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

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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 4 h after ASCI, then peaked at 16 h, and declined significantly from 16 to 24 h. However, the mitochondrial levels of Bcl-2 increased significantly at 2 h, peaked at 4 h, and subsequently significantly decreased from 4 to 24 h after ASCI. In addition, Mdivi-1(1.2 mg/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 16 h and 3 days after ASCI, and also inhibited the caspase-3 activation and decrease of the percentage of apoptotic cells at 16 h, 3 and 10 days, further, ameliorated the motor dysfunction greatly from 3 to 10 days after ASCI in rats. This neuroprotective effect was dose-dependent. However, Mdivi-1(1.2 mg/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 16 h 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.

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Acknowledgments

This study was supported by a Grant from National Natural Science Foundation of China (Grant No. 81272074); Doctoral Scientific Research Starting Fundation of Liao Ning Province (Grant No. 20121094); Program for Liaoning Excellent Talents in University (Grant No. 2014091).

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Authors and Affiliations

  1. Department of Orthopaedics, The First Affiliated Hospital, Liaoning Medical University, 5-2 Renmin Street, Guta District, Jinzhou, 121000, Liaoning Province, People’s Republic of China

    Gang Li, Zhiqiang Jia, Yang Cao, Yansong Wang, Haotian Li, Gang Lv & Zhongkai Fan

  2. Department of Orthopaedics, The First Affiliated Hospital, China Medical University, Shenyang, 110001, Liaoning Province, People’s Republic of China

    Zhenyu Zhang

  3. Key Laboratory of Neurodegenerative Diseases, Liaoning Medical University, Jinzhou, 121000, Liaoning Province, People’s Republic of China

    Jing Bi

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  1. Gang Li
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Correspondence to Gang Lv or Zhongkai Fan.

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Li, G., Jia, Z., Cao, Y. et al. Mitochondrial Division Inhibitor 1 Ameliorates Mitochondrial Injury, Apoptosis, and Motor Dysfunction After Acute Spinal Cord Injury in Rats. Neurochem Res 40, 1379–1392 (2015). https://doi.org/10.1007/s11064-015-1604-3

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