ABSTRACT
Chemotherapy-induced cognitive impairment (CICI) is one of the major adverse effects of antineoplastic drugs, which decrease the quality of life in cancer survivors. Extensive experimental and clinical research suggests that chemotherapeutic drugs generate an enormous amount of reactive oxygen species (ROS), contributing to oxidative stress, neuroinflammation, blood-brain barrier (BBB) disruption, and neuronal death, eventually leading to CICI. Despite the progress in exploring different pathological mechanisms of CICI, effective treatment to prevent CICI progression has not been developed yet. Nrf2 is the principal transcription factor that regulates cellular redox balance and inflammation-related gene expression. Emerging evidence suggests that upregulation of Nrf2 and its target genes could suppress oxidative stress, and neuroinflammation, restore BBB integrity, and increase neurogenesis. This review discusses the role of Nrf2 in CICI, how it responds to oxidative stress, inflammation, neurotoxicity, and potential Nrf2 activators that could be used to enhance Nrf2 activation in CICI.
Subject(s)
Chemotherapy-Related Cognitive Impairment , NF-E2-Related Factor 2 , Humans , NF-E2-Related Factor 2/metabolism , Neuroinflammatory Diseases , Quality of Life , Oxidative Stress , Signal TransductionABSTRACT
Alcohol is one of the most widely used substances. Alcohol use accounts for 5.1% of the global disease burden, contributes substantially to societal and economic costs, and leads to approximately 3 million global deaths yearly. Alcohol use disorder (AUD) includes various drinking behavior patterns that lead to short-term or long-lasting effects on health. Ethanol, the main psychoactive molecule acting in alcoholic beverages, directly impacts the GABAergic system, contributing to GABAergic dysregulations that vary depending on the intensity and duration of alcohol consumption. A small number of interventions have been developed that target the GABAergic system, but there are promising future therapeutic avenues to explore. This review provides an overview of the impact of alcohol on the GABAergic system, the current interventions available for AUD that target the GABAergic system, and the novel interventions being explored that in the future could be included among first-line therapies for the treatment of AUD.
Subject(s)
Alcoholism , Humans , Alcoholism/drug therapy , Alcohol Drinking , Ethanol/therapeutic useABSTRACT
Chemotherapy-induced cognitive impairment (CICI) is a common complication associated with the use of chemotherapeutics. Doxorubicin (DOX) is a reactive oxygen species (ROS) producing anticancer agent capable of causing potential neurotoxic effects via cytokine-induced oxidative and nitrosative damage to brain tissues. On the other hand, alpha-lipoic acid (ALA), a nutritional supplement, is reputable for its excellent antioxidant, anti-inflammatory, and anti-apoptotic activities. Consequently, the objective of the current investigation was to examine any potential neuroprotective and memory-improving benefits of ALA against DOX-induced behavioral and neurological anomalies. DOX (2 mg/kg/week, i.p.) was administrated for 4 weeks to Sprague-Dawley rats. ALA (50, 100, and 200 mg/kg) was administered for 4 weeks. The Morris water maze (MWM) and novel objective recognition task (NORT) tests were used to assess memory function. Biochemical assays with UV-visible spectrophotometry were used to analyze oxidative stress markers [malondialdehyde (MDA), protein carbonylation (PCO)], endogenous antioxidants [reduced glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px)] and acetylcholinesterase (AChE) activity in hippocampal tissue. Inflammatory markers [tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and nuclear factor kappa B (NF-κB)], nuclear factor erythroid 2-related factor-2 (NRF-2) and hemeoxygenase-1 (HO-1) levels were estimated using enzyme-linked immunosorbent assay (ELISA). In addition, reactive oxygen species (ROS) levels were measured in hippocampus tissue using 2-7-dichlorofluorescein-diacetate (DCFH-DA) assay with fluorimetry. ALA treatment significantly protected against DOX-induced memory impairment. Furthermore, ALA restored hippocampal antioxidants, halted DOX-induced oxidative and inflammatory insults via upregulation of NRF-2/HO-1 levels, and alleviated the increase in NF-κB expression. These results indicate that ALA offers neuroprotection against DOX-induced cognitive impairment, which could be attributed to its antioxidant potential via the NRF-2/HO-1 signaling pathway.
