Escitalopram and N-acetylcysteine alleviate major depressive disorder with cognitive impairment through YTHDC1/ATF4/CHOP-mediated pyroptosis.

BACKGROUND: Cognitive impairment (CI) is an important factor contributing to poor prognosis in major depressive disorder (MDD). Endoplasmic reticulum stress and microglial inflammatory response are closely associated with the occurrence and development of MDD with CI. Escitalopram (ESC) and N-acetylcysteine (NAC) are two drugs used to improve depression. However, the therapeutic efficacy and underlying molecular mechanisms of ESC and NAC in treating MDD with CI are still not fully understood.

METHODS: The depression rat was established using the chronic unpredictable mild stress (CUMS) protocol. The antidepressant effects of ESC and NAC were evaluated through behavioral tests including the open field test, sucrose preference test, and Morris water maze test and. The underlying molecular mechanisms were investigated using ELISA and immunofluorescence techniques.

RESULTS: The CUMS group of rats showed decreased responsiveness and memory capacity, which were significantly improved following intervention with ESC and NAC. Treatment with ESC and NAC alleviated hippocampal injury in the CUMS group of rats. The expression of microglial activation markers CD68 and IBA1 in hippocampal tissue was significantly reduced. The levels of NLRP3 inflammasome and pro-inflammatory cytokines IL-6, IL-18, and IL-1β in the hippocampus were significantly decreased. Mechanistically, ESC and NAC downregulate ATF4/CHOP expression by inhibiting the m6A reader YTHDC1, thereby reducing hippocampal cell pyroptosis.

CONCLUSION: This study demonstrates that ESC and NAC alleviate hippocampal tissue damage by modulating YTHDC1/ATF4/CHOP-mediated pyroptosis, thereby improving MDD with CI. These findings provide experimental evidence supporting the therapeutic potential of targeting YTHDC1/ATF4/CHOP-mediated pyroptosis in MDD-associated CI.