Oxidative Stress In Hippocampus Research Articles

The influence of sleep disorders on perioperative neurocognitive disorders among the elderly: A narrative review.

This review comprehensively assesses the epidemiology, interaction, and impact on patient outcomes of perioperative sleep disorders (SD) and perioperative neurocognitive disorders (PND) in the elderly. The incidence of SD and PND during the perioperative period in older adults is alarmingly high, with SD significantly contributing to the occurrence of postoperative delirium. However, the clinical evidence linking SD to PND remains insufficient, despite substantial preclinical data. Therefore, this study focuses on the underlying mechanisms between SD and PND, underscoring that potential mechanisms driving SD-induced PND include uncontrolled central nervous inflammation, blood-brain barrier disruption, circadian rhythm disturbances, glial cell dysfunction, neuronal and synaptic abnormalities, impaired central metabolic waste clearance, gut microbiome dysbiosis, hippocampal oxidative stress, and altered brain network connectivity. Additionally, the review also evaluates the effectiveness of various sleep interventions, both pharmacological and nonpharmacological, in mitigating PND. Strategies such as earplugs, eye masks, restoring circadian rhythms, physical exercise, noninvasive brain stimulation, dexmedetomidine, and melatonin receptor agonists have shown efficacy in reducing PND incidence. The impact of other sleep-improvement drugs (e.g., orexin receptor antagonists) and methods (e.g., cognitive-behavioral therapy for insomnia) on PND is still unclear. However, certain drugs used for treating SD (e.g., antidepressants and first-generation antihistamines) may potentially aggravate PND. By providing valuable insights and references, this review aimed to enhance the understanding and management of PND in older adults based on SD.

Combination of Vitamin D Intake and Aerobic Exercise Protected Young Female Rats From Oxidative Stress and Memory Impairment Caused by Maternal Vitamin D Deficiency

Background: Vitamin D deficiency (VDD) is a crucial global health issue that causes increased oxidative stress (OS) and memory disorders. This study aimed to evaluate the effects of vitamin D (VD) and aerobic exercise (EXE) combination therapy on OS and memory impairment caused by maternal VDD in young female rats. Methods: Forty female Wistar rats, aged 3 weeks and weighing 70±5 g, were divided into five groups. The Sham with a standard diet (SSD) group received a standard diet (SD) 6 weeks before mating until the end of lactation, and the VDD group consumed VDD a week before mating until the last day of lactation. The VDD+VD group received SD containing 1,000 IU/kg VD a week before mating until the end of lactation, and the VDD+EXE group received SD one week before mating until the last day of gestation and underwent treadmill exercise from a week before mating until gestational day 20. The last group received VDD+VD+EXE. Finally, spatial memory was assessed, and the animals were sacrificed on post-natal day 40. Left hippocampal OS status was evaluated using the enzyme-linked immunosorbent assay. Results: Maternal VDD caused an elevation in hippocampal OS along with memory impairment (P < 0.05). Vitamin D supplementation and aerobic exercise, alone or in combination, improved memory performance in the T-maze and novel object recognition test tasks by reducing lipid peroxidation levels and increasing enzymatic antioxidant activity in the hippocampus (P < 0.05). Conclusion: The findings indicated that vitamin D supplementation and aerobic exercise can effectively reduce the amount of OS and thus improve the level of memory in rats.

Rice bran extract mitigates depressive-like behavior in dextran sulfate sodium-induced colitis: Involvement of the gut-brain axis and Sirt1 signaling pathway

Inflammatory bowel disease (IBD) patients frequently suffer from depressive disorders as well. The present study was carried out to explore whether treatment with a standardized rice bran extract (RBE) could affect depression-like behavior in rats with dextran sulfate sodium (DSS)-induced colitis. Male Wistar rats were treated with RBE (100 mg/kg/day; p.o.) for 2 weeks. During the second week, colitis was induced by feeding the rats with 5 % (w/v) DSS in drinking water. RBE protected against DSS-induced body weight loss as well as against the macro- and microscopic inflammatory changes of the colon. Additionally, RBE mitigated DSS-induced dysregulation in blood–brain barrier tight junctional proteins, preserved the hippocampal histopathological architecture and improved the animal behavior in the forced swimming test. This was associated with modulation of hippocampal oxidative stress marker; GSH as well as hippocampal pro-inflammatory mediators; NF-ĸB and IL-1β. Treatment with RBE also led to a profound increase in the hippocampal levels of Sirt1, PGC-1α, Nrf2, and HO-1, which were drastically dropped by DSS. In conclusion, the study revealed the protective effect of RBE against DSS-induced depressive-like behavior through modulation of different parameters along the gut-brain axis and up-regulated the Sirt1/PGC-1α/Nrf2/HO-1 signaling pathway.

