Abstract

Post-stroke depression (PSD) is a common neuropsychiatric complication after stroke and is associated with impaired recovery and reduced quality of life. Increasing evidence suggests that neuroinflammation, serotonergic dysfunction, and synaptic impairment may all contribute to its pathophysiology. Celastrol, a bioactive compound with anti-inflammatory and neuroprotective properties, has shown potential therapeutic effects in several central nervous system disorders; however, its role in PSD remains insufficiently understood. In the present study, we investigated the effects of celastrol in a rat model of PSD induced by middle cerebral artery occlusion (MCAO) combined with chronic unpredictable mild stress (CUMS). Behavioral assessments showed that celastrol increased sucrose preference, reduced immobility time in the forced swim test, and improved exploratory activity in the open field test. Transcriptomic analysis of hippocampal tissue revealed enrichment of pathways related to inflammatory responses, neurotransmission, and synaptic function. Molecular analyses further showed that celastrol was associated with reduced microglial M1-related markers, increased expression of serotonergic-related proteins, and partial restoration of synaptic proteins, including postsynaptic density protein 95 and synapsin I. In addition, Golgi-Cox staining showed that celastrol treatment was accompanied by improved dendritic spine morphology in hippocampal CA1 pyramidal neurons. Together, these findings indicate that celastrol alleviated depressive-like behaviors in PSD rats and was associated with changes in neuroinflammatory, serotonergic, and synaptic markers. These results support further investigation of celastrol as a potential multi-target therapeutic candidate for PSD.