Extracts of Coriaria nepalensis ameliorate MK-801-induced schizophrenia-like behaviors via regulation of neurotransmitter imbalance and neuroinflammation.

ETHNOPHARMACOLOGICAL RELEVANCE: Coriaria nepalensis Wall. is a traditional ethnomedicine used by the Dong ethnic group in Guizhou Province, China, for the treatment of schizophrenia. However, its pharmacological effects and the bioactive constituents responsible for its therapeutic efficacy remain largely unknown. AIM OF THE STUDY: To evaluate the anti-schizophrenic effects of C. nepalensis extracts and investigate their underlying mechanisms and potential bioactive constituents. MATERIALS AND METHODS: An MK-801-induced schizophrenia-like Sprague-Dawley rat model was established to evaluate the therapeutic effects in the blank control group, model group, positive drug group, and different dose groups of C. nepalensis extracts (EA-H, EA-M, EA-L, SJ-H, SJ-M, and SJ-L). Schizophrenia-like behaviors were assessed using the open-field, Y-maze, three-chamber social interaction, and prepulse inhibition (PPI) tests. Neurotransmitter levels in the hippocampus and prefrontal cortex were determined by LC-MS, inflammatory cytokines were quantified by ELISA, and the expression of signaling pathway-related proteins and glutamate decarboxylase 67 (GAD67) was analyzed by Western blotting. Plasma-absorbed constituents of the active extract were characterized using HPLC-MS/MS. RESULTS: C. nepalensis extracts alleviated MK-801-induced schizophrenia-like behavioral abnormalities to different extents, including altered locomotor activity, impaired spatial working memory, and social deficits. Among all treatments, the low-dose ethanol extract (EA-L) produced the most pronounced effects. EA-L significantly improved sensorimotor gating deficits in the PPI test and showed a stronger ameliorative than risperidone under the present experimental conditions. Mechanistically, EA-L restored neurotransmitter homeostasis in the hippocampus and prefrontal cortex, attenuated neuroinflammatory responses, regulated the abnormal activation of inflammation-related signaling pathways, and normalized GAD67 expression. These changes were associated with improvements in schizophrenia-like negative symptoms, cognitive deficits, and sensorimotor gating impairment. Chemical profiling identified 251 constituents in the ethanol extract, of which 57 were detected in rat serum after oral administration, suggesting that these absorbed compounds may contribute to the observed pharmacological activity. CONCLUSION: Extracts of C. nepalensis, particularly EA-L, ameliorated MK-801-induced schizophrenia-like behavioral abnormalities by restoring neurotransmitter homeostasis and suppressing the aberrant activation of neuroinflammation-related signaling pathways.