to fish. However, the potential mechanisms of CPF and GLY to induce toxicity have not been fully explored. To identify the adverse impacts of CPF and GLY on fish, either alone or in combination (MIX), CPF (25 μg/L) and GLY (3.5 mg/L) were set up according to an environmentally relevant concentration to expose to common carp for 21 days. After exposure, CPF and GLY decreased the activities of acetylcholinesterase and Na+/K+-ATPase, altered monoamine oxidase levels, decreased antioxidant enzyme activities (superoxide dismutase, catalase, glutathione S-transferase and glutamic reductase), and induced the accumulation of malondialdehyde in the carp brain. The parameters in the MIX groups had a greater impact compared to that in the CPF or GLY group, suggesting that both single and combined exposure could affect neurological signaling systems and cause oxidative stress and lipid peroxidation damage in carp brains, and that MIX exposure increases the impact of each pollutant. RNA-seq results showed that single or combined exposure to CPF and GLY induced global transcriptomic changes in fish brains, and the number of differentially expressed genes in MIX-treated carp brains were globally increased compared to either the CPF or GLY groups, suggesting that the effects of co-exposure were greater than single exposure. Further analysis results revealed that the global transcriptomic changes participated in oxidative stress, immune dysfunction, and apoptosis of fish brains, and identified that the P13k-Akt signaling pathway participates in both single and combined exposure of CPF- and GLY-induced toxicity. Taken together, our results demonstrated that the interaction of CPF and GLY might be synergic and provided novel insights into the molecular mechanisms of fish brains coping with CPF and GLY.

Breast cancer 1 (BRCA1) protection in altered gene expression and neurodevelopmental disorders due to physiological and ethanol-enhanced reactive oxygen species formation

The breast cancer 1 (Brca1) susceptibility gene regulates the repair of reactive oxygen species (ROS)-mediated DNA damage, which is implicated in neurodevelopmental disorders. Alcohol (ethanol, EtOH) exposure during pregnancy causes fetal alcohol spectrum disorders (FASD), including abnormal brain function, associated with enhanced ROS-initiated DNA damage. Herein, oxidative DNA damage in fetal brains and neurodevelopmental disorders were enhanced in saline-exposed +/- vs. +/+ Brca1 littermates. A single EtOH exposure during gestation further enhanced oxidative DNA damage, altered the expression of developmental/DNA damage response genes in fetal brains, and resulted in neurodevelopmental disorders, all of which were BRCA1-dependent. Pretreatment with the ROS inhibitor phenylbutylnitrone (PBN) blocked DNA damage and some neurodevelopmental disorders in both saline- and EtOH-exposed progeny, corroborating a ROS-dependent mechanism. Fetal BRCA1 protects against altered gene expression and neurodevelopmental disorders caused by both physiological and EtOH-enhanced levels of ROS formation. BRCA1 deficiencies may enhance the risk for FASD.

Monoacylglycerol Lipase Inhibition Prevents Short-Term Mitochondrial Dysfunction and Oxidative Damage in Rat Brain Synaptosomal/Mitochondrial Fractions and Cortical Slices: Role of Cannabinoid Receptors.

Inhibition of enzymes responsible for endocannabinoid hydrolysis represents an invaluable emerging tool for the potential treatment of neurodegenerative disorders. Monoacylglycerol lipase (MAGL) is the enzyme responsible for degrading 2-arachydonoylglycerol (2-AG), the most abundant endocannabinoid in the central nervous system (CNS). Here, we tested the effects of the selective MAGL inhibitor JZL184 on the 3-nitropropinic acid (3-NP)-induced short-term loss of mitochondrial reductive capacity/viability and oxidative damage in rat brain synaptosomal/mitochondrial fractions and cortical slices. In synaptosomes, while 3-NP decreased mitochondrial function and increased lipid peroxidation, JZL184 attenuated both markers. The protective effects evoked by JZL184 on the 3-NP-induced mitochondrial dysfunction were primarily mediated by activation of cannabinoid receptor 2 (CB2R), as evidenced by their inhibition by the selective CB2R inverse agonist JTE907. The cannabinoid receptor 1 (CB1R) also participated in this effect in a lesser extent, as evidenced by the CB1R antagonist/inverse agonist AM281. In contrast, activation of CB1R, but not CB2R, was responsible for the protective effects of JZL184 on the 3-NP-iduced lipid peroxidation. Protective effects of JZL184 were confirmed in other toxic models involving excitotoxicity and oxidative damage as internal controls. In cortical slices, JZL184 ameliorated the 3-NP-induced loss of mitochondrial function, the increase in lipid peroxidation, and the inhibition of succinate dehydrogenase (mitochondrial complex II) activity, and these effects were independent on CB1R and CB2R, as evidenced by the lack of effects of AM281 and JTE907, respectively. Our novel results provide experimental evidence that the differential protective effects exerted by JZL184 on the early toxic effects induced by 3-NP in brain synaptosomes and cortical slices involve MAGL inhibition, and possibly the subsequent accumulation of 2-AG. These effects involve pro-energetic and redox modulatory mechanisms that may be either dependent or independent of cannabinoid receptors' activation.