Subject(s)
Cognitive Dysfunction , Thioctic Acid , Animals , Rats , Acetylcholinesterase/metabolism , Antioxidants , Cognitive Dysfunction/chemically induced , Cognitive Dysfunction/drug therapy , Cognitive Dysfunction/prevention & control , Doxorubicin/toxicity , Hippocampus/metabolism , Neuroinflammatory Diseases , NF-kappa B/metabolism , Oxidative Stress , Rats, Sprague-Dawley , Reactive Oxygen Species/metabolism , Signal TransductionABSTRACT
The gut barrier - including tight junction proteins (TJPs) and mucus layers, is the first line of defense against physical, chemical or pathogenic incursions. This barrier is compromised in various health disorders. Capsaicin, a dietary agonist of Transient receptor potential vanilloid 1 (TRPV1) channel, is reported to alleviate the complications of obesity. While it is well known to improve energy expenditure and metabolism, and prevent dysbiosis, the more local effects on the host gut - particularly the gut barrier and mucus system remain elusive. To investigate the effect of capsaicin on the gut barrier and mucus production and to understand the involvement of mucus, bacteria, and TRPV1 in these phenomena, we employed a diet-induced obesity model in C57BL/6 mice, and capsaicin (2 mg/kg/day p.o.) or mucin (1 g/kg/day p.o.) as interventions, for 12 weeks. Parameters like weight gain, glucose homeostasis, TJPs expression, mucus staining, intestinal permeability etc were studied. 16 S rDNA sequencing and in vitro Ca2+ measurement experiments were performed to explore the role of microbiota in the beneficial effects. Mucin feeding reflected several anti-obesity effects produced by capsaicin, suggesting that mucus modulation might play a crucial role in capsaicin-induced anti-obesity effects. 16 S rDNA sequencing and in vitro Ca2+ measurement experiments pointed to TRPV1 modulation by bacteria besides capsaicin. Capsaicin, bacteria and the host mucus system seem to act in a cyclic cascade involving TRPV1, which can be activated by capsaicin and various bacteria. These findings provide new insight into the role of TRPV1 in maintaining a healthy gut environment.
Subject(s)
Capsaicin , Microbiota , Mucins , Obesity , TRPV Cation Channels/agonists , Animals , Capsaicin/metabolism , Capsaicin/pharmacology , Diet, High-Fat/adverse effects , Disease Models, Animal , Intestinal Mucosa/drug effects , Intestinal Mucosa/metabolism , Membrane Glycoproteins/metabolism , Mice , Microbiota/drug effects , Microbiota/physiology , Mucins/metabolism , Mucins/pharmacology , Obesity/drug therapy , Obesity/metabolism , Sensory System Agents/pharmacology , TRPV Cation Channels/metabolism , Tight Junction Proteins/metabolismABSTRACT
The nuclear factor erythroid 2-related factor (Nrf2) signaling pathway has recently emerged as a novel therapeutic target in treating various diseases. Therefore, the present study aimed to assess the protective role of the Nrf2 activator, dimethyl fumarate (DMF) in the complete Freund's adjuvant (CFA)- induced arthritis model. DMF (25, 50, and 100 mg/kg) and dexamethasone (2 mg/kg) were orally administered for 14 days. Pain-related tests, paw volume, and arthritic scores were measured weekly. Serum TNF-α, IL-1ß, cyclic citrullinated peptide (CCP), C-reactive protein (CRP), and rheumatoid factor (RF) levels were estimated. Nitrite, malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione (GSH), catalase (CAT), and myeloperoxidase (MPO) levels were also evaluated. NF-κB, Nrf2, HO-1, and COX-2 levels were estimated in the joint tissue. DMF treatment exerted anti-arthritic activity by enhancing the nociceptive threshold, improving arthritis scores, and reducing paw edema. Also, DMF suppressed changes in oxidative stress markers and inflammatory mediators and enhanced Nrf2 and HO-1 levels in CFA-injected rats. These findings indicate that the anti-arthritic activity of DMF may be mediated by the activation of the Nrf2/HO-1 pathway, which reduced oxidative damage and inflammation.