NEUROPROTECTIVE EFFECT OF PERILLYL ALCOHOL IN EXPERIMENTAL SPORADIC AD

AbstractBackgroundAlzheimer’s is most common neurodegenerative disorder characterized by memory loss due to accumulation of amyloid‐ β fibrils. There are different pathologies that count for AD like neuro inflammation. This study highlights the role of oxidative stress and inflammation in progression of AD where as Perillyl alcohol (POH) shows antioxidative & anti‐inflammatory properties.MethodSprague Dawley ICV‐STZ (3mg/kg) rats (250‐300g, 7‐8 weeks) were treated with Perillyl alcohol treated with three different doses of (25, 50 and 100mg/kg p.o.) for 13 days from 15th to 27th day. Weight measured on 1st and 28th day. Behavioral analysis done using Open Field Test and Morris Water Maze.ResultPerillyl alcohol treatment significantly attenuates declined body weight in ICV‐STZ induced dementia in rats, showed significant increase in crossing number, and active time. Dementia induced rats were unable to discriminate familiar and novel objects, which is improved by POH. POH attenuates STZ induced acquisition deficits and retention time, increased MDA and nitrite levels. POH attenuated depleted levels of GSH, Catalase, SOD comparable to standard drug donepezil, POH decreased AChE levels in cortex and hippocampus.ConclusionStudy outcomes demonstrate neuroprotective potential of Perillyl alcohol against ICV‐STZ administration of streptozotocin induced behavioural and biochemical abnormalities. Biventricular STZ infusion produced significant impairment in learning, memory, cholinergic hypofunction and elevation in hippocampal oxidative stress in rats. Rats showed poor learning, memory and unable to discriminate between familiar & novel objects in MWM and ORT. POH administration significantly attenuated STZ induced biochemical consequences. Observed beneficial effects of POH include restored cholinergic functions and antioxidant mechanism

Disruption of Cdk5-GluN2B complex by a small interfering peptide attenuates social isolation-induced escalated intermale attack behavior and hippocampal oxidative stress in mice

Social isolation has emerged as a significant issue during the COVID-19 pandemic that can adversely impact human mental health and potentially lead to pathological aggression. Given the lack of effective therapeutic interventions for aggressive behavior, alternative approaches are necessary. In this study, we utilized a genetic method combined with a pharmacological approach to identify and demonstrate the crucial role of Cdk5 in escalated intermale attack behavior induced by 2-week social isolation. Moreover, we developed a small peptide that effectively disrupts the interaction between Cdk5 and GluN2B, given the known involvement of this complex in various neuropsychiatric disorders. Administration of the peptide, either systemically or via intrahippocampal injection, significantly reduced oxidative stress in the hippocampus and attenuated intermale attack behavior induced by 2-week social isolation. These findings highlight the previously unknown role of the hippocampal Cdk5-GluN2B complex in social isolation-induced aggressive behavior in mice and propose the peptide as a promising therapeutic strategy for regulating attack behavior and oxidative stress.

Effect of vitamin E on doxorubicin and paclitaxel-induced memory impairments in male rats.

