Rhynchophylline inhibits cluster of differentiation 36 (CD36) on endothelial cells to reduce fibrotic scar formation and enhance functional recovery after spinal cord injury.

BACKGROUND

Spinal cord injury (SCI) causes severe neurological deficits due to extensive neurodegeneration and secondary pathological events, including disruption of the blood-spinal cord barrier (BSCB). Restoration of endothelial integrity is critical for limiting inflammation and promoting recovery. Rhynchophylline (Rhy), a tetracyclic oxindole naturally occurring alkaloid with known neuroprotective effects, has not been fully investigated for its role in maintaining BSCB integrity and endothelial function after SCI.

PURPOSE: This study aimed to evaluate the therapeutic potential of Rhy in preserving endothelial function and promoting neurovascular repair following SCI, and to elucidate its underlying molecular mechanisms, particularly the role of cluster of differentiation (CD36) signaling in vascular pathology.

METHODS

The therapeutic potential of Rhy was evaluated using a mouse model of SCI and complementary in vitro assays. Behavioral assessments and histological analyses were performed to examine functional recovery, vascular integrity, fibrosis, and remyelination. In vitro, bEnd.3 endothelial cells were exposed to IL-1β to induce inflammatory stress, and the effects of Rhy on CD36 expression, tight junction proteins, and trans-endothelial permeability were analyzed. Neuronal survival and neurite outgrowth assays were conducted to assess Rhy's neuroprotective actions.

RESULTS

Rhy treatment significantly reduced vascular damage and inflammation following SCI via downregulating CD36 expression in endothelial cells, supported by molecular docking, qPCR, and immunohistochemistry. In vitro, Rhy preserved tight junction integrity and reduced trans-endothelial permeability under inflammatory conditions. Furthermore, Rhy promoted neuronal survival, enhanced neurite outgrowth, reduced fibrotic scar formation, supported remyelination, and improved endothelial migration. These effects collectively contributed to enhanced functional recovery in vivo.

CONCLUSION

Rhy exerts neurovascular protective effects after SCI by preserving endothelial integrity, inhibiting CD36-mediated vascular damage, and promoting neural repair. These findings identify Rhy as a promising therapeutic candidate for mitigating vascular and neuronal dysfunction following SCI.