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This highlights a critical need for novel treatment strategies. Our study investigated the antidepressant effects of benazepril, a non-centrally acting angiotensin-converting enzyme (ACE) inhibitor, and compared it with perindopril, a centrally acting ACE inhibitor. We utilized a rat model of depression induced by chronic unpredictable mild stress (CUMS) to evaluate their efficacy. The CUMS protocol effectively caused several depression-like behaviors and impaired neurobehavioral functions in the rats. Analysis of brain tissues from these animals revealed several key pathological hallmarks: diminished monoamine neurotransmitter levels, heightened oxidative stress, robust inflammatory responses, and increased apoptotic processes. Our findings demonstrated that both perindopril and benazepril significantly reversed these CUMS-induced deficits. Specifically, both ACE inhibitors exhibited potent antioxidant, anti-inflammatory, and anti-apoptotic properties. This was coupled with their effective inhibition of the renin-angiotensin-aldosterone system (RAAS) signaling pathway, a mechanism known to be implicated in stress responses and mood disorders. Notably, while many ACE inhibitors have been extensively studied for their central effects, research on benazepril\u2019s direct effects within the brain or central nervous system in rats is notably limited. This study is among the first to highlight the antidepressant potential of benazepril, a non-centrally acting ACE inhibitor, and provides novel insights into its comparative efficacy against perindopril. These results collectively emphasize the broader therapeutic potential of ACE inhibitors in treating depression and underscore the need for further research to fully explore their underlying mechanisms and diverse applications in psychiatric disorders.<\/jats:p>\n          <jats:p>\n            <jats:bold>Graphical Abstract<\/jats:bold>\n          <\/jats:p>","DOI":"10.1007\/s11481-025-10244-z","type":"journal-article","created":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T07:22:12Z","timestamp":1759994532000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Comparative Study on the Neuroprotective Effects of Perindopril and Benazepril in Experimentally-induced Chronic Mild Stress in Rats"],"prefix":"10.1007","volume":"20","author":[{"given":"Alaa M.","family":"Badawy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amany M.","family":"Gad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amany E.","family":"Abdel-Maged","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haidy E.","family":"Michel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reem N.","family":"El-Naga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0253-8280","authenticated-orcid":false,"given":"Samar S.","family":"Azab","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,9]]},"reference":[{"issue":"1","key":"10244_CR1","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1186\/s43094-025-00793-8","volume":"11","author":"RD Abdrabou","year":"2025","unstructured":"Abdrabou RD, Salama RM, El-Naga RN, Azab SS (2025) Luteolin mitigates doxorubicin-induced hepatotoxicity and neurotoxicity: modulating the liver\u2013brain axis via IRE1\u03b1\/GRP78\/ATF6 endoplasmic reticulum stress pathways and miRNA-199a-5p expression. 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