Recent advances in toxicological research of di-(2-ethylhexyl)-phthalate: Focus on endoplasmic reticulum stress pathway.

The plasticizer di-(2-ethylhexyl)-phthalate (DEHP) is the most significant phthalate in production, usage, and environmental occurrence. DEHP is found in products such as personal care products, furniture materials, cosmetics, and medical devices. DEHP is noncovalently bind with plastic therefore, repeated uses lead to leaching out of it. Exposure to DEHP plasticizers leads to toxicity in essential organs of the body through various mechanisms. The main objective of this review article is to focus on the DEHP-induced endoplasmic reticulum (ER) stress pathway implicated in the testis, brain, lungs, kidney, heart, liver, and other organs. Not only ER stress, PPAR-related pathways, oxidative stress and inflammation, Ca2+ homeostasis disturbances in mitochondria are also identified as the relative mechanisms. ER is involved in various critical functions of the cell such as Protein synthesis, protein folding, calcium homeostasis, and lipid peroxidation but, DEHP exposure leads to augmentation of misfolded/unfolded protein. This review complies with various recently reported DEHP-induced toxicity studies and some pharmacological interventions that have been shown to be effective through ER stress pathway. DEHP exposure does assess health risks and vulnerability to populations across the globe. This study offers possible targets and approaches for addressing various DEHP-induced toxicity.

Environmental toxicants and nephrotoxicity: Implications on mechanisms and therapeutic strategies.

Kidneys are one of the most important organs in the human body. In addition to filtering 200 liters of fluid every 24 hours, the kidney also regulates acid-base balance, maintains electrolyte balance, and removes waste and toxicants from the body. Nephrotoxicity is the term used to describe the deterioration of kidney function caused by the harmful effects of medications and various types of environmental toxicants. Exposure to environmental toxicants is an inevitable side effect in the world's increasing industrialization and even more prevalent in underdeveloped nations. Growing data over the past few years has illuminated the probable connection between environmental toxicants and nephrotoxicity. Phthalates, microplastics, acrylamide and bisphenol A are environmental toxicants of particular concern, which are known to have nephrotoxic effects. Such toxicants may accumulate in the kidneys of humans after being consumed, inhaled, or come into contact with the skin. They can enter cells through endocytosis and accumulate in the cytoplasm. Small-sized nephrotoxicants can cause a variety of ailments including inflammation with increased production of pro-inflammatory cytokines, oxidative stress, mitochondrial dysfunction, autophagy, and apoptosis. This study uncovers the potential for new insights concerning the relationship between various environmental toxicants and kidney health. The objectives of this review is to establish information gaps, assess and identify the toxicity mechanisms of different nephrotoxicants, identify innovative pharmacological therapies that demonstrate promising therapeutic benefits/ relevance, and discuss the predictions for the future based on the analysis of the literature.

Metabolism configures immune response across multi-systems: Lessons from COVID-19.

Several studies over the last decade demonstrate the recruitment of immune cells, increased inflammatory cytokines, and chemokine in patients with metabolic diseases, including heart failure, parenchymal inflammation, obesity, tuberculosis, and diabetes mellitus. Metabolic rewiring of immune cells is associated with the severity and prevalence of these diseases. The risk of developing COVID-19/SARS-CoV-2 infection increases in patients with metabolic dysfunction (heart failure, diabetes mellitus, and obesity). Several etiologies, including fatigue, dyspnea, and dizziness, persist even months after COVID-19 infection, commonly known as Post-Acute Sequelae of CoV-2 (PASC) or long COVID. A chronic inflammatory state and metabolic dysfunction are the factors that contribute to long COVID. Here, this study explores the potential link between pathogenic metabolic and immune alterations across different organ systems that could underlie COVID-19 and PASC. These interactions could be utilized for targeted future therapeutic approaches.

Natural activators of AMPK signaling: potential role in the management of type-2 diabetes.