Subject(s)
Antirheumatic Agents/pharmacology , Arthritis, Experimental/prevention & control , Dimethyl Fumarate/pharmacology , Heme Oxygenase (Decyclizing)/metabolism , Joints/drug effects , NF-E2-Related Factor 2/metabolism , Analgesics/pharmacology , Animals , Anti-Inflammatory Agents/pharmacology , Antioxidants/pharmacology , Arthritis, Experimental/chemically induced , Arthritis, Experimental/enzymology , Arthritis, Experimental/pathology , Cytokines/metabolism , Female , Freund's Adjuvant , Inflammation Mediators/metabolism , Joints/enzymology , Joints/pathology , Oxidative Stress/drug effects , Pain Threshold/drug effects , Rats, Wistar , Signal TransductionABSTRACT
The night shift paradigm induces a state of chronic partial sleep deprivation (CPSD) and enhances the vulnerability to neuronal dysfunction. However, the specific neuronal impact of CPSD has not been thoroughly explored to date. In the current study, the night shift condition was mimicked in female Swiss albino mice. The classical sleep deprivation model, i.e., Modified Multiple Platform (MMP) method, was used for 8 h/day from Monday to Friday with Saturday and Sunday as a weekend off for nine weeks. Following nine weeks of night shift schedule, their neurobehavioral profile and physiological parameters were assessed along with the activity of the mitochondrial complexes, oxidative stress, serotonin levels, and inflammatory markers in the brain. Mice showed an overall hyperactive behavioral profile including hyperlocomotion, aggression, and stereotyped behavior accompanied by decreased activity of mitochondrial enzymes and serotonin levels, increased oxidative stress and inflammatory markers in whole brain homogenates. Collectively, the study points towards the occurrence of a hyperactive behavioral profile akin to mania and psychosis as a potential consequence of CPSD.
Subject(s)
Sleep Deprivation/psychology , Sleep Disorders, Circadian Rhythm/psychology , Aggression , Animals , Anxiety/etiology , Anxiety/psychology , Brain Chemistry , Chronic Disease , Depression/etiology , Depression/psychology , Female , Hyperkinesis/etiology , Hyperkinesis/psychology , Inflammation Mediators/metabolism , Mice , Mitochondria/metabolism , Motor Activity , Oxidative Stress , Serotonin/metabolism , Stereotyped BehaviorABSTRACT
Growing experimental evidences have suggested the reciprocal correlation between sleep deprivation and pain. Inflammation and oxidative stress are among the key pathways underlying this correlation. Therefore, the present study was aimed to assess the effect of antioxidant and anti-inflammatory compound naringenin (NGN) against chronic sleep deprivation (CSD)-induced mechanical and thermal hyperalgesia in female Swiss albino mice. In this study, mice were chronically sleep-deprived for 8 h a day for five days a week with the weekend as a free sleep period and continued for nine weeks using a modified multiple platform method. The pain behavioral tests were conducted at the end of the fourth week to assess the development of hyperalgesia followed by the administration of NGN and a combination of NGN with Sirtinol (SIR, a sirtuin1 inhibitor) till the end of the study. After nine weeks, pain behavioral tests, along with oxidative stress and inflammatory parameters in cortex and striatum, were assessed. Results indicated that CSD-induced hyperalgesia in mice accompanied by increased oxidative stress and inflammatory markers in cortex and striatum of the brain. NGN combatted the hyperalgesic response and also decreased levels of oxidative stress and inflammatory markers. Furthermore, the pharmacological effect of NGN was mitigated with SIR. Thus, the findings of the present study reveal that NGN is acting via sirtuin1 to exert its antinociceptive activity against CSD-induced hyperalgesia.