In addition to peripheral neuronal dysfunction, conventional chemotherapy can be associated with other neurological treatment-limiting adverse effects, including cognitive dysfunction, memory impairment, and anxiety, which are referred to as "chemobrain". This study aimed to investigate the effects of doxorubicin (DOX) and paclitaxel (PAC) on learning and memory in rats using radial arm water maze (RAWM) and investigated a potential beneficial effect of vitamin E(Vit. E). Adult male rats were injected with four doses of 2mg/kg/week DOX, or 2mg/kg PAC every other day intraperitoneally. Vit. Ewas co-administered with these drugs in other groups to study its antioxidative effects. Using the RAWM, each rat was assessed for learning and memory performance through two sets of six trials separated by a 5-min rest period evaluating both short- and long-term effects on memory. There was no deficit in learning or long-term memory in both drug groups compared to control. However, rats in both drug groups made significantly more errors in all short-term memory trials. This effect was mitigated when Vit. E was co-administered with either drug. Moreover, PAC (but not DOX) induced hippocampal lipid peroxidation by increasing the levels of standard biomarker thiobarbituric acid reactive substances(TBARS). Interestingly, Vit. E prevented PAC-induced hippocampal oxidative stress. Furthermore, both DOX and PAC were correlated with reduction in Brain-Derived Neurotrophic Factor (BDNF) expression levelsin the hippocampus, which was overcome by the co-administration of Vit. E. There is a potential role of Vit. E in alleviating short-term memory impairment in rats exposed to chemotherapy, possibly by reducing hippocampal oxidative stress and neurodegeneration.

Protective effects of alpha-lipoic acid on anxiety-like behavior, memory and prevention of hippocampal oxidative stress in methamphetamine-treated rats.

Alpha-lipoic acid is an essential cofactor for aerobic metabolism and acts as a potent antioxidant in the body. It has been shown that acute exposure to methamphetamine induces oxidative stress, which is responsible for severe cognitive deficits in animals. The hippocampus plays a crucial role in the processing of memory and anxiety-like behavior. In this study, preventive effect of the alpha-lipoic acid on memory impairment in methamphetamine-induced neurotoxicity was investigated. Wistar male rats (200-220g) were allocated to five groups (seven rats in each group): (1) saline + saline, (2) saline + vehicle (sunflower oil as alpha-lipoic acid solvent), (3) methamphetamine + vehicle, (4) methamphetamine + alpha-lipoic acid 10mg/kg, and (5) methamphetamine + alpha-lipoic acid 40mg/kg. Rats received intraperitoneal methamphetamine repeatedly (2 × 20mg/kg, 2h interval). Alpha-lipoic acid was injected 30min, 24h, and 48h after the last injection of methamphetamine. The passive avoidance test and open field were used for evaluation of memory retrieval and anxiety, respectively. After behavioral test, rats were anesthetized, their brains were extracted, and after preparing hippocampal homogenates, malondialdehyde (MDA) level, catalase, and superoxide dismutase (SOD) activities were evaluated. Statistical analysis showed that injection of saline or sunflower oil had no significant effect on anxiety, memory, or oxidative stress markers. Methamphetamine induced memory impairment, increased anxiety-like behavior and MDA level, but it reduced catalase and SOD activity. Treatment with alpha-lipoic acid decreased MDA, increased catalase and SOD activity, and also prevented memory impairment and anxiety-like behavior. Our results showed that alpha-lipoic acid protected the hippocampus from oxidative stress by elevating SOD and CAT activities and reduced memory impairment following acute methamphetamine injection. These findings suggest that alpha-lipoic acid may have a protective effect against the adverse effects of methamphetamine exposure on the hippocampus. Therefore, the current data indicated that ALA can reduce oxidative stress predominantly by its antioxidant property.

Evaluating the protective role of trimetazidine versus nano-trimetazidine in amelioration of bilateral renal ischemia/reperfusion induced neuro-degeneration: Implications of ERK1/2, JNK and Galectin-3 /NF-κB/TNF-α/HMGB-1 signaling

BackgroundRenal ischemia/reperfusion (I/R) is a primary culprit of acute kidney injury. Neurodegeneration can result from I/R, but the mechanisms are still challenging. We studied the implications of bilateral renal I/R on brain and potential involvement of the oxidative stress (OS) driven extracellular signal-regulated kinase1/2, c-Jun N-terminal kinase (ERK1/2, JNK) and Galectin-3 (Gal-3)/nuclear factor Kappa B (NF-қB)/tumor necrosis factor-alpha (TNF-α), high mobility group box-1 (HMGB-1), and caspase-3 paths upregulation. We tested the impact of Nano-trimetazidine (Nano-TMZ) on these pathways being a target of its neuroprotective effects. MethodsStudy groups; Sham, I/R, TMZ+I/R, and Nano-TMZ+I/R. Kidney functions, cognition, hippocampal OS markers, Gal-3, NF-қB, p65 and HMGB-1 gene expression, TNF-α level, t-JNK/p-JNK and t-ERK/p-ERK proteins, caspase-3, glial fibrillary acidic protein (GFAP) and ionized calcium binding protein-1 (Iba-1) were assessed. ResultsNano-TMZ averted renal I/R-induced hippocampal impairment by virtue of its anti: oxidative, inflammatory, and apoptotic properties. ConclusionNano-TMZ is more than anti-ischemic.