Neuroprotective effect of quercetin and nano-quercetin against cyclophosphamide-induced oxidative stress in the rat brain: Role of Nrf2/ HO-1/Keap-1 signaling pathway

Quercetin (Qu) is a powerful flavanol antioxidant that is naturally found in plants and is part of the flavonoid family. Qu has a wide range of biological properties, such as neuroprotective, anti-cancer, anti-diabetic, anti-inflammatory, and radical scavenging capabilities. However, the in vivo application of Qu is limited by its poor water solubility and low bioavailability. These issues could be addressed by utilizing Qu nanoformulations. Cyclophosphamide (CP) is a potent chemotherapeutic agent that causes severe neuronal damage and cognitive impairment due to reactive oxygen species (ROS) overproduction. The present study aimed to explore the proposed neuroprotective mechanism of quercetin (Qu) and quercetin-loaded Chitosan nanoparticles (Qu-Ch NPs) against the brain oxidative damage induced by CP in male albino rats. For this aim, thirty-six adult male rats were randomly divided into six groups (n = 6). Rats were pretreated with Qu and Qu-Ch NPs orally in doses of 10 mg/kg bwt/day for 2 weeks, and CP (75 mg/kg bwt) was administered intraperitoneally 24 h before the termination of the experiment. After 2 weeks, some neurobehavioral parameters were evaluated, and then euthanization was done to collect the brain and blood samples. Results showed that CP induces neurobehavioral deteriorations and impaired brain neurochemical status demonstrated by a significant decrease in brain glutathione (GSH), serum total antioxidant capacity (TAC), and serotonin (5-HT) levels while malondialdehyde (MDA), nitric oxide (NO), Tumor necrosis factor α (TNFα), and choline esterase (ChE) concentrations increased significantly compared to the control group. Pretreatment with Qu and Qu-Ch NPs showed a significant anti-oxidative, anti-depressive, and neuroprotective effect through modification of the above-mentioned parameters. The results were further validated by assessing the expression levels of selected genes in brain homogenates and histopathological investigations were done to pinpoint the exact brain-altered regions. It could be concluded that Qu and Qu-Ch NPs can be useful neuroprotective adjunct therapy to overcome neurochemical damage induced by CP.

Curcumin preconditioning enhances the neuroprotective effects of olfactory mucosa-derived mesenchymal stem cells on experimental intracerebral hemorrhage

Oxidative stress is essential in brain injury after intracerebral hemorrhage (ICH). Ferroptosis, iron-dependent oxidative cell death, overwhelms the antioxidant system. Recently, Olfactory mucosa-derived mesenchymal stem cells (OM-MSCs) hold great potential for treating ferroptosis-mediated oxidative brain damage after ICH. However, massive grafted cell death, possibly caused by a hostile host brain microenvironment, lessens the effectiveness of OM-MSCs. Therefore, it is necessary to develop strategies to upregulate the therapeutic efficacy of OM-MSCs in ICH. Curcumin, a well-established traditional herbal substance, has potent antioxidant property. In the present study, curcumin preconditioning might enhance the anti-oxidative activity of OM-MSCs, thereby augmenting the therapeutic efficacy of OM-MSCs in ICH. In vitro model of ICH, we demonstrated that curcumin-preconditioned OM-MSCs co-culture is more effective in attenuating the cell injury, oxidative stress, and ferroptosis of neuronal cells compared to the native OM-MSCs treatment. In vivo model of ICH, transplantation of curcumin-preconditioned OM-MSCs also showed better neuroprotective effects. Moreover, curcumin pretreatment promoted the survival of OM-MSCs under a conditioned medium from hemin-insulted neurons by improving the anti-oxidative capacities of OM-MSCs. Collectively, our investigation suggested that curcumin preconditioning effectively enhanced the survival and neuroprotective effects of OM-MSCs in the ICH model by upregulating the anti-oxidative capacities of OM-MSCs. Curcumin-preconditioned OM-MSCs might be taken as a novel therapeutic strategy for treating ICH.