Subject(s)
Analgesics/therapeutic use , Flavanones/therapeutic use , Hyperalgesia/drug therapy , Sirtuin 1/metabolism , Animals , Body Weight/drug effects , Female , Hyperalgesia/etiology , Hyperalgesia/metabolism , Interleukin-6/metabolism , Mice , Oxidative Stress/drug effects , Sleep Deprivation/complications , Sleep Deprivation/metabolism , Tumor Necrosis Factor-alpha/metabolismABSTRACT
AIMS: Insulin resistance (IR) has become one of the major causative factors for the pathogenesis of various metabolic and neurometabolic diseases. The sedentary lifestyle in association with the consumption of protein-deficient and high-calorie diet results in IR development. This study was aimed to evaluate the neuroprotective effects of Saroglitazar (SGZ), a dual peroxisome-proliferator activated receptor (PPAR-α/γ) in a high fat-low protein diet (HFLPD) fed mouse model of MetS and associated cognitive deficits. METHODS: Adult male C57BL/6J mice were fed with HFLPD plus 15% oral fructose solution for 16 weeks. Starting at the 13th week, SGZ (5 & 10 mg/kg; p.o.) was administered along with HFLPD for four weeks, i.e., the 12th to 16th week of the study groups. Various physiological, serum metabolic, neurobehavioral, neuroinflammatory, and oxidative stress parameters were assessed. The brain histopathology and mRNA expression of diverse genes in specific brain regions were also estimated. RESULTS: The treatment with SGZ at both doses have significantly reversed various HFLPD-induced metabolic and cognitive alterations by improving the glucose and lipid profile in the periphery in addition to the enhanced cerebral glucose homeostasis, BBB integrity, reduced oxidative stress, and neuroinflammation. Furthermore, the SGZ improved locomotion and memory retention while reducing the HFLPD-induced anxiety-like behaviors in the mice. CONCLUSIONS: SGZ treatment showed significant metabo-neuroprotective effects in mice fed with HFLPD, possibly through peripherally mediated activation of PPAR-α/γ and insulin downstream signaling in the cortex and hippocampus.
Subject(s)
Cognitive Dysfunction/drug therapy , Diet, High-Fat/adverse effects , Diet, Protein-Restricted/adverse effects , Metabolic Diseases/drug therapy , PPAR alpha/agonists , PPAR gamma/agonists , Phenylpropionates/therapeutic use , Pyrroles/therapeutic use , Animals , Cognitive Dysfunction/etiology , Cognitive Dysfunction/metabolism , Male , Metabolic Diseases/etiology , Metabolic Diseases/metabolism , Mice , Mice, Inbred C57BL , PPAR alpha/metabolism , PPAR gamma/metabolism , Phenylpropionates/pharmacology , Pyrroles/pharmacologyABSTRACT
OBJECTIVE: Methylphenidate (MPH) is a first-line treatment option for attention-deficit hyperactive disorder and narcolepsy. MPH is one of the most abused psychostimulants by the adults and young population to stay awake, perform better, or improve concentration. The scanty reports say that the medical users or abusers mostly consider the administration of benzodiazepines to overcome the adverse effects, i.e., mood- and anxiety-related problems associated with MPH chronic abuse. This work aims to study the effect of alprazolam (ALZ) on MPH-associated adverse effects on liver and kidney. MATERIALS AND METHODS: Female Wistar rats (n = 58) were administered with MPH (10, 20, and 40 mg/kg) and ALZ (5, 10, and 20 mg/kg) alone and in combination for 28 days. Bodyweight, feed intake, and water intake were monitored weekly. Parameters related to liver and renal function, oxidative stress, and histopathology were performed to evaluate the toxic impacts on the liver and kidneys. RESULTS: ALZ, along with MPH, increased the serum alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, creatinine, and urea levels. The co-abuse also led to elevated oxidative stress and structural abnormalities in the liver and kidney tissues. CONCLUSION: The co-abuse of ALZ has amplified the hepato-renal toxic effects of MPH. Therefore, it is a significant concern for public safety, and their co-abuse must be restricted and discouraged.