Nilotinib treatment induces cognitive impairment by elevating hippocampal oxidative stress in rats.

Protein tyrosine kinases (TKs) play a critical role in the regulation of various functions of a cell, including cellular proliferation, differentiation, and growth, and inhibitors of TKs have emerged as next-generation therapeutic agents in various types of cancer. Nilotinib, one of the TK inhibitors used to treat chronic myeloid leukemia, has been poorly investigated for its potential impact on memory function despite its ability to cross the blood-brain barrier (BBB). Thus, in this study, we investigated the effect of nilotinib on hippocampal-dependent cognitive functions and its potential mechanisms. Wistar albino male rats were divided into three groups of 10 each. The animals of group I (normal control) received drinking water only, while groups II and III were treated with nilotinib at doses of 15 mg/kg and 30 mg/kg, p.o. respectively, once daily for two weeks. The animals were subjected to behavioral tests after completion of drug treatment for the assessment of cognitive function using the Y-maze, novel object recognition (NOR) test, and elevated plus maze (EPM). The animals were euthanized after the estimation of blood glucose, and hippocampal tissues were dissected for the estimation of markers of oxidative stress. Nilotinib produced impairment of memory function on the Y-maze, NOR test, and EPM. These results were also supported by a significant increase in glutathione (GSH), malondialdehyde (MDA), Akt, glycogen synthase kinase-3 beta (GSK3β), and total antioxidant capacity (TAC) in hippocampal tissue without altering the blood glucose level. Nilotinib treatment produced significant impairment of cognitive function by inducing oxidative stress in the hippocampal tissue of rats.

Sevoflurane-induced hypotension causes cognitive dysfunction and hippocampal inflammation in mice

Sevoflurane commonly adopted for anesthetic in clinical practice, however, its influences on cerebral blood flow and cognitive function remain controversial. Herein, the sevoflurane-induced hypotension on arterial blood pressure, cerebral blood flow, cognitive function, and hippocampal inflammation was investigated in mice. A significant decrease in arterial blood pressure and cerebral blood flow was indicated by the sevoflurane anesthesia treatment. Moreover, sevoflurane-induced hypotension was associated with the impaired cognitive function and the increased levels of NLRP3 inflammasome activation and oxidative stress in hippocampus. These findings suggest that sevoflurane-induced hypotension may lead to the cognitive dysfunction and hippocampal inflammation.

Prangos ferulacea (L.) ameliorates behavioral alterations, hippocampal oxidative stress markers, and apoptotic deficits in a rat model of autism induced by valproic acid.

Prenatal exposure to valproic acid (VPA) may enhance the risk of autism spectrum disorder (ASD) in children. This study investigated the effect of Prangos ferulacea (L.) on behavioral alterations, hippocampal oxidative stress markers, and apoptotic deficits in a rat model of autism induced by valproic acid. Pregnant rats received VPA (600mg/kg, intraperitoneally [i.p.]) or saline on gestational day 12.5 (E 12.5). Starting from the 30th postnatal day (PND 30), the pups were i.p. administered Prangos ferulacea (PF, 100 and 200mg/kg), or the vehicle, daily until PND 58. On PND 30 and 58, various behavioral tasks were used to evaluate pups, including the open field, elevated plus-maze, hot-plate, and rotarod test. On PND 65, the animals were euthanized, and their brains were removed for histopathological and biochemical assay. Prenatal exposure to VPA caused significant behavioral changes in the offspring, reversed by administering an extract of Prangos ferulacea (L.). Additionally, prenatal VPA administration resulted in increased levels of malondialdehyde and deficits in antioxidant enzyme activities in the hippocampus, including catalase and glutathione, ameliorated by PF. Likewise, postnatal treatment with PF improved VPA-induced dysregulation of Bax and Blc2 in the hippocampus and reduced neuronal death in CA1, CA3, and dentate gyrus. The findings of this study suggest that postnatal administration of PF can prevent VPA-induced ASD-like behaviors by exhibiting antiapoptotic and antioxidant properties. Therefore, PF may have the potential as an adjunct in the management of ASD.

