Rhoifolin as a potential anxiolytic drug for the effects of nicotine withdrawal: beneficial effects on behavior, neuroinflammation, and oxidative stress.

Cigarette smoke exposure induces oxidative stress and neuroinflammation, contributing to nicotine dependence and withdrawal-related anxiety. Rhoifolin (ROF), a naturally occurring flavonoid glycoside, possesses notable oxidative stress and inflammation reducing properties. This study investigated the potential ameliorative effects of ROF against cigarette smoke-induced neuroinflammation, oxidative damage, and withdrawal-induced anxiety-like behavior in rats. Rats were allocated into four treatment groups: a control group subjected only to ambient air; a nicotine (NIC) group exposed to cigarette smoke five days a week for seven weeks; a NIC/ROF group similarly exposed to smoke, but also treated with 20 mg/kg ROF daily for the last three weeks; and a ROF-only group treated with ROF while subjected to room air. Cigarette smoke exposure evoked anxiety during withdrawal periods, elevated levels of proinflammatory cytokines IL-1β and TNF-α, and a markedly reduced levels of key antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase. ROF treatment significantly reversed these effects, reducing anxiety, lowering inflammatory markers, and restoring antioxidant enzyme activity to near-normal levels. Molecular modeling simulations showed a potential binding interaction for ROF at an allosteric pocket in each of the antioxidant enzyme structures, providing a potential mechanism by which ROF might act as an activator of these enzymes, thereby promoting antioxidant activity. Our findings suggest that ROF exhibits anxiolytic effects related to cigarette smoke exposure, likely mediated by its ameliorative role against inflammation and oxidative stress, supporting its potential role in improving behavioral outcomes of cigarette smoke withdrawal.