Polylactic Acid-Based Microplastic Particles Induced Oxidative Damage in Brain and Gills of Goldfish Carassius auratus

The effect of 96 h exposure of the goldfish Carassius auratus to two different types of bioplastic particles, originating from commercial shopping bag (Bag, ~5 mm) and polylactic acid-based (PLA) cup (Cup, ≤5 mm), and petroleum-based polyamide particles (PA, 0–180 µm) was studied. All particles were studied as virgin and after simulated UV-degradation (at concentration 30 mg L−1). The experiments were conducted according to OECD 203 test guidelines. The toxicity endpoint evaluated in fish brain and gills was lipid peroxidation (LPO) quantified as nmol thiobarbituric acid reactive substances (TBARs) mg−1 protein. The results indicated that indicatively compostable PLA bioplastic Cup induced significant LPO in the brain and/or gills of the goldfish, in contrast to the particles from Bag and PA (in the brain, Cup > Bag > PA; in the gills, Cup > Bag). The UV-degradation of the particles of all studied types had no significant effect on the LPO level compared to virgin particles. While the increase of LPO in fish gills and brain upon exposure to PLA-plastic particles can be transitory in the long-term perspective, our results point to the necessity of a thorough investigation of the hazard of bioplastics at different state of environmental degradation/weathering.

Feeding crocin ameliorate cognitive dysfunction, oxidative stress and neuroinflammation induced by unpredictable chronic mild stress in rats.

The aim of the current study was to investigate the probable mechanism and effect of crocin on brain oxidative damage and memory deficits induced by unpredictable chronic mild stress (UCMS). Male Wistar rats were randomly divided into six groups consisting of one vehicle group (received normal saline), four groups included rats who received UCMS 4 weeks out of which three groups were pretreated with different doses of crocin (10, 20, and 30mg/kg/day) concomitantly. To assess the pure effect of crocin, the last experimental group received a high dose of crocin (30mg/kg/day) without exposure to the UCMS procedure. The behavioral tests including Morris water maze (MWM) and passive avoidance (PA) were performed and eventually they were sacrificed for the estimation of biochemical parameters. The increase in Malondialdehyde (MDA) as an oxidative stress indicator and nitrite levels in the hippocampus were observed in UCMS rats, along with memory deficits in behavioral tests including passive avoidance and Morris water maze (MWM) test. Moreover, treatment with crocin decreased MDA, nitrite, pro-inflammatory cytokine such as TNF-α, and pathological hallmark of Alzheimer's disease including amyloid-β (Aβ), and glial fibrillary acidic protein (GFAP) in the hippocampus, whereas antioxidant agents including total thiol content, SOD, and catalase activity were increased. Also behavioral test demonstrated a positive effect of crocin on memory deficit induced by UCMS. Interlukin-10 as an important anti-inflammatory agent was increased as well. Interestingly, in some behavioral and biochemical findings, treatment with 30mg/kg of crocin has given better results compared to vehicle group, which means the administration of crocin could have preventive effects on learning and memory impairment. The present study strongly confirmed the positive effect of crocin and has the potential as an antioxidant and anti-inflammatory agent that could improve memory impairment induced by UCMS.

