Mitochondrial Division Inhibitor 1 Ameliorates Mitochondrial Injury, Apoptosis, and Motor Dysfunction After Acute Spinal Cord Injury in Rats.

Abstract

Mitochondrial division inhibitor 1 (Mdivi-1) is the most effective pharmacological inhibitor of mitochondrial fission. Spinal cord injury (SCI) is a common and serious trauma, which lacks efficient treatment. This study aimed to detect the role of Mdivi-1 in neuronal injury and its underlying mechanism after acute SCI (ASCI) in rats. Western blot analysis showed that Bax levels on the mitochondrial outer membrane, and release of cytochrome C (cytC) and apoptosis-inducing factor (AIF) from the mitochondria began to increase significantly at 4h after ASCI, then peaked at 16h, and declined significantly from 16 to 24h. However, the mitochondrial levels of Bcl-2 increased significantly at 2h, peaked at 4h, and subsequently significantly decreased from 4 to 24h after ASCI. In addition, Mdivi-1(1.2mg/kg) significantly suppressed the translocation of dynamin-related protein 1 (Drp1) and Bax to the mitochondria, mitochondrial depolarization, decrease of ATP and reduced Glutathione, increase of the Malondialdehyde, cytC release, and AIF translocation at 16h and 3days after ASCI, and also inhibited the caspase-3 activation and decrease of the percentage of apoptotic cells at 16h, 3 and 10days, further, ameliorated the motor dysfunction greatly from 3 to 10days after ASCI in rats. This neuroprotective effect was dose-dependent. However, Mdivi-1(1.2mg/kg) had no effects on the translocation of Bcl-2 and fission protein 1 on the mitochondria, and did not affect the expression of total Drp1 at 16h after ASCI. Our experimental findings indicated that Mdivi-1 can protect rats against ASCI, and that its underlying mechanism may be associated with inhibition of Drp1 translocation to the mitochondria, alleviation of mitochondrial dysfunction and oxidative stress, and suppression of caspase-dependent and -independent apoptosis.