Dynasore Improves Motor Function Recovery via Inhibition of Neuronal Apoptosis and Astrocytic Proliferation after Spinal Cord Injury in Rats

摘要

Spinal cord injury (SCI) is a common and devastating central nervous system insult which lacks efficient treatment. Our previous experimental findings indicated that dynamin-related protein 1 (Drp1) mediates mitochondrial fission during SCI, and inhibition of Drp1 plays a significant protective effect after SCI in rats. Dynasore inhibits GTPase activity at both the plasma membrane (dynamin 1, 2) and the mitochondria membrane (Drp1). The aim of the present study was to investigate the beneficial effects of dynasore on SCI and its underlying mechanism in a rat model. Sprague-Dawley rats were randomly assigned to sham, SCI, and 1, 10, and 30 mg dynasore groups. The rat model of SCI was established using an established Allen's model. Dynasore was administered via intraperitoneal injection immediately. Results of motor functional test indicated that dynasore ameliorated the motor dysfunction greatly at 3, 7, and 10 days after SCI in rats (P < 0.05). Results of western blot showed that dynasore has remarkably reduced the expressions of Drp1, dynamin 1, and dynamin 2 and, moreover, decreased the Bax, cytochrome C, and active Caspase-3 expressions, but increased the expressions of Bcl-2 at 3 days after SCI (P < 0.05). Notably, the upregulation of proliferating cell nuclear antigen (PCNA) and glial fibrillary acidic protein (GAFP) are inhibited by dynasore at 3 days after SCI (P < 0.05). Results of immunofluorescent double labeling showed that there were less apoptotic neurons and proliferative astrocytes in the dynasore groups compared with SCI group (P < 0.05). Finally, histological assessment via Nissl staining demonstrated that the dynasore groups exhibited a significantly greater number of surviving neurons compared with the SCI group (P < 0.05). This neuroprotective effect was dose-dependent (P < 0.05). To our knowledge, this is the first study to indicate that dynasore significantly enhances motor function which may be by inhibiting the activation of neuronal mitochondrial apoptotic pathway and astrocytic proliferation in rats after SCI.