Ginsenoside Re blocks Bay k-8644-induced neurotoxicity via attenuating mitochondrial dysfunction and PKCδ activation in the hippocampus of mice: Involvement of antioxidant potential.

Although the anticonvulsant effects of ginsenosides are recognized, little is known about their effects on the convulsive behaviors induced by the activation of L-type Ca2+ channels. Here, we investigated whether ginsenoside Re (GRe) modulates excitotoxicity induced by the L-type Ca2+ channel activator Bay k-8644. GRe significantly attenuated Bay k-8644-induced convulsive behaviors and hippocampal oxidative stress in mice. GRe-mediated antioxidant potential was more pronounced in the mitochondrial fraction than cytosolic fraction. As L-type Ca2+ channels are thought to be targets of protein kinase C (PKC), we investigated the role of PKC under excitotoxic conditions. GRe attenuated Bay k-8644-induced mitochondrial dysfunction, PKCδ activation, and neuronal loss. The PKCδ inhibition and neuroprotection mediated by GRe were comparable to those by the ROS inhibitor N-acetylcysteine, the mitochondrial protectant cyclosporin A, the microglial inhibitor minocycline, or the PKCδ inhibitor rottlerin. Consistently, the GRe-mediated PKCδ inhibition and neuroprotection were counteracted by the mitochondrial toxin 3-nitropropionic acid or the PKC activator bryostatin-1. GRe treatment did not have additional effects on PKCδ gene knockout-mediated neuroprotection, suggesting that PKCδ is a molecular target of GRe. Collectively, our results suggest that GRe-mediated anticonvulsive/neuroprotective effects require the attenuation of mitochondrial dysfunction and altered redox status and inactivation of PKCδ.

Neuroprotective Effect of Perillyl alcohol in Experimental Sporadic Alzheimer’s disease

AbstractBackgroundAlzheimer’s is most common neurodegenerative disorder characterized by memory loss due to accumulation of amyloid‐ β fibrils. There are different pathologies that count for AD like neuro‐inflammation. This study highlights the role of oxidative stress and inflammation in progression of AD whereas Perillyl alcohol (POH) shows ant oxidative & anti‐inflammatory properties.Method54 Sprague Dawley ICV‐STZ (3mg/kg) rats (250‐300g, 7‐8 weeks) were treated with three different doses of Perillyl alcohol (25, 50 and 100mg/kg p.o.) for 13 days from 15th to 27th day. Weight measured on 1st and 28th day. Behavioral analysis had done using OFT and MWM.ResultPerillyl alcohol treatment significantly attenuates declined body weight in ICV‐STZ induced dementia in rats, showed significant increase in crossing number, and active time. Dementia induced rats were unable to discriminate familiar and novel objects, which is improved by POH. POH attenuates STZ induced acquisition deficits and retention time, increased MDA and nitrite levels. POH attenuated depleted levels of GSH, Catalase, SOD comparable to standard drug donepezil, POH decreased AChE levels in cortex and hippocampus.ConclusionStudy outcomes demonstrate neuroprotective potential of Perillyl alcohol against ICV‐STZ administration of streptozotocin induced behavioural and biochemical abnormalities. Biventricular STZ infusion produced significant impairment in learning, memory, cholinergic hypo function and elevation in hippocampal oxidative stress in rats. Rats showed poor learning, memory and unable to discriminate between familiar & novel objects in MWM and ORT. POH administration significantly attenuated STZ induced biochemical consequences. Observed beneficial effects of POH include restored cholinergic functions and antioxidant mechanisms.

