Neuroprotective Efficacy of Menthol Against Ipomoea carnea-Induced Neurotoxicity in Rats: A Mechanistic Study on Oxidative Stress, Neuroinflammation, and Pyroptosis.

Ipomoea carnea, an invasive plant widespread in tropical and subtropical regions, contains the toxic alkaloids swainsonine and calystegines, which induce lysosomal dysfunction, neurodegeneration, and neuroinflammation. Menthol, a cyclic terpene alcohol from peppermint oil, exhibits antioxidant, anti-inflammatory, and neuroprotective properties. This study is the first to investigate the neuroprotective efficacy of menthol against neurotoxicity induced by I. carnea leaf extract in rats, with a novel focus on the pyroptosis pathway. Twenty-four male Sprague Dawley rats were divided into four groups: control, I. carnea extract (15 mg/kg, oral), I. carnea extract plus menthol (5 mg/kg, i.p.), and I. carnea extract plus menthol (10 mg/kg, i.p.) for 8 weeks. I. carnea extract significantly reduced feed intake, body weight gain, feed efficiency, brain weight, and dopamine and serotonin levels in serum and brain, while increasing oxidative stress markers (MDA, NO), inflammatory cytokines (IL-6, TNF-α), and pyroptosis-related gene expression (Casp-1, Casp-3, Casp-11, NLRP-3, GSDMD, IL-1β, IL-18). Histopathology revealed marked ischemic neuronal changes, vacuolation, and malacia. Notably, we provide the first evidence that I. carnea triggers pyroptotic cell death in the brain, and that menthol dose-dependently suppresses this pathway. Correlation analyses further revealed strong inter-relationships among oxidative stress, inflammasome activation, and neurotransmitter depletion. Menthol co-administration, especially at 10 mg/kg, prevented these alterations, attenuated oxidative stress and neuroinflammation, prevented the upregulation of pyroptosis-related genes, and preserved neuronal architecture. These findings demonstrate that menthol exerts significant neuroprotection through modulation of oxidative stress, inflammation, and the newly identified pyroptosis pathway, positioning it as a promising candidate for mitigating plant alkaloid-induced neurotoxicity.