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Unfortunately, traditional antidepressants induce many side effects which limit patient compliance thus, exploring alternative therapies with fewer adverse effects became urgent. This study aimed to investigate the effect of trimetazidine (TMZ); a well-known anti-ischemic drug in lipopolysaccharide (LPS) mouse model of depression focusing on its ability to regulate toll-like receptor 4 (TLR4)\/nuclear factor-\u03baB (NF-\u03baB) as well as nuclear factor erythroid 2 related factor 2 (Nrf2)\/ heme oxygenase-1 (HO-1) signaling pathways. Male Swiss albino mice were injected with LPS (500 \u00b5g\/kg, i.p) every other day alone or parallel with oral doses of either escitalopram\u00a0(Esc)\u00a0(10\u00a0mg\/kg\/day)\u00a0or\u00a0TMZ\u00a0(20\u00a0mg\/kg\/day)\u00a0for 14 days. Treatment with TMZ attenuated LPS-induced animals' despair with reduced immobility time inforced\u00a0swimming\u00a0test.\u00a0TMZ\u00a0also diminished LPS-\u00a0induced neuro-inflammation\u00a0via inhibition of TLR4\/NF-\u03baB pathway contrary to Nrf2\/HO-1 cascade activation with consequent increase in reduced glutathione (GSH) and HO-1 levels whereas the pro-inflammatory cytokines; tumor necrosis factor-\u03b1 (TNF-\u03b1) and interleukin (IL)-1\u03b2 were evidently reduced.\u00a0Besides, TMZ replenished brain serotonin levels via serotonin transporter (SERT) inhibition. Thus, TMZ hindered LPS-induced neuro-inflammation, oxidative stress, serotonin deficiency besides its anti-apoptotic effect which was reflected by decreased caspase-3 level. Neuroprotective effects of TMZ were confirmed by the histological photomicrographs which showed prominent neuronal survival. Here we showed that TMZ is an affluent nominee for depression management via targeting TLR4\/NF-\u03baB and Nrf2\/HO-1 pathways. Future research addressing TMZ-antidepressant activity in humans is mandatory to enroll it as a novel therapeutic strategy for depression.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical Abstract<\/jats:bold>\n                  <\/jats:p>","DOI":"10.1007\/s11481-024-10149-3","type":"journal-article","created":{"date-parts":[[2024,9,23]],"date-time":"2024-09-23T03:03:04Z","timestamp":1727060584000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Targeting Toll-like Receptor 4\/Nuclear Factor-\u03baB and Nrf2\/Heme Oxygenase-1 Crosstalk via Trimetazidine Alleviates Lipopolysaccharide-Induced Depressive-like Behaviors in Mice"],"prefix":"10.1007","volume":"19","author":[{"given":"Sarah S.","family":"Mohamed","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nora O. 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