Adenosine 5'-monophosphate-activated protein kinase (AMPK) is an evolutionarily conserved serine/threonine kinase involved in the homeostasis of cellular energy. AMPK has developed as an appealing clinical target for the diagnosis of multiple metabolic diseases such as diabetes mellitus, obesity, inflammation, and cancer. Genetic and pharmacological studies indicate that AMPK is needed in response to glucose deficiency, dietary restriction, and increased physical activity for preserving glucose homeostasis. After activation, AMPK influences metabolic mechanisms contributing to enhanced ATP production, thus growing processes that absorb ATP simultaneously. In this review, several natural products have been discussed which enhance the sensitivity of AMPK and alleviate sub complications or different pathways by which such AMPK triggers can be addressed. AMPK Natural products as potential AMPK activators can be developed as alternate pharmacological intervention to reverse metabolic disorders including type 2 diabetes.

Neuroprotective Efficacy of Edaravone against Arsenic-Induced Behavioral and Neurochemical Deficits in Rats: Amelioration of Cholinergic and Mitochondrial Functions.

BACKGROUND: A substantial amount of evidence indicates that long-term arsenic exposure leads to various types of pathological complications, especially cognitive dysfunction. OBJECTIVE: The present study was designed to assess the neuroprotective potential of edaravone (a potent free radical scavenger) against arsenic-induced neurotoxicity in Wistar rats. METHODS: Adult male Wistar rats were randomly divided into five groups. Arsenic (20 mg/kg/day; p.o.) and Edaravone (5 and 10 mg/kg/day; i.p.) were administered in different experimental groups for 28 days. RESULTS: The results of various behavioral test paradigms revealed that arsenic caused significant learning and memory deficits, along with anxiety-like behavior. In biochemical analysis, we found marked elevations of oxidative-nitrosative stress (indicated by augmentation of lipid peroxidation and nitrite) and a reduction of glutathione levels in the hippocampus and frontal cortex region of arsenictreated rats. Moreover, arsenic administration caused mitochondrial complexes impairment and reduction of acetylcholinesterase level. On the other hand, chronic treatment with edaravone (10 mg/kg) significantly ameliorated the arsenic-induced behavioral deficits and neurochemical anomalies. CONCLUSION: This study suggests that edaravone confers neuroprotection against arsenic-induced memory impairment and anxiety-like behavior, which may be attributed to the inhibition of oxidativenitrosative stress and amelioration of cholinergic and mitochondrial functions.

Targeting endoplasmic reticulum stress using natural products in neurological disorders.

The primary aim of this review is to summarize the literature on natural products that are effective in the treatment of various neurological disorders by targeting endoplasmic reticulum stress (ERS). Various electronic databases such as SCOPUS, PubMed, Web of Science, and Google Scholar were searched for relevant publications. ERS has been implicated in the pathogenesis of numerous neurological disorders such as cerebral ischemia, Parkinson's disease, and Alzheimer's disease. Several natural products targeting ERS signalling pathways provide therapeutic options for neurological diseases, and in this review, the potential neuroprotective properties of these products are discussed.

Binge alcohol consumption exacerbates high-fat diet-induced neurobehavioral anomalies: Possible underlying mechanisms.

The current study aimed to validate the mice model of alcohol (ALC), high-fat diet (HFD), and HFD + ALC combination affecting neurobehavioral and neurochemical anomalies via inflammatory cascade, lowered neurogenesis, enhanced microgliosis, reactive astrogliosis, activated IDO-1 (indoleamine 2,3-dioxygenase), and reduce CHAT (choline acetyltransferase) signaling in the hippocampus (HIP). The adult male Swiss albino mice were provided with ALC (3-15%) and in-house prepared HFD for continuous 12 weeks. The HFD and HFD + ALC consumption impacted the liver and mediated HIP damage. The liver biomarkers (AST, ALT, γ-GT, TG, HDL-C, and LDL-C), oxidative stress, and proinflammatory cytokines (IL-1ß and TNF-α) level were found significantly higher in the liver and HIP tissue of HFD + ALC. Furthermore, the neurobehavioral deficits that include cognitive dysfunction, depressive, and, anxiety-like behavior were found severely affected in HFD + ALC consumed mice. The overactivated HPA axis, intense oxidative insults, and increased AChE activity were seen in the HIP of HFD + ALC grouped mice. The gene and protein expression also confirmed disrupted NF-κB-mediated inflammatory and Nrf2-regulated antioxidant balance and dysregulated TrκB/BDNF signaling. Hence, our new findings explain the insight mechanism of chronic alcoholism in exacerbating the deleterious effect of chronic high-fat diet consumption on the HIP.

