Paroxetine ameliorates corticosterone-induced myelin damage by promoting the proliferation and differentiation of oligodendrocyte precursor cells.

Depression is frequently associated with demyelination in the prefrontal cortex (PFC), and promoting remyelination can improve neuronal signaling and alleviate depressive symptoms. Paroxetine, a classic selective serotonin reuptake inhibitor (SSRI), is known to exert its antidepressant effects by increasing serotonin levels. However, its potential to alleviate myelin damage in depression remains unclear. A corticosterone (CORT)-induced mouse model of depression was used in this study. Myelin staining and transmission electron microscopy (TEM) were employed to assess myelin damage in the PFC, while immunofluorescence and western blot were performed to evaluate the expression of myelin-associated proteins. The primary oligodendrocyte precursor cells (OPCs) were cultured in vitro. The results demonstrated that paroxetine significantly alleviated CORT-induced depressive-like behaviors, including increased sucrose preference and spontaneous activity in the open field, while reduced immobility time in the tail suspension and forced swimming tests. Paroxetine also increased myelin thickness and restoring myelin integrity in the PFC. Moreover, paroxetine upregulated the expression of MBP, MAG, and neurofilament light chain protein (NFEL). Immunofluorescence analysis that paroxetine significantly increased the number of OPC (Olig2+/NG2+) and promoted OL differentiation (Olig2+/CC-1+), as well as upregulating the expression of PDGFRα. BrdU assays further confirmed that paroxetine enhanced OPC proliferation. In vitro, paroxetine significantly increased the viability of primary OPCs and promoted their proliferation and differentiation, with the most potent effect observed at 20 nM. These findings suggest that paroxetine alleviates CORT-induced myelin damage and improves depressive-like behaviors by promoting OPC proliferation and differentiation, providing new insights into its antidepressant mechanisms.