Minocycline effects on memory and learning impairment in the beta-amyloid-induced Alzheimer’s disease model in male rats using behavioral, biochemical, and histological methods

Alzheimer’s disease (AD), as an advanced neurodegenerative disease, is characterized by the everlasting impairment of memory, which is determined by hyperphosphorylation of intracellular Tau protein and accumulation of beta-amyloid (Aβ) in the extracellular space. Minocycline is an antioxidant with neuroprotective effects that can freely cross the blood-brain barrier (BBB). This study investigated the effect of minocycline on the changes in learning and memory functions, activities of blood serum antioxidant enzymes, neuronal loss, and the number of Aβ plaques after AD induced by Aβ in male rats. Healthy adult male Wistar rats (200–220g) were divided randomly into 11 groups (n = 10). The rats received minocycline (50 and 100 mg/kg/day; per os (P.O.)) before, after, and before/after AD induction for 30 days. At the end of the treatment course, behavioral performance was measured by standardized behavioral paradigms. Subsequently, brain samples and blood serum were collected for histological and biochemical analysis. The results indicated that Aβ injection impaired learning and memory performances in the Morris water maze test, reduced exploratory/locomotor activities in the open field test, and enhanced anxiety-like behavior in the elevated plus maze. The behavioral deficits were accompanied by hippocampal oxidative stress (decreased glutathione (GSH) peroxidase enzyme activity and increased malondialdehyde (MDA) levels in the brain (hippocampus) tissue), increased number of Aβ plaques, and neuronal loss in the hippocampus evidenced by Thioflavin S and H&E staining, respectively. Minocycline improved anxiety-like behavior, recovered Aβ-induced learning and memory deficits, increased GSH and decreased MDA levels, and prevented neuronal loss and the accumulation of Aβ plaques. Our results demonstrated that minocycline has neuroprotective effects and can reduce memory dysfunction, which are due to its antioxidant and anti-apoptotic effects.

Effects of Ocimum basilicum L. Extract on Hippocampal Oxidative Stress, Inflammation, and BDNF Expression in Amnesic Aged Rats

ABSTRACT The present study was conducted to investigate the effects of Ocimum basilicum L. (OB) extract on learning and memory impairment in aged rats. Male rats were divided into the following experimental groups: Group 1 (control): including 2 months old rats, Group 2 (aged) including 2 years old rats, Groups 3–5 (aged-OB): including 2 years old rats received 50, 100, and 150 mg/kg OB for 8 weeks by oral gavage. Aging increased the delay to find the platform but, however, decreased the time spent in the target quadrant when tested by Morris water maze (MWM). Aging also reduced the latency to enter the dark chamber in the passive avoidance (PA) test compared to the control group. Moreover, interleukin-6 (IL-6) and malondialdehyde (MDA) levels were raised in the hippocampus and cortex of aged rats. In contrast, thiol levels and enzymatic activity of superoxide dismutase (SOD) and catalase (CAT) significantly reduced. In addition, aging significantly reduced BDNF expression. Finally, OB administration reversed the mentioned effects. The current research showed that OB administration improves learning/memory impairment induced by aging. It also found that this plant extract protects the brain tissues from oxidative damage and neuroinflammation.

Chronic hyperglycaemia increases the vulnerability of the hippocampus to oxidative damage induced during post-hypoglycaemic hyperglycaemia in a mouse model of chemically induced type 1 diabetes

Aims/hypothesisChronic hyperglycaemia and recurrent hypoglycaemia are independently associated with accelerated cognitive decline in type 1 diabetes. Recurrent hypoglycaemia in rodent models of chemically induced (streptozotocin [STZ]) diabetes leads to cognitive impairment in memory-related tasks associated with hippocampal oxidative damage. This study examined the hypothesis that post-hypoglycaemic hyperglycaemia in STZ-diabetes exacerbates hippocampal oxidative stress and explored potential contributory mechanisms.MethodsThe hyperinsulinaemic glucose clamp technique was used to induce equivalent hypoglycaemia and to control post-hypoglycaemic glucose levels in mice with and without STZ-diabetes and Nrf2−/− mice (lacking Nrf2 [also known as Nfe2l2]). Subsequently, quantitative proteomics based on stable isotope labelling by amino acids in cell culture and biochemical approaches were used to assess oxidative damage and explore contributory pathways.ResultsEvidence of hippocampal oxidative damage was most marked in mice with STZ-diabetes exposed to post-hypoglycaemic hyperglycaemia; these mice also showed induction of Nrf2 and the Nrf2 transcriptional targets Sod2 and Hmox-1. In this group, hypoglycaemia induced a significant upregulation of proteins involved in alternative fuel provision, reductive biosynthesis and degradation of damaged proteins, and a significant downregulation of proteins mediating the stress response. Key differences emerged between mice with and without STZ-diabetes following recovery from hypoglycaemia in proteins mediating the stress response and reductive biosynthesis.Conclusions/interpretationThere is a disruption of the cellular response to a hypoglycaemic challenge in mice with STZ-induced diabetes that is not seen in wild-type non-diabetic animals. The chronic hyperglycaemia of diabetes and post-hypoglycaemic hyperglycaemia act synergistically to induce oxidative stress and damage in the hippocampus, possibly leading to irreversible damage/modification to proteins or synapses between cells. In conclusion, recurrent hypoglycaemia in sub-optimally controlled diabetes may contribute, at least in part, to accelerated cognitive decline through amplifying oxidative damage in key brain regions, such as the hippocampus.Data availabilityThe datasets generated during and/or analysed during the current study are available in ProteomeXchange, accession no. 1-20220824-173727 (www.proteomexchange.org). Additional datasets generated during and/or analysed during the present study are available from the corresponding author upon reasonable request.Graphical abstract