Potential role of nicotinamide analogues against SARS-COV-2 target proteins.

BACKGROUND AND OBJECTIVE: Coronavirus 2019 (COVID-19) is caused by 'severe acute respiratory syndrome coronavirus 2' (SARS-CoV-2), first reported in Wuhan, China in December 2019, which eventually became a global disaster. Various key mediators have been reported in the pathogenesis of COVID-19. However, no effective pharmacological intervention has been available to combat COVID-19 complications. The present study screens nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) as potential inhibitors of this present generation coronavirus infection using an in-silico approach. MATERIALS AND METHODS: The SARS-CoV-2 proteins (nucleocapsid, proteases, post-fusion core, phosphatase, endoriboruclease) and ACE-2 protein were selected. The 2D structure of nicotinamide ribonucleoside and nicotinamide ribonucleotide was drawn using ChemDraw 14.0 and saved in .cdx format. The results were analyzed using two parameters: full fitness energy and binding free energy (ΔG). RESULTS: The full fitness energy and estimated ΔG values from docking of NM, and NMN with selected SARS-CoV-2 target proteins, ADMET prediction and Target prediction indicate the interaction of NR and NMN in the treatment of COVID-19. CONCLUSIONS: Based on full fitness energy and estimated ΔG values from docking studies of NM and NAM with selected SARS-CoV-2 target proteins, ADME prediction, target prediction and toxicity prediction, we expect a possible therapeutic efficacy of NR in the treatment of COVID-19.

Mangiferin ameliorates intracerebroventricular-quinolinic acid-induced cognitive deficits, oxidative stress, and neuroinflammation in Wistar rats.

INTRODUCTION: Mangiferin (MGF), a xanthonoid polyphenol, confers neuroprotection via combating oxidative stress and inflammation. The current investigation aimed to assess the neuroprotective potential of MGF on behavioral and neurochemical anomalies evoked by administration of quinolinic acid (QA) through intrastriatal injection in male Wistar rats and to reveal the associated mechanisms. MATERIALS AND METHODS: QA (300 nm/4 µl saline) was administered intracerebroventricular in the striatum (unilaterally) once. Thereafter, MGF 20 and 40 mg/kg (peroral) was administered to the animals for 21 days. RESULTS: QA administration caused marked alteration in motor activity (rotatod), footprint analysis, and cognitive function (Morris water maze test, and novel object recognition test). Furthermore, oxido-nitrosative stress (increased nitrite content, lipid peroxidation, with reduction of GSH), cholinergic dysfunction, and mitochondrial complex (I, II, and IV) dysfunction were observed in hippocampus and striatal region of QA-treated rats in comparison to normal control. Pro inflammatory mediators (tumor necrosis factor-alpha TNF-α and interleukin-1ß) were noted to increase in the hippocampus and striatum of QA-treated rats. In addition, we observed BDNF depletion in both the hippocampus and striatum of QA-treated animals. MGF treatment significantly ameliorated memory and motor deficits in QA-administered rats. Moreover, MGF treatment (40 mg/kg) restored the GSH level and reduced the MDA, nitrite level, and pro-inflammatory cytokines in striatum and hippocampus. Furthermore, QA-induced cholinergic dysfunction (AChE), BDNF depletion and mitochondrial impairment were found to be ameliorated by MGF treatment. CONCLUSION: The results suggest that MGF offers the neuroprotective potential that may be a promising pharmacological approach to ameliorate cognitive deficits associated with neurodegeneration.

7,8-Dihydroxyflavone alleviated the high-fat diet and alcohol-induced memory impairment: behavioral, biochemical and molecular evidence.

