title: Sodium Phenylbutyrate and Edaravone Abrogate Chronic Restraint Stress-Induced Behavioral Deficits: Implication of Oxido-Nitrosative, Endoplasmic Reticulum Stress Cascade, and Neuroinflammation.
abstract: 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.
authors.affiliation: Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education & Research (NIPER), Guwahati, Assam, 781032, India.
authors.forename: Ashok
authors.initials: A
authors.lastname: Jangra
authors.affiliation: Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education & Research (NIPER), Guwahati, Assam, 781032, India.
authors.forename: Chandra Shaker
authors.initials: CS
authors.lastname: Sriram
authors.affiliation: Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education & Research (NIPER), Guwahati, Assam, 781032, India.
authors.forename: Shubham
authors.initials: S
authors.lastname: Dwivedi
authors.affiliation: Department of Biotechnology, National Institute of Pharmaceutical Education & Research (NIPER), Guwahati, Assam, 781032, India.
authors.forename: Satendra Singh
authors.initials: SS
authors.lastname: Gurjar
authors.affiliation: State Biotech Hub, College of Veterinary Science, Khanapara, Guwahati, Assam, 781022, India.
authors.forename: Md Iftikar
authors.initials: MI
authors.lastname: Hussain
authors.affiliation: State Biotech Hub, College of Veterinary Science, Khanapara, Guwahati, Assam, 781022, India.
authors.forename: Probodh
authors.initials: P
authors.lastname: Borah
authors.affiliation: Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education & Research (NIPER), Guwahati, Assam, 781032, India. dr.lahkarniper@gmail.com.|Department of Pharmacology, Gauhati Medical College, Guwahati, Assam, 781032, India. dr.lahkarniper@gmail.com.
authors.forename: Mangala
authors.initials: M
authors.lastname: Lahkar
mesh_terms: D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D002908:Chronic Disease; D003863:Depression / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D000077553:Edaravone; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000502:physiology; D016166:Free Radical Scavengers / Q000494:pharmacology / Q000627:therapeutic use; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D051379:Mice; D015538:Nitrosation / Q000187:drug effects / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D010654:Phenylbutyrates / Q000494:pharmacology / Q000627:therapeutic use*; D012149:Restraint, Physical; D013315:Stress, Psychological / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D016166:Free Radical Scavengers; D010654:Phenylbutyrates; C075773:4-phenylbutyric acid; D000077553:Edaravone; D000983:Antipyrine
keywords: Anxiety; Cognitive impairment; Depression; Endoplasmic reticulum stress; Neuroinflammation; Oxido-nitrosative stress