Protective role of Cannabidiol against nicotine pouch-induced seizure aggravation and alterations in brain glymphatic biomarkers.

Abstract

Nicotine pouches are increasingly popular as a smokeless alternative to tobacco, yet their long-term neurological effects remain poorly understood. In this preclinical study, we investigated the time-dependent impact of oral nicotine pouch exposure on seizure susceptibility, glymphatic function, and neuroinflammation in mice, and evaluated the therapeutic potential of inhaled cannabidiol (CBD). Using the Racine scale, we found that acute nicotine exposure transiently reduced seizure severity, while chronic exposure significantly exacerbated seizures and impaired glymphatic integrity, as evidenced by downregulation of aquaporin-4 (AQP4). Chronic nicotine also elevated circulating levels of HMGB1 and IL-6, indicating sustained systemic inflammation. Notably, inhaled CBD reversed these pathological changes, reducing seizure severity, restoring AQP4 expression, and normalizing inflammatory markers. Molecular analyses further revealed upregulation of BDNF and c-FOS with chronic nicotine exposure, which was also mitigated by CBD. In conclusion, these findings suggest that while nicotine pouches may confer short-term neurophysiological modulation, chronic use poses significant risks for seizure vulnerability and glymphatic dysfunction. Inhaled CBD demonstrates strong neuroprotective potential and may serve as a promising therapeutic approach for individuals exposed to prolonged nicotine use. HighlightsO_LIChronic exposure to oral nicotine pouches exacerbates seizure severity in a preclinical model. C_LIO_LINicotine-induced seizures are associated with elevated neuroinflammation and impaired glymphatic function. C_LIO_LIInhaled cannabidiol (CBD) reverses nicotine-induced increases in HMGB1, IL-6, and seizure activity. C_LIO_LICBD restores Aquaporin-4 expression and reestablishes glymphatic integrity disrupted by nicotine. C_LIO_LISystems biology analysis reveals an IL-6-centered protein network targeted by CBD, offering mechanistic insight into its neuroprotective effects. C_LI