Targeting TLR4/NF-κB and Nrf2/HO-1 Crosstalk via Trimetazidine alleviates LPS-induced Depressive Like Behaviors in mice

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Abstract Depression is a global psychiatric disorder that imposes a substantial economic burden. Trimetazidine (TMZ); a well-known anti-ischemic drug, could exert neuroprotection in cerebral ischemia. Aims: This study aimed to investigate the effect of TMZ in lipopolysaccharide (LPS) mouse model of depression with empathises on its ability to regulate toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) as well as nuclear factor erythroid 2 related factor 2 (Nrf2)/ heme oxygenase-1(HO-1) signaling pathways. Main methods: Male Swiss albino mice were injected with LPS (500 µg/kg, i.p) every other day alone or concurrently with oral doses of either TMZ (20 mg/kg/day) or escitalopram (Esc) (10 mg/kg/day) for 14 days. Key findings: Administration of TMZ attenuated LPS-induced animals' despair with decreased immobility time in forced swimming test. Additionally, TMZ diminished LPS–induced neuro-inflammation via inhibition of TLR4/NF-κB 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 –α (TNF-α) and interleukin (IL)-1β were markedly reduced. Besides, TMZ replenished brain serotonin levels owing to serotonin transporter (SERT) inhibition. Thus, TMZ hindered LPS-induced neuro-inflammation, oxidative stress, serotonin deficiency in addition to its anti-apoptotic effect which was reflected by decreased caspase-3 level. The formerly mentioned neuroprotective effects of TMZ were verified by the histological photomicrographs which revealed prominent neuronal survival with minimal records of neuronal damage. Significance: Consequently, TMZ is proposed as an affluent nominee for depression management via targeting TLR4/NF-κB and Nrf2/HO-1 pathways.