Post-treatment with the cyclosporin derivative, NIM811, reduced indices of cell death and increased the volume of spared tissue in the acute period following spinal cord contusion

J Neurotrauma. 2007 Oct;24(10):1618-30. doi: 10.1089/neu.2007.0329.

Abstract

Cyclosporin A (CsA) is a potent immunosuppressive drug shown to inhibit mitochondrial permeability transition (mPT). Although the therapeutic efficacy of CsA in traumatic brain injury is being investigated, CsA is highly neurotoxic and any neuroprotective effect in models of spinal cord injury (SCI) is unclear. NIM811 is a non-immunosuppressive CsA derivative that inhibits mPT, and is significantly less cytotoxic than CsA. Presently, we investigated the effects of NIM811 post-treatment on indices of apoptosis, lesion size, and tissue sparing at acute time-points following SCI. Adult rats received a "mild/moderate" contusion to the spinal cord, and were administered either 20 mg/kg NIM811 or vehicle by oral gavage 15 min later. One group of rats was euthanized at 1, 4, or 24 h post-injury, and the cytosolic levels of cytochrome c and fragmented DNA in the spinal cord were quantified. The remaining rats received an additional dose of NIM811 or vehicle at 24 h post-injury, and were euthanized on day 7 for morphometric assessments of the lesion and tissue spared. Control groups included rats that received sham surgery or no surgery. The results revealed that NIM811 post-treatment reduced the cytosolic levels of cytochrome c and fragmented DNA during the first 24 h following SCI. NIM811 also reduced the volume of the lesion, and enhanced the volumes of spared gray and white matter at 7 days post-injury. Together, these findings suggest that NIM811 treatment promoted tissue survival following SCI, in part, through inhibition of apoptotic mechanisms. This is the first study to demonstrate the therapeutic potential of NIM811 post-treatment in a model of acute SCI, and supports the need for continued investigation into NIM811 as a neuroprotective treatment for human SCI.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Cyclosporine / administration & dosage*
  • Cytochromes c / analysis
  • Cytochromes c / drug effects
  • Cytosol / chemistry
  • Cytosol / metabolism
  