Vitamin D’s influence on aging brain function: Literature review

AbstractBackgroundVitamin D receptors are located in neurons and glial cells of the brain. Vitamin D protects the nervous system by stimulating the synthesis of neurotrophin and neuromodulators, maintaining intracellular calcium homeostasis, and preventing oxidative brain damage. Vitamin D deficiency/insufficiency affects around 50% of the population, with rates varying according to race and ethnic origin. Vitamin D deficiency/insufficiency is a major public health concern because of its association with cognitive impairment and dementia. We aim to do a follow‐up review of the literature on the association between vitamin D insufficiency and cognitive impairment, including dementia.MethodWe reviewed vitamin D insufficiency and cognitive function studies published between 2010 and 2021. Except for animal models and research on human subjects with dementia, stroke, or brain malignancies, we reviewed clinical trials, case‐control, cohort, cross‐sectional, systematic reviews, and meta‐analyses. Adults worldwide were the target demographic. There were no limits on vitamin D levels or intake. PubMed, Cochrane, Clinicaltrials.gov, and Google Scholar were all accessed databases using keyword combinations such as “Vitamin D AND Alzheimer’s,” “Vitamin D AND cognitive,” “Vitamin D AND Geriatric,” and “Vitamin D AND Dementia”. All team members reviewed and verified the studies.ResultNine studies matched our inclusion criteria, involving 69,643 people with an average age of 53.6 years old. Vitamin D deficiency/insufficiency has been linked to impaired executive function, processing speed, visuoperceptual ability, and dementia in five studies. Two investigations established a direct proportional association between the degree of vitamin D insufficiency and the severity of memory and cognitive impairment. Vitamin D supplementation, according to one study, increases cognitive and memory functions.ConclusionAdults with vitamin D deficiency have reduced cognitive function and an increased risk of dementia. A significant limitation is that Africans, Hispanics, and Asians are underrepresented in the studies. Additionally, larger randomized controlled trials are needed to examine the many effects of vitamin D deficiency/insufficiency, supplementation, and its relationship to cognition in the aging brain.

Repeated donkey milk consumption reduces anxiety-like behaviors and brain oxidative damage to lipids in mice

Donkey milk (DM) is a source of bioactive compounds that can benefit neural functioning. In the present study, we investigated the effects of DM consumption on anxiolytic-related, despair-like, locomotion and coordination behaviors, as well as the provision of protection from oxidative damage to lipids and proteins in brain tissues and melatonin plasma levels. To achieve this, male mice orally received DM (4 g.kg-1) or vehicle for 18 days. Their behavior was assessed in the following tests: elevated plus maze (EPM), open field and rotarod tests (OF, RR) and forced swimming test (FST). Acute treatments with diazepam (DZP, 1.5 mg.kg-1, v.o.), fluoxetine (FLX, 20 mg.kg-1, i.p.) and nortriptyline (NTP, 20 mg.kg-1, i.p.) were used as positive controls. On the eighteenth day, the animals were euthanized and brain tissue and blood were collected to measure oxidative damage, and melatonin plasma levels. Similar to DZP, repeated DM consumption reduced exploration to open areas in the EPM test. Under our experimental conditions, conventional antidepressants reduced immobility time in the FST, and the benzodiazepine treatment impaired motor coordination in mice. No significant differences in locomotion, motor coordination and despair-related behaviors were observed in the mice treated with DM when assessed in the EPM, OF, RR and FST, respectively. Biochemical assays showed that repeated DM exposition protected against oxidative damage to lipids and increased plasma levels of melatonin. These findings suggest consumption of DM may be a promising food for the treatment of anxiety-related disorders, without depressant effects on the central nervous system.

Memantine, an NMDA receptor antagonist, protected the brain against the long-term consequences of sepsis in mice