Metformin mitigates amyloid β1-40-induced cognitive decline via attenuation of oxidative/nitrosative stress and neuroinflammation.

Metformin is an antidiabetic medicine widely used for management of type 2 diabetes with neuroprotective effects and promising potential to attenuate cognitive impairment. The efficacy of metformin in attenuation of Alzheimer's disease (AD) pathology has not been well-documented. Thus, this study was designed to assess protective effect of metformin against Aβ1-40-instigared cognitive impairment. After intra-CA1 microinjection of aggregated Aβ1-40, rats received oral metformin (50 and/or 200mg/kg/day) for two weeks. Cognition function was analyzed in various behavioral tasks besides measurement of hippocampal oxidative stress, apoptosis, and inflammation along with H&E staining and 3-nitrotyrosine (3-NT) immunohistochemistry. Obtained data showed significant improvement of discrimination score in novel object recognition test, higher alternation score in Y maze, greater latency in passive avoidance task, and lower working and reference memory errors in radial arm maze in metformin-treated Aβ-injured group. Moreover, metformin treatment attenuated hippocampal levels of nitrite, MDA, protein carbonyl, ROS, TNFα, GFAP, DNA fragmentation intensity, caspase 3 activity, AChE activity, and increased SOD activity and level of IL-10 as an anti-inflammatory factor. In addition, metformin treatment was associated with lower CA1 neuronal loss and it also decreased intensity of 3-NT immunoreactivity as an indicator of nitrosative stress. Taken together, obtained findings showed neuroprotective and anti-dementia property of metformin in male rats and this may have potential benefit in attenuation of cognitive decline and related complications in patients with neurodegenerative disorders such as AD besides diabetes mellitus.

Effects of Curcuma longa on Status Epilepticus Induced by Pilocarpine in Rats

Background and Aim: The purpose of the present study is to provide a basis for the use of Curcuma longa extract as a therapeutic agent for status epilepticus. Methods: The effect of Curcuma longa extract on the status epilepticus in rat model was investigated. The rat’s model of SE induced by pilocarpine and the effect of Curcuma longa extract was evaluated through the measurement of seizure duration, brain oedema and hippocampal oxidative stress in this model. Results: In rat pre-treated with Curcuma longa extract (400mg/kg) seizure duration, brain water content and the level of MDA significantly were decreased and activities of SOD and CAT significantly were increased in the hippocampal. Conclusion: Our data provide that Curcuma longa may be useful for management and treatment of SE.

