Dietary flavonoids-rich Citrus reticulata peel extract interacts with CREB signaling to suppress seizures and linked neurobehavioral impairments in a kindling mouse model.

Objectives: The citrus fruits peel contains a variety of bioactive metabolites that have shown multiple therapeutic effects. However, despite having substantial ethnomedicinal value, citrus peels remained underexplored and regarded as bio-waste. This present study was planned to investigate the effect of a characterized peel extract of Citrus reticulata c.v. (CRE) in pentylenetetrazole (PTZ)-induced kindling and associated cognitive and behavioral impairments in a mouse model.Methods: The kindled animals were treated daily with CRE (100 and 200 mg/kg) and challenged with a sub-effective dose of PTZ every 5th day to record the severity of seizures. In the end, different tests were performed to record behavioral and cognitive performance.Results: CRE-treated kindled animals showed a significant suppression in seizure severity following 20 days of the treatment. In the T-maze test, the extract treatment resulted in a marked increase in the spontaneous alternations, whereas it showed no change in anxiety behavior of kindled animals in the elevated plus-maze test. In both forced swim and tail suspension tests, CRE treatment demonstrated a considerable reduction in immobility time. However, no change in overall locomotion was observed in the open field test among all the groups. An increase in the hippocampal Creb and Bdnf expression and decreased glutamate-to-GABA ratio were observed in the CRE-treated kindled animals.Discussion: The results showed that CRE treatment suppresses epileptic seizures and associated cognitive deficits and depression-like behavior in kindled mice. The gene expression findings supported that the observed protective effects of CRE be due to its interaction with CREB signaling.