{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T02:27:05Z","timestamp":1789612025705,"version":"build-2803163510"},"reference-count":55,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,2,15]],"date-time":"2023-02-15T00:00:00Z","timestamp":1676419200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Magnesium sulfate has demonstrated marked neuroprotection in eclampsia, hypoxia, stroke, and post-traumatic brain injury rodent models. However, its potential impact against chronic-restraint-stress (CRS)-induced depression-like neuropathology and associated alterations in endoplasmic reticulum (ER) stress have not been adequately examined. The present study aimed to investigate the neuroprotective potential of magnesium sulfate in a rat model of CRS-triggered depression-like behavioral disturbance and the underlying molecular mechanisms. Herein, CRS was induced by placing rats into restraining tubes for 6 h\/day for 21 days and the animals were intraperitoneally injected with magnesium sulfate (100 mg\/kg\/day) during the study period. After stress cessation, the depression-like behavior was examined by the open-field test, sucrose preference test, and forced swimming test. The present data demonstrated that CRS triggered typical depression-like behavioral changes which were confirmed by the Z-normalization scores. Mechanistically, serum circulating corticosterone levels spiked, and the hippocampi of CRS-exposed animals demonstrated a significant decline in serotonin, norepinephrine, and dopamine neurotransmitters. At the molecular level, the hippocampal pro-inflammatory TNF-alpha and IL-1\u03b2 cytokines and the oxidative stress marker 8-hydroxy-2\u2032-deoxyguanosine (8-HG) increased in stressed animals. In tandem, enhancement of hippocampal ER stress was evidenced by the activation of iNOS\/PERK\/GRP78\/CHOP axis seen by increased protein expression of iNOS, PERK, GRP78, and CHOP signal proteins in the hippocampi of stressed rats. Interestingly, magnesium sulfate administration attenuated the depression-like behavioral outcomes and the histopathological changes in the brain hippocampi. These favorable actions were driven by magnesium sulfate\u2019s counteraction of corticosterone spike, and hippocampal neurotransmitter decline, alongside the attenuation of neuroinflammation, pro-oxidation, and ER stress. In conclusion, the current results suggest the promising neuroprotective\/antidepressant actions of magnesium sulfate in CRS by dampening inflammation, ER stress, and the associated PERK\/GRP78\/CHOP pathway.<\/jats:p>","DOI":"10.3390\/ph16020300","type":"journal-article","created":{"date-parts":[[2023,2,15]],"date-time":"2023-02-15T04:47:24Z","timestamp":1676436444000},"page":"300","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Targeting the Endoplasmic Reticulum Stress-Linked PERK\/GRP78\/CHOP Pathway with Magnesium Sulfate Attenuates Chronic-Restraint-Stress-Induced Depression-like Neuropathology in Rats"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4195-6901","authenticated-orcid":false,"given":"Hany H.","family":"Arab","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Khames","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Sohag University, Sohag 82511, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5567-6169","authenticated-orcid":false,"given":"Shuruq E.","family":"Alsufyani","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3726-0386","authenticated-orcid":false,"given":"Azza A. K.","family":"El-Sheikh","sequence":"additional","affiliation":[{"name":"Basic Health Sciences Department, College of Medicine, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amany M.","family":"Gad","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Sinai University, Kantara Branch, Ismailia 41636, Egypt"},{"name":"Department of Pharmacology, Egyptian Drug Authority (EDA)\u2014Formerly NODCAR, Giza 12654, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"151","DOI":"10.31887\/DCNS.2006.8.2\/fbenazzi","article-title":"Various forms of depression","volume":"8","author":"Benazzi","year":"2022","journal-title":"Dialogues Clin. 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