RATIONALE: Alcoholism and obesity impart a deleterious impact on human health and affects the quality of life. Chronic consumption of alcohol and western diet has been reported to cause memory deficits. 7,8-dihydroxyflavone (7,8-DHF), a TrkB agonist, comprises antioxidant and anti-inflammatory properties in treating various neurological disorders. OBJECTIVES: The current study was aimed to determine the protective effect and molecular mechanism of 7,8-DHF against alcohol and high-fat diet (HFD)-induced memory deficits in rats. METHODS: The adult male Wistar rats were given alcohol (3-15%) and HFD ad libitum for 12 weeks in different experimental groups. 7,8-DHF (5 mg/kg) was intraperitoneally injected daily for the last 4 weeks (9th-12th week). RESULTS: The alcohol and HFD administration caused cognitive impairment as evaluated through the Morris water maze (MWM) test in alcohol, HFD, and alcohol + HFD-fed animals. The last 4-week treatment of 7,8-DHF (5 mg/kg; i.p.) attenuated alcohol and HFD-induced memory loss. 7,8-DHF treatment also restored the glutathione (GSH) level along with attenuation of nitrite, malondialdehyde content (markers of oxidative and nitrosative stress), and reduction of the acetylcholinesterase activity in the hippocampus of alcohol and HFD-fed animals. Furthermore, the administration of 7,8-DHF caused downregulation of NF-κB, iNOS, and caspase-3 and upregulation of Nrf2, HO-1, and BDNF mRNA level in rat hippocampus. CONCLUSION: 7,8-DHF administration conferred beneficial effects against alcohol and HFD-induced memory deficit via its unique antioxidant, anti-inflammatory, anti-apoptotic potential, along with the activation of TrkB/BDNF signaling pathway in the hippocampus.

Amelioration of Repeated Restraint Stress-Induced Behavioral Deficits and Hippocampal Anomalies with Taurine Treatment in Mice.

Taurine, an essential neutraceutical, has been reported to exhibit antioxidant and anti-inflammatory properties. Substantial evidence indicates that prolonged stress is one of the leading causes of psychological and physiological anomalies. Restraint stress (RS) rat model is the most widely used experimental model for the induction of chronic psycho-emotional stress. In the present study, Swiss albino male mice were restrained for 6 h/day for 28 consecutive days. Animals were divided into four groups: control, RS, RS + taurine, and taurine control group. Taurine, a potent antioxidant, was administered (200 mg/kg) orally along with RS for 28 days. The taurine intervention significantly restored the RS-induced neurobehavioral alterations evident by the elevated plus-maze, Morris water maze test, forced swim test, tail suspension test, and a sucrose preference test. Moreover, taurine significantly prevented hippocampal oxidative stress (lipid peroxidation, reduced glutathione, and nitrite) and other neurochemical (acetylcholinesterase, and IL-1ß) anomalies. Using western blotting analyses, we demonstrate that taurine treatment significantly ameliorated the alterations in Brain-derived neurotrophic factor, caspase-3, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) level in the hippocampus. Thus, Taurine effectively inhibited RS-induced oxidative stress, neuroinflammation, and apoptosis via a mechanism involving the inhibition of the NF-κB signaling pathway. In summary, our study is the first to demonstrate that NF-κB and caspase-3 inhibition, as well as BDNF augmentation, was involved in neuroprotective potential of taurine against RS-induced behavioural anomalies.

Hepatoprotective potential of 7,8-Dihydroxyflavone against alcohol and high-fat diet induced liver toxicity via attenuation of oxido-nitrosative stress and NF-κB activation.

BACKGROUND: Fatty liver diseases are the most common and major health concern arises from the modern lifestyle and alcohol (ethanol) abuse. The prevalence of non-alcoholic fatty liver diseases (NAFLD) has been observed prominently in obese and diabetic individuals, while alcoholic liver disease is common in alcoholic persons. Fatty liver disease, such as steatohepatitis, leads to fibrosis, cirrhosis and eventually hepatocellular carcinoma. The present study was designed to investigate the effect of 7,8-Dihydroxyflavone (7,8-DHF) against high-fat diet (HFD) and ethanol (EtOH)-induced hepatotoxicity in rats. METHODS: Male Wistar rats (150-200 g) were fed HFD (58% calories from fat) and EtOH (3-15% in drinking water) for 12 weeks. 7,8-DHF was administered intraperitoneally at the dose of 5 mg/kg/day for the last four weeks. After 12 weeks, biochemical, ELISA, RT-PCR, and histological studies have been carried out. RESULTS: Biochemical analyses revealed the involvement of oxidative stress and inflammation in the liver of HFD and EtOH-fed rats. 7,8-DHF treatment significantly reduced HFD and EtOH-induced oxidative stress as evidenced by the reduction of lipid peroxidation and augmentation of reduced glutathione level. Moreover, IL-1ß level was found significantly reduced in 7,8-DHF treated EtOH, HFD and EtOH+HFD groups. The semi-quantitative RT-PCR results indicated down-regulation of Nrf-2 and HO-1 and up-regulation of NF-κB and iNOS mRNA expression level in the liver of HFD and EtOH-fed rats, which was ameliorated by 7,8-DHF treatment. CONCLUSION: The present study suggested that 7,8-DHF could be an effective pharmacological intervention in combating HFD and EtOH-induced hepatotoxicity.

