Journal Article Ahead of print
PubMed: 42034031 DOI: 10.1016/j.phymed.2026.158215
Kaempferol alleviates schizophrenia-like social and cognitive deficits through cholinergic modulation.
Phytomedicine 156:158215
Authors: Minzhu Li, Boshi Wang, Chenshu Gao, Jingwen Sun, Jiaying Liu, Ling Xiao, Fangjie Ding, Heming Cheng, Kang Liu, Cenglin Xu, Qin Wang, Yi Wang, Zhong Chen, Li Cheng
Affiliations
- Zhejiang Key Laboratory of Neuropsychopharmacology, School of Pharmaceutical Sciences, The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China.
- School of Pharmaceutical Sciences, Hangzhou First People's Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 311402, China.
- Zhejiang Key Laboratory of Neuropsychopharmacology, School of Pharmaceutical Sciences, The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China.
- Zhejiang Key Laboratory of Neuropsychopharmacology, School of Pharmaceutical Sciences, The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China.
Abstract
BACKGROUND
Conventional antipsychotics exhibit limited efficacy in treating the negative symptoms and cognitive deficits of schizophrenia. Although the dietary flavonoid kaempferol has demonstrated neuroprotective effects in various neurological disorders, its exact role and underlying mechanisms in schizophrenia remain poorly understood.
PURPOSE
This study aimed to elucidate the therapeutic role of kaempferol in schizophrenia and to investigate the underlying neural mechanisms.
METHODS
Behavioral deficits relevant to schizophrenia were evaluated using an MK-801-induced mouse model. Conditional knockout of the Hrh1 gene in cholinergic neurons and chemogenetic inhibition of cholinergic neurons in the nucleus of the horizontal limb of the diagonal band (HDB) were performed to further validate the observed behavioral phenotypes. Choline acetyltransferase (ChAT) expression in the HDB was assessed by immunohistochemistry, and calcium activity of HDB cholinergic neurons was monitored during behavioral tasks using fiber photometry.
RESULTS
Kaempferol significantly ameliorated MK-801-induced deficits in sensorimotor gating, social novelty preference, and novel object recognition in mice. Conditional knockout of the Hrh1 gene in cholinergic neurons, or chemogenetic inhibition of HDB cholinergic neurons, recapitulated schizophrenia-like social and cognitive deficits, which were notably alleviated by kaempferol treatment. Furthermore, kaempferol reversed the MK-801-induced reductions in ChAT expression in the HDB and in calcium signaling dynamics of HDB cholinergic neurons associated with social and cognitive behaviors.
CONCLUSION
Our findings suggest that kaempferol alleviates schizophrenia-like social and cognitive deficits by modulating cholinergic function in the HDB, highlighting its potential as a natural therapeutic agent for addressing these specific symptom domains of schizophrenia.
MeSH
Choline, Genes, Neurons, Schizophrenia, Calcium, Cognition Disorders, Therapeutics, Cholinergic Neurons, Cholinergic Agents, Chemogenetics