{"doi":"10.1093/ntr/ntaf253","title":"Protective Role of CBD Against Nicotine Pouch–Induced Seizure Aggravation and Alterations in Brain Glymphatic Biomarkers","abstract":"INTRODUCTION: Nicotine pouches are rapidly increasing in popularity, yet their long-term neurological consequences remain poorly understood. Emerging evidence suggests nicotine may influence seizure susceptibility and neuroimmune signaling, while cannabidiol (CBD) has demonstrated neuroprotective and anti-inflammatory effects. This study investigated the time-dependent impact of acute versus chronic oral nicotine exposure on seizure vulnerability, neuroinflammation, and glymphatic function, and evaluated whether inhaled CBD can reverse these pathological changes. METHODS: Mice were exposed to acute or 7-day chronic nicotine pouch prior to kainic acid-induced seizures. Seizure severity was scored using the Racine scale. Neuroinflammatory markers (IL-6, HMGB1), neuronal activation markers (BDNF, c-FOS), and Aquaporin-4 (AQP4) expression were quantified via flow cytometry, immunofluorescence, and western blotting. Glymphatic function was assessed using cisterna magna injection of rhodamine dextran tracers. An ex vivo IL-6 modulation assay evaluated nicotine-induced cytokine production and CBD-mediated suppression, with or without IL-6 receptor blockade. RESULTS: Acute nicotine transiently reduced seizure severity, whereas chronic exposure significantly exacerbated seizures, elevated IL-6, HMGB1, BDNF, and c-FOS, and markedly downregulated AQP4. CSF tracer studies confirmed impaired glymphatic influx following chronic nicotine exposure. CBD inhalation effectively reversed seizure severity restored AQP4 expression, normalized IL-6 and HMGB1 levels, and reduced c-FOS protein expression. The IL-6R blockade assay showed that nicotine induces IL-6 production in brain-derived immune cells, while CBD suppresses this response upstream of IL-6 signaling. CONCLUSIONS: Chronic nicotine pouch exposure promotes seizure susceptibility through converging neuroimmune and glymphatic disruptions. Inhaled CBD counteracts these effects, supporting its potential as a targeted therapeutic strategy for nicotine-associated neurological risk. IMPLICATIONS: This study provides the first evidence that chronic nicotine pouch exposure disrupts glymphatic function, amplifies neuroinflammation, and increases seizure susceptibility through an IL-6-centered neuroimmune network. These findings challenge the perception of nicotine pouches as low-risk products and highlight previously unrecognized neurological vulnerabilities associated with long-term use. The ability of inhaled CBD to reverse these pathological effects identifies a promising therapeutic strategy and underscores the need for further investigation into neuroimmune-glymphatic interactions in nicotine-related brain health.","journal":"Nicotine & Tobacco Research","year":2025,"id":549424,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9568,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":956587,"name":"Sahar Emami Naeini","orcid":"0000-0003-2907-2414","position":1,"is_corresponding":false},{"id":1444141,"name":"Hannah M. Rogers","orcid":null,"position":2,"is_corresponding":false},{"id":1443642,"name":"Abdulhakeem Al-Hashim","orcid":"0000-0001-9610-4020","position":3,"is_corresponding":false},{"id":672991,"name":"Jack C. Yu","orcid":null,"position":4,"is_corresponding":false},{"id":1443643,"name":"Mohammad Seyyedi","orcid":"0000-0002-3120-8459","position":5,"is_corresponding":false},{"id":1443644,"name":"Nancy L. Young","orcid":"0000-0002-1739-3299","position":6,"is_corresponding":false},{"id":420262,"name":"Ahmed A. Elmarakby","orcid":"0000-0002-3065-4457","position":7,"is_corresponding":false},{"id":671966,"name":"Évila Lopes Salles","orcid":"0000-0001-6956-7409","position":8,"is_corresponding":false},{"id":983657,"name":"Lei P. Wang","orcid":null,"position":9,"is_corresponding":false},{"id":288628,"name":"Babak Baban","orcid":"0000-0002-3144-2288","position":10,"is_corresponding":false},{"id":982970,"name":"Bidhan Bhandari","orcid":"0000-0002-4933-711X","position":0,"is_corresponding":true}],"reference_count":13,"raw_metadata":null,"created_at":"2026-07-19T02:54:07.823422Z","pmid":"41384771","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}