Subject(s)
Alprazolam/toxicity , Central Nervous System Stimulants/toxicity , Hypnotics and Sedatives/toxicity , Kidney/drug effects , Liver/drug effects , Methylphenidate/toxicity , Substance-Related Disorders/complications , Animals , Disease Models, Animal , Female , Kidney/metabolism , Kidney/pathology , Liver/metabolism , Liver/pathology , Oxidative Stress/drug effects , Rats, Wistar , Substance-Related Disorders/metabolism , Substance-Related Disorders/pathologyABSTRACT
BACKGROUND: In the previous decade, abuse of several types of prescription drugs, particularly anxiolytics, opioid analgesics, and stimulants has increased significantly worldwide. Methylphenidate (MPH) and Alprazolam (ALZ) are extensively used drugs for the treatment of attention deficit hyperactivity disorder (ADHD) and anxiety disorders, respectively. However, these drugs have a high risk of being misused or abused alone, and their combination in some peculiar cases has shown their deleterious effects. In this study, we evaluated the extent of damage both these drugs (MPH and ALZ) may cause in the brain at different dosages. METHODS: Female Wistar rats were administered with MPH (10, 20, 40mg/kg) and ALZ (5, 10, 20mg/kg) alone and in combination. Following the treatment, neurobehavioral studies were conducted, and later brain tissue was removed for studying the extent of oxidative stress and inflammation in the hippocampus and cortex region of the brain. Further histopathological parameters, along with neurotransmitter levels, were also assessed. RESULTS: Both MPH and ALZ, in combination, enhanced oxidative stress, inflammation, and neurobehavioral alterations in a dose-dependent manner. These toxic effects were associated with histopathological alterations and neurotransmitters levels CONCLUSIONS: In this study, it is found that the combination of psychostimulant (MPH) and depressant (ALZ) tends to enhance toxicity in the brain, and their long-term usage is a significant public health concern. Therefore, their co-administration should be strictly monitored by medical practitioners, and under compulsive circumstances, their use must be restricted to lower doses.
Subject(s)
Attention Deficit Disorder with Hyperactivity , Central Nervous System Stimulants , Methylphenidate , Alprazolam/therapeutic use , Animals , Central Nervous System Stimulants/therapeutic use , Central Nervous System Stimulants/toxicity , Female , Methylphenidate/toxicity , Rats , Rats, WistarABSTRACT
BACKGROUND: Astaxanthin (ATX), a natural xanthophyll carotenoid, has shown to exert significant protective effects against various diseases via its antioxidant and anti-inflammatory properties. However, its potential role in arthritis is still not reported. Therefore, the aim of the present study was to investigate the potential anti-arthritic properties of ATX against complete Freund's adjuvant (CFA)-induced arthritis rats. METHODS: Adjuvant arthritis was induced by single intraplantar injection of complete Freund's adjuvant (CFA) in the left hind paw of adult female Wistar rats. ATX (25, 50 and 100 mg/kg) and indomethacin (5 mg/kg) were given orally from days 14 to 28. The anti-arthritic activity was evaluated through various nociceptive behavioral tests (mechanical allodynia, mechanical hyperalgesia, cold allodynia, and thermal hyperalgesia), paw edema assessment, and arthritis scores. Serum tumor necrosis factor-α (TNF-α), C-reactive protein (CRP) and cyclic citrullinated peptide (CCP) antibody levels were assessed. Moreover, malondialdehyde (MDA), nitrite, glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) levels were also evaluated. RESULTS: Oral administration of ATX (50 and 100 mg/kg) exhibited significant anti-arthritic activity via enhancing the nociceptive threshold, reducing paw edema and improving arthritis scores. Moreover, ATX treatment also markedly suppressed inflammatory and oxidative mediators in adjuvant-administered rats. CONCLUSIONS: Our findings suggest that ATX possesses potential anti-arthritic activity, which could be attributed to its anti-inflammatory and antioxidant properties.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Antirheumatic Agents/pharmacology , Arthritis, Experimental/drug therapy , Administration, Oral , Animals , Anti-Inflammatory Agents/administration & dosage , Antioxidants/administration & dosage , Antioxidants/pharmacology , Antirheumatic Agents/administration & dosage , Arthritis, Experimental/pathology , Behavior, Animal/drug effects , Dose-Response Relationship, Drug , Female , Freund's Adjuvant , Indomethacin/pharmacology , Inflammation/drug therapy , Inflammation/pathology , Oxidative Stress/drug effects , Rats , Rats, Wistar , Xanthophylls/administration & dosage , Xanthophylls/pharmacologyABSTRACT