Ameliorative effect of fisetin against lipopolysaccharide and restraint stress-induced behavioral deficits via modulation of NF-κB and IDO-1.

BACKGROUND: Fisetin, a plant active polyphenol, is well known for its antioxidant and free radical scavenging activities. The present study was designed to explore the detailed molecular mechanism underlying its neuroprotective effects. METHODS: The young male mice were either administered a single dose of lipopolysaccharide (0.83 mg/kg) or subjected to restraint stress (6 h per day for 28 days) to induce behavioral deficits in different groups. Fisetin (15 mg/kg) was orally administered for the last 14 days of the study. RESULTS: Lipopolysaccharide (LPS) as well as restraint stress (RS) exposure caused behavioral alterations (anxiety and depressive-like behavior). Gene expression analysis showed upregulation of nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) and indoleamine 2,3-dioxygenase (IDO)-1 gene expression along with downregulation of Nrf-2 (nuclear factor erythroid 2-related factor 2), HO-1 (heme oxygenase-1), and ChAT (choline acetyltransferase) gene expression level in RS and RS+LPS groups. Fisetin administration significantly ameliorated behavioral and neurochemical deficits in LPS, RS, and RS+LPS groups. CONCLUSION: These findings clearly indicated that fisetin administration improved behavioral functions and suppressed the NF-κB and IDO-1 (indoleamine 2,3-dioxygenase) activation along with their antioxidant effect, suggesting fisetin as an intriguing nutraceutical for the management of inflammation-associated neurological disorders.

Voluntary alcohol consumption exacerbated high fat diet-induced cognitive deficits by NF-κB-calpain dependent apoptotic cell death in rat hippocampus: Ameliorative effect of melatonin.

Modern sedentary lifestyle with altered dietary habits imposes the risk of human health towards several metabolic disorders such as obesity. The metabolic insults negatively affect the mental health status and quality life of affected individuals. Melatonin is a potent antioxidant with anti-inflammatory and neuroprotective properties. The aim of the present study was to investigate the protective effect of melatonin on the cognitive and neurochemical deficits induced by the high-fat diet (HFD) and alcohol (ALC) alone or in combination (HFD + ALC) in rats. Male Wistar rats were given ALC (3-15% i.e. increased gradually) and HFD for 12 weeks in different experimental groups. After 12 weeks, we found that simultaneous consumption of HFD and ALC exacerbates cognitive dysfunction and neurochemical anomalies. However, melatonin (10 mg/kg/day, i.p.) treatment for four weeks significantly prevented memory deficits, oxidative stress and neuroinflammation in HFD, ALC and HFD + ALC groups. RT-PCR analysis showed down-regulation of nuclear factor erythroid 2-related factor 2 (Nrf-2) and heme oxygenase-1 (HO-1) in ALC and HFD + ALC groups. Moreover, caspase-3 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) mRNA expression level were found up-regulated in hippocampus of HFD, ALC and HFD + ALC groups. However, calpain expression was found up-regulated only in the hippocampus of HFD + ALC group. Chronic treatment with melatonin significantly restored the aberrant gene expression level in HFD, ALC and HFD + ALC group. In conclusion, our findings indicated that melatonin can mitigate the HFD and ALC-induced cognitive deficits via attenuation of oxidative stress and calpain-1 dependent as well as independent caspase-3 mediated neuronal cell death.