AimsLong-term neuroinflammation and brain dysfunction have frequently been reported in sepsis survivors. In this study, the protective effect of memantine (an NMDA receptor antagonist) on the long-term consequences of sepsis on the brain was investigated in mice. Materials and methodsEighty-five male C57 mice were included. Memantine was administrated through gavage at 5, 10, and 20 mg/kg three days before sepsis and continued for three days after sepsis induction. Sepsis was induced by intraperitoneal injection of 5 mg/kg LPS. A cohort of mice was sacrificed on the 4th day post sepsis to measure NF-κB, TNF-α, and IL-1β mRNA expression and oxidative stress markers in the brain. The second cohort was used for behavioral tests one month after sepsis induction and then sacrificed for oxidative stress markers and acetylcholinesterase (AChE) activity measurement. Key findingsMDA levels and mRNA expression of NF-κB, TNF-α, and IL-1β ameliorated by memantine at the early days of sepsis induction, and total thiol content and SOD activity were increased. Post-septic mice showed significant disruption of recognition memory in novel object recognition (NOR) and depressive and anxiety-like behaviors in tail suspension test, elevated plus maze (EPM), and open field tests one month after sepsis. Memantine at 10 and 20 mg/kg dose-dependently ameliorated behavioral abnormalities, reduced AChE activity and MDA levels, and enhanced SOD activity and thiol content one month after sepsis. SignificanceThese findings suggest that early treatment of septic mice with memantine could ameliorate brain inflammation and oxidative damage and prevent long-term behavioral consequences of sepsis.

331 A Randomized Controlled Clinical Trial using α-Tocopherol and Ascorbic Acid in the Treatment of Moderate Traumatic Brain Injury

INTRODUCTION: Traumatic Brain Injury (TBI) is a major public health concern and a leading cause of disability worldwide. It accounts for 40% of all deaths from acute injuries worldwide. Oxidative brain damage is one of the most validated pathophysiologic hallmark of secondary traumatic brain injury. METHODS: 120 patients admitted to Jos University Teaching Hospital with moderate TBI were included in this study. Patients were randomized into 4 equally sized groups: control, enteral α-Tocopherol, intravenous ascorbic acid, or a combination of the latter treatments. Patients were administered the designated drugs for a period of one week in addition to the standard management of head injuries. The control group received neither of these drugs but just the standard management of head injury. Outcome data were collected prospectively including demographics, head injury characteristics, mortality, length of stay (LoS) and Glasgow outcome score (GOS). RESULTS: 92.5% (n = 111) of patients were male. The most common cause for TBI was road traffic accidents (n = 102). GOS was significantly higher in all treatment groups when compared to the control group at discharge (ascorbic acid p < 0.01, α-Tocopherol p < 0.001, combination p < 0.001), and at 1 and 3 months follow up. Overall mortality was significantly lower in patients treated with either α-Tocopherol (n = 1, 3.3%), ascorbic acid (n = 1, 3.3%) or a combination (n = 0, 0%) compared to the placebo group (n = 8, 26.7%, p < 0.05). The lenght of hospital stay was significantly reduced in the α-Tocopherol (p < 0.05) and the combination groups (p < 0.001) CONCLUSIONS: The use of ascorbic acid and/or α-Tocopherol improved survival in this cohort. A combination of both drugs had a potentially synergistic effect in these patients.

HIGH CONCENTRATIONS OF FRUCTOSE CAUSE BRAIN DAMAGE IN MICE.

Excessive fructose consumption is associated with the incidence of obesity and systemic inflammation, resulting in increased oxidative stress and damage to the function of brain structures. Thus, we hypothesized that fructose consumption will significantly increase inflammation, oxidative damage and mitochondrial dysfunction in the mouse brain and, consequently, memory damage. The effects of different fructose concentrations on inflammatory and biochemical parameters in the mouse brain were evaluated. Male Swiss mice were randomized into four groups: control, with exclusive water intake, 5%, 10% and 20% fructose group. The 10% and 20% fructose groups showed an increase in epididymal fat, in addition to higher food consumption. Inflammatory markers were increased in epididymal fat and in some brain structures. In the evaluation of oxidative stress, it was possible to observe significant increases in the hypothalamus, prefrontal cortex and hippocampus. In the epididymal fat and in the prefrontal cortex, there was a decrease in the activity of the mitochondrial respiratory chain complexes and an increase in the striatum. Furthermore, short memory was impaired in the 10% and 20% groups, but not for long memory. In conclusion, excess fructose consumption can cause fat accumulation, inflammation, oxidative damage and mitochondrial dysfunction, which can damage brain structures and consequently memory.