Approximately one-third of the world population is suffering from MetS, and the same is expected to rise in the years to come. Worldwide, most of the staple diets contain high amounts of carbohydrates, fats and comparatively low quantities of proteins. The goal of this study was to evaluate the effect of high fat-low protein diet in the development of the metabolic syndrome and associated cognitive deficits in the female rats. The rats fed with high fat-low protein diet (HFLPD) and 15% oral fructose solution for 24 weeks. Body weight, food intake, water intake, fasting blood glucose, oral glucose tolerance, glycosylated hemoglobin (HbA1C), and serum lipid profile were measured after every 4 weeks. Serum insulin, HOMA-IR index, rectal temperature, and systolic blood pressure were measured to confirm the manifestation of the hallmarks of metabolic syndrome. Behavioral tests for locomotion, anxiety, learning, and spatial memory were performed from the 12th week to till the end of the study. At the 24th week, oxidative stress assays and histopathology of liver, kidney, brain, and WAT were also performed. HFLPD significantly altered the physiologic and metabolic parameters which contributed to the manifestation of MetS. HFLPD also impaired the cognitive functions along with significant structural changes in the liver, kidney, WAT, and brain. The findings of this study reveal that HFLPD has the potential to induce the physiological, metabolic and histological alterations in rats, which eventually led to the development of MetS and also disrupted the cognitive functions in female rats.
Subject(s)
Cognitive Dysfunction/etiology , Diet, High-Fat/adverse effects , Diet, Protein-Restricted/adverse effects , Hyperglycemia/etiology , Insulin Resistance/physiology , Metabolic Syndrome/etiology , Animals , Behavior, Animal/physiology , Blood Glucose/metabolism , Cognitive Dysfunction/metabolism , Female , Hyperglycemia/metabolism , Lipids/blood , Memory/physiology , Metabolic Syndrome/metabolism , Motor Activity/physiology , Oxidative Stress/physiology , Rats , Rats, WistarABSTRACT
BACKGROUND & AIMS: Alzheimer's disease is suggested to be primarily metabolic, mainly characterized by brain insulin resistance. Chronic fructose feeding results in hippocampal insulin resistance. However, variable opinion exists regarding the concentration and duration of fructose feeding to trigger insulin resistance and resultant cognitive insults. Therefore this study was planned to construct a time-response curve of the appearance of fructose-induced insulin resistance and memory insufficiencies in rats over a period of 24 weeks. Further, Pearson's correlations were drawn between indices of insulin resistance and markers of memory deficits at various time points. METHODS: Male Wistar rats (6 weeks old; 155 ± 5 g) were fed with 15% fructose in normal drinking water for a period of 24 weeks. Body weight, food and water intake were weekly monitored. Fasting blood glucose, glycosylated hemoglobin (HbA1C), lipid profiling, plasma insulin, HOMA-IR index, and systolic blood pressure were estimated to confirm the manifestation of insulin resistance. Cognitive derangements were evaluated by Elevated plus maze and Morris water maze at different time points during the study. RESULTS: Most of the parameters including insulin resistance became evident at the 7th week and continued until the end of study (24th week) whereas cognitive insufficiency became significantly distinct at the 20th, 22nd and 24th week. Significantly increased serum nitro-oxidative stress, inflammatory cytokines and serum homocysteine levels were intensely connected with fructose-induced neuronal deficits. CONCLUSIONS: The construction of time response study reveals that the hallmark characteristics of insulin resistance appear from the 7th week of fructose feeding whereas the cognitive dysfunction appears on the 20th week and both persist till the end of the study. Fructose-induced oxidative stress and neuroinflammation plausibly impair neuronal signaling and synaptic plasticity.