Cognitive deficits induced by combined exposure of stress and alcohol mediated through oxidative stress-PARP pathway in the hippocampus.

Several studies reported that stress can enhance the consumption of alcohol in humans and animals. However, the combinatorial effect of stress and alcohol on cognitive function and neurochemical alterations is quite understudied. In the present study, we have elucidated the involvement of oxidative stress-PARP cascade in alcohol and restraint stress (RS)-exposed animals using a PARP inhibitor, 1,5-isoquinolinediol (3mg/kg for 14days). Male Swiss albino mice were given alcohol (ALC) or RS (2h per day) or both in ALC+RS group for 28days. Behavioral analysis revealed cognitive dysfunction in ALC+RS group. Furthermore, oxidative stress and raised level of pro-inflammatory cytokines were found in the hippocampus region of ALC+RS group. Semi-quantitative reverse transcriptase PCR showed overactivation of PARP-1 gene in ALC+RS group. 1,5-isoquinolinediol treatment significantly prevented cognitive deficits and aforementioned neurochemical alterations. Overall, our findings showed that ALC+RS exerted deleterious effects on the hippocampus which involves oxidative stress-PARP overactivation cascade.

Alcohol aggravates stress-induced cognitive deficits and hippocampal neurotoxicity: Protective effect of melatonin.

Stressful events and alcohol abuse are the cumbersome situations which can synergistically predispose the negative effects on the brain. Oxidative stress generated by chronic immobilization and alcohol consumption cause severe neurotoxicity in the hippocampus region that ultimately leads to cognitive dysfunction. In the current study, we have investigated the involvement of NF-κB/Nrf/HO-1 transduction pathway in stress and alcohol exposed animals. Male Swiss albino mice were given alcohol (ALC) (15% v/v) or restraint stress (RS) or both (RS for 6h per day) up to 28days. We found increased ALC consumption in the ALC+RS group as compared to the ALC group. Morris water maze (MWM) test and novel object recognition test (NORT) revealed the spatial and recognition memory impairment in RS and ALC+RS group. ALC+RS group showed more profound oxidative stress and augmentation of pro-inflammatory cytokine (IL-1ß) as compared to RS or ALC group alone. Melatonin (20mg/kg, p.o) treatment for 14days significantly prevented the raised oxidative stress, release of IL-1ß, GSH depletion and augmentation of AChE activity in the hippocampus. Moreover, semi-quantitative reverse transcriptase PCR results showed that combined exposure of ALC and RS leads to over-activation of NF-κB transduction inflammatory pathway and down-regulation of the Nrf2/HO-1 axis which was significantly ameliorated by the melatonin treatment. In conclusion, our results indicated that ALC+RS exerted the deleterious effects on the hippocampus which were alleviated by the melatonin treatment.

Sodium Phenylbutyrate and Edaravone Abrogate Chronic Restraint Stress-Induced Behavioral Deficits: Implication of Oxido-Nitrosative, Endoplasmic Reticulum Stress Cascade, and Neuroinflammation.

Chronic stress exposure can produce deleterious effects on the hippocampus (HC) which eventually leads to cognitive impairment and depression. Endoplasmic reticulum (ER) stress has been reported as one of the major culprits in the development of stress-induced cognitive impairment and depression. We investigated the neuroprotective efficacy of sodium phenylbutyrate (SPB), an ER stress inhibitor, and edaravone, a free radical scavenger, against chronic restraint stress (CRS)-induced cognitive deficits and anxiety- and depressive-like behavior in mice. Adult male Swiss albino mice were restrained for 6 h/day for 28 days and injected (i.p.) with SPB (40 and 120 mg/kg) or edaravone (3 and 10 mg/kg) for the last seven days. After stress cessation, the anxiety- and depressive-like behavior along with spatial learning and memory were examined. Furthermore, oxido-nitrosative stress, proinflammatory cytokines, and gene expression level of ER stress-related genes were assessed in HC and prefrontal cortex (PFC). CRS-exposed mice showed anxiety- and depressive-like behavior, which was significantly improved by SPB and edaravone treatment. In addition, SPB and edaravone treatment significantly alleviated CRS-induced spatial learning and memory impairment. Furthermore, CRS-evoked oxido-nitrosative stress, neuroinflammation, and depletion of Brain-derived neurotrophic factor were significantly ameliorated by SPB and edaravone treatment. We found significant up-regulation of ER stress-related genes in both HC and PFC regions, which were suppressed by SPB and edaravone treatment in CRS mice. Our study provides evidence that SPB and edaravone exerted neuroprotective effects on CRS-induced cognitive deficits and anxiety- and depressive-like behavior, which is possibly coupled with inhibition of oxido-nitrosative stress, neuroinflammation, and ER stress cascade.