Therapeutic effects of transcranial direct current stimulation on ketamine-induced schizophrenia-like behaviors and oxidative stress

Schizophrenia is a serious neuropsychiatric disorder that affects 1% of the world's population. It plays an important role in psychiatric symptoms, including major depression and schizophrenia. However, it is also known that one of the main reasons underlying the pathogenesis of schizophrenia is oxidative stress. Transcranial direct current stimulation (tDCS) has recently been a promising method for modifying neuronal membrane stimulation, cognition, and behavioral function. Our aim in this study is to explore the effects of 0.5 mA anodal tDCS stimulation on schizophrenia-like behaviors and oxidative stress in a ketamine-induced schizophrenia model. 30 male Balb/C mice were divided into 3 groups as control, schizophrenia, and schizophrenia+tDCS. The schizophrenia model was created by administering 25mg/kg/day ketamine for 7 days. tDCS treatment was performed by giving 0.5 mA anodal tDCS stimulation for 7 days. On day 14 of the experiment, SCZ-like behaviors were assessed using a novel object recognition test (NOR), open field test (OF), and tail suspension test (TST), and also oxidative stress in hippocampus and prefrontal tissues was estimated. Results showed that locomotor activity, depressive and anxiety-like behaviors of the schizophrenia group increased significantly compared to the control group and decreased after tDCS stimulation (p<0.05). In addition, it was investigated that tDCS stimulation also significantly increased learning that decreased after schizophrenia (p<0.05). All together, it was observed that the total antioxidant capacity of the schizophrenia group decreased while the total oxidant capacity of the schizophrenia group rose in the prefrontal cortex and hippocampus tissues compared to the control group (p<0.05). Otherwise, 0.5 mA anodal tDCS stimulation increased the total antioxidant capacity of the schizophrenia+tDCS group compared to the schizophrenia group, while it decreased total oxidant capacity (p<0.05). Based on our results displayed that 0.5 mA anodal tDCS stimulation for 30 minutes for 7 days reduced schizophrenia-like behaviors and oxidative stress by modulation of N-methyl-D-aspartic acid (NMDA) receptors in the glutamatergic pathway in a ketamine-induced, NMDA antagonist, schizophrenia model.

Interactions of alcohol and combination antiretroviral (cART) drug in diabetic male Sprague Dawley rats: Hippocampal perturbations and toxicosis.

Hippocampal pathology in diabetes is constantly investigated but the resultant health impact of the concomitant presence of alcohol and combined antiretroviral therapy (cART) in diabetes requires further studies to delineate toxicities inimical to hippocampal normal function. Forty-eight male Sprague Dawley rats were divided into eight groups (n=6): negative control (NC), alcohol (AL), cART (AV), alcohol-cART (AA), diabetic control (DB), diabetes-alcohol (DAL), diabetes-cART (DAV), and diabetes-alcohol-cART (DAA) exposure groups. Following diabetes induction and sub-chronic (90 days) treatment exposure, hippocampal homogenates were profiled for pro-inflammatory cytokines and oxidative stress (MDA and GPx) using immunoassay, while apoptotic genes (BAX, Bcl2, and Caspase-3), insulin receptor genes (INSR and IRS-1), and blood-brain barrier (BBB) junctional proteins (claudin-5, and occludin) gene expression were assessed using qPCR. Histomorphology of hippocampal neuronal number, nuclei area, and volume of dentate gyrus and neurogenesis were accessed using Giemsa stain, Ki67, and DCX histochemistry respectively. A central hippocampal effect that underpins all treatments is the reduction of DG neuronal number and antioxidant (GPx), highlighting the venerability of the hippocampal dentate gyrus neurons to diabetes, alcohol, cART, and their combinatorial interactions. Additionally, elevated BAX, Bcl2, and IRS1 mRNA levels in the DAL group, and their downregulation in AA, suggests IRS-1-regulated apoptosis due to differential modulating effects of alcohol treatment in diabetes (DAL) in contrast to alcohol with cART (AA). Although the interaction in AA therapy ameliorated the independent alcohol and cART effects on MDA levels, pro-inflammatory cytokines, and DCX, the interaction in AA exacerbated a deficiency in the expression of INSR, IRS-1 (insulin sensitivity), and BBB mRNA which are implicated in the pathogenies of diabetes. Furthermore, the diabetic comorbidity groups (DAV, DAL, and DAA) all share a central effect of elevated hippocampal oxidative stress, BAX, and Caspase-3 mRNA expression with the reduced number of hippocampal neurons, dentate gyrus volume, and neurogenesis, highlighting neurodegenerative and cognitive deficiency implication of these comorbidity treatments. Considering these findings, assessment of hippocampal well-being in patients with these comorbidities/treatment combinations is invaluable and caution is advised particularly in alcohol use with cART prophylaxis in diabetes.