Naringenin ameliorates neuropsychiatric deficits in mice fed a methionine-choline-deficient diet

Neuropsychiatric dysfunction is increasingly being acknowledged as a disabling complication of non-alcoholic steatohepatitis (NASH), but there are no therapeutic approaches. We investigated in the present study the neuroprotective effectiveness of naringenin, a citrus flavonoid with known anti-inflammatory and neurotrophic effects, in a murine NASH model induced by an 8-week methionine-choline-deficient (MCD) diet. Male C57BL/6 mice (n = 8/group) were treated with naringenin (50 mg/kg/day, i.p.) during the final 4 weeks. In behavioral tests, naringenin counteracted cognitive impairment in novel object recognition, reduced anxiety in both open field and elevated plus maze paradigms, and decreased immobility in the forced swim test, indicating antidepressant-like activity. Mechanistically, naringenin restored hippocampal apoptotic balance, normalizing the MCD diet-induced Bax upregulation and Bcl2 downregulation. Notably, while the MCD diet suppressed both Bdnf and Ntrk2 expression, naringenin treatment partially restored Bdnf (but not Ntrk2) mRNA levels, implicating Bdnf-related neuroplasticity in its therapeutic effects. The research highlights naringenin's neuroprotective functions and its multitarget therapeutic potential in the MCD diet model of steatohepatitis, as evidenced by its effects on hippocampal gene expression and behavioral outcomes. Additional studies are needed to validate the effect in clinical settings and establish optimal dosing regimens.