Epigenetic Modifications, Alcoholic Brain and Potential Drug Targets.

Acute and chronic alcohol exposure evidently influences epigenetic changes, both transiently and permanently, and these changes in turn influence a variety of cells and organ systems throughout the body. Many of the alcohol-induced epigenetic modifications can contribute to cellular adaptations that ultimately lead to behavioral tolerance and alcohol dependence. The persistence of behavioral changes demonstrates that long-lasting changes in gene expression, within particular regions of the brain, may contribute importantly to the addiction phenotype. The research activities over the past years have demonstrated a crucial role of epigenetic mechanisms in causing long lasting and transient changes in the expression of several genes in diverse tissues, including brain. This has stimulated recent research work that is aimed at characterizing the influence of epigenetic regulatory events in mediating the long lasting and transient effects of alcohol abuse on the brain in humans and animal models of alcohol addiction. In this study, we update our current understanding of the impact of alcohol exposure on epigenetic mechanisms in the brain and refurbish the knowledge of epigenetics in the direction of new drugs development.

Edaravone alleviates cisplatin-induced neurobehavioral deficits via modulation of oxidative stress and inflammatory mediators in the rat hippocampus.

Cisplatin is a chemotherapeutic agent used in the treatment of malignant tumors. A major clinical limitation of cisplatin is its potential toxic effects, including neurotoxicity. Edaravone, a potent free radical scavenger, has been reported to have the neuroprotective effect against neurological deficits. The aim of the present study was to determine the neuroprotective effect of edaravone against cisplatin-induced behavioral and biochemical anomalies in male Wistar rats. Our results showed that cisplatin (5mg/kg/week, i.p.) administration for seven weeks caused marked cognitive deficits and motor incoordination in rats. This was accompanied by oxido-nitrosative stress, neuroinflammation, NF-κB activation and down-regulation of Nrf2/HO-1 gene expression level in the hippocampus. Edaravone (10mg/kg/week, i.p.) treatment for seven weeks inhibited the aforementioned neurobehavioral and neurochemical deficits. Furthermore, edaravone was found to up-regulate the gene expression level of Nrf2/HO-1 and prevented the cisplatin-induced NF-κB activation. These findings demonstrated that oxido-nitrosative stress and inflammatory signaling mediators play a key role in the development of cisplatin-induced neurobehavioral deficits which were prevented by edaravone treatment.

Naringin and Sertraline Ameliorate Doxorubicin-Induced Behavioral Deficits Through Modulation of Serotonin Level and Mitochondrial Complexes Protection Pathway in Rat Hippocampus.

The present study was designed to investigate the neuroprotective effect of naringin (NR) alone as well as its combination with sertraline (SRT) against doxorubicin (DOX)-induced neurobehavioral and neurochemical anomalies. DOX (15 mg/kg; i.p.) administration caused behavioral alterations, oxidative stress, neuroinflammation, mitochondrial dysfunction and monoamines alteration in male Wistar rats. NR (50 and 100 mg/kg; i.p.) and SRT (5 mg/kg; i.p.) treatment significantly attenuated DOX-induced anxiety and depressive-like behavior as evident from elevated plus maze (EPM) and modified forced swimming test (mFST), respectively. NR treatment significantly attenuated DOX-induced raised plasma corticosterone (CORT), tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1ß) levels in the hippocampus (HC). Furthermore, we found that combination of NR and SRT regimen ameliorated DOX-induced behavioral anomalies through modulation of the 5-HT level and mitochondrial complexes protection pathway along with alleviation of oxidative stress in the HC region. Therefore, NR treatment alone or in combination with SRT could be beneficial against DOX-induced neurotoxicity.