AD−1 Small Molecule Improves Learning and Memory Function in Scopolamine-Induced Amnesic Mice Model through Regulation of CREB/BDNF and NF-κB/MAPK Signaling Pathway

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 AD-1 small molecule, we here explored the possible underlying mechanisms of the protective effect of AD-1 small molecule against scopolamine-induced oxidative stress, neuroinflammation, and neuronal apoptosis. According to our findings, scopolamine administration resulted in increased AChE activity, MDA levels, and decreased antioxidant enzymes, as well as the downregulation of the antioxidant response proteins of Nrf2 and HO-1 expression; however, treatment with AD-1 small molecule mitigated the generation of oxidant factors while restoring the antioxidant enzymes status, in addition to improving antioxidant protein levels. Similarly, AD-1 small molecule significantly increased the protein expression of neuroprotective markers such as BDNF and CREB and promoted memory processes in scopolamine-induced mice. Western blot analysis showed that AD-1 small molecule reduced activated microglia and astrocytes via the attenuation of iba-1 and GFAP protein expression. We also found that scopolamine enhanced the phosphorylation of NF-κB/MAPK signaling and, conversely, that AD-1 small molecule significantly inhibited the phosphorylation of NF-κB/MAPK signaling in the brain regions of hippocampus and cortex. We further found that scopolamine promoted neuronal loss by inducing Bax and caspase-3 and reducing the levels of the antiapoptotic protein Bcl-2. In contrast, AD-1 small molecule significantly decreased the levels of apoptotic markers and increased neuronal survival. Furthermore, AD-1 small molecule ameliorated scopolamine-induced impairments in spatial learning behavior and memory formation. These findings revealed that AD-1 small molecule attenuated scopolamine-induced cognitive and memory dysfunction by ameliorating AChE activity, oxidative brain damage, neuroinflammation, and neuronal apoptosis.

Prenatal stress induces a depressive-like phenotype in adolescent rats: The key role of TGF-β1 pathway.

Stressful experiences early in life, especially in the prenatal period, can increase the risk to develop depression during adolescence. However, there may be important qualitative and quantitative differences in outcome of prenatal stress (PNS), where some individuals exposed to PNS are vulnerable and develop a depressive-like phenotype, while others appear to be resilient. PNS exposure, a well-established rat model of early life stress, is known to increase vulnerability to depression and a recent study demonstrated a strong interaction between transforming growth factor-β1 (TGF-β1) gene and PNS in the pathogenesis of depression. Moreover, it is well-known that the exposure to early life stress experiences induces brain oxidative damage by increasing nitric oxide levels and decreasing antioxidant factors. In the present work, we examined the role of TGF-β1 pathway in an animal model of adolescent depression induced by PNS obtained by exposing pregnant females to a stressful condition during the last week of gestation. We performed behavioral tests to identify vulnerable or resilient subjects in the obtained litters (postnatal day, PND > 35) and we carried out molecular analyses on hippocampus, a brain area with a key role in the pathogenesis of depression. We found that female, but not male, PNS adolescent rats exhibited a depressive-like behavior in forced swim test (FST), whereas both male and female PNS rats showed a deficit of recognition memory as assessed by novel object recognition test (NOR). Interestingly, we found an increased expression of type 2 TGF-β1 receptor (TGFβ-R2) in the hippocampus of both male and female resilient PNS rats, with higher plasma TGF-β1 levels in male, but not in female, PNS rats. Furthermore, PNS induced the activation of oxidative stress pathways by increasing inducible nitric oxide synthase (iNOS), NADPH oxidase 1 (NOX1) and NOX2 levels in the hippocampus of both male and female PNS adolescent rats. Our data suggest that high levels of TGF-β1 and its receptor TGFβ-R2 can significantly increase the resiliency of adolescent rats to PNS, suggesting that TGF-β1 pathway might represent a novel pharmacological target to prevent adolescent depression in rats.

ApoE4 is associated with lower antioxidant levels and increased oxidative damage in human and mouse brain

ApoE4 is associated with lower antioxidant levels and increased oxidative damage in human and mouse brain

Chemical hypermethioninemia in young mice: oxidative damage and reduction of antioxidant enzyme activity in brain, kidney, and liver.

High levels of methionine (Met) and its metabolites, such as methionine sulfoxide (MetO), found in hypermethioninemia, can be detrimental to the body; however, the underlying mechanisms are still uncertain. Using a recently standardized protocol, the aim of this study was to investigate the effects of chronic administration of Met and/or MetO on parameters of oxidative damage in the total brain, liver, and kidney of young mice. Swiss male mice were subcutaneously injected with Met and MetO at concentrations of 0.35-1.2g/kg body weight and 0.09-0.3g/kg body weight, respectively, from the 10th-38th day post-birth, while the control group was treated with saline solution. Results showed that Met and/or MetO caused an increase in reactive oxygen species (ROS) and lipoperoxidation, along with a reduction of superoxide dismutase (SOD) and catalase (CAT) activities in the brain. In the liver, Met and/or MetO enhanced ROS and nitrite levels, and reduced SOD, CAT, and delta aminolevulinic dehydratase activities. The effects on the kidney were an increase in ROS production and SOD activity, and a reduction in thiol content and CAT activity. These data demonstrated the contribution of redox imbalance to the systemic changes found in patients with hypermethioninemia. In conclusion, our findings may help future studies to better understand the pathophysiological mechanisms of hypermethioninemia as well as contribute to the search for new therapeutic agents for this pathology.

The protective effect of arbutin against potassium bromate-induced oxidative damage in the rat brain.

This study aimed to investigate the protective effects of arbutin (ARB) against brain injury induced in rats with potassium bromate (KBrO3 ). The rats were divided into four groups as Group 1: Control (0.9% NaCl ml/kg/day p.), Group 2: KBrO3 (100 mg/kg (gavage), Group 3: ARB (50 mg/kg/day p.), and Group 4: KBrO3 + ARB (100 mg/kg (gavage) + 50 mg/kg/day p.). At the end of the fifth day of the study, the rats in all groups were killed, and their brain tissues were collected. In the collected brain tissues, malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT) levels were measured, and routine histopathological examinations were made. The MDA levels in the group that was exposed to KBrO3 were significantly higher than those in the control group (p ˂ 0.001). In comparison to the KBrO3 group, the MDA levels in the KBrO3 + ARB group were significantly lower (p ˂ 0.001). It was observed that SOD and CAT enzyme activity levels were significantly lower in the KBrO3 group compared to the control group (p ˂ 0.001), while these levels were significantly higher in the KBrO3 + ARB group than in the KBrO3 group (p ˂ 0.001). Additionally, the group that was subjected to KBrO3 toxicity, as well as ARB administration, had much lower levels of histopathologic signs than the group that was subjected to KBrO3 toxicity only. Consequently, it was found that KBrO3 exposure led to injury in the brain tissues of the rats, and using ARB was effective in preventing this injury.

Biochemical regulatory processes in the control of oxidants and antioxidants production in the brain of rats with iron and copper chronic overloads.

Iron [Fe(II)] and copper [Cu(II)] overloads in rat brain are associated with oxidative stress and damage. The purpose of this research is to study whether brain antioxidant enzymes are involved in the control of intracellular redox homeostasis in the brain of rats male Sprague-Dawley rats (80-90g) that received drinking water supplemented with either 1.0g/L of ferrous chloride (n = 24) or 0.5g/L cupric sulfate (n = 24) for 42days. Nicotinamide adenine dinucleotide phosphate(NADPH) oxidase, superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx) and glutathione transferase (GT) activities in brain were determined by spectrophotometric methods and NO production by the content of nitrite concentration in the organ. Chronic treatment with Fe(II) and Cu(II) led to a significant decrease of nitrite content and SOD activity in brain. Activity of NADPH oxidase increased with Cu(II) treatment. Concerning Fe(II), catalase and GT activities increased in brain after 28 and 4days of treatment, respectively. In the case of Cu(II), catalase activity decreased whereas GT activity increased after 2 and 14days, respectively. The regulation of redox homeostasis in brain involves changes of the activity of these enzymes to control the steady state of oxidant species related to redox signaling pathways upon Cu and Fe overload. NO may serve to detoxify cells from superoxide anion and hydrogen peroxide with the concomitant formation of peroxynitrite. However, the latest is a powerful oxidant which leads to oxidative modifications of biomolecules. These results suggest a common pathway to oxidative stress and damage in brain for Cu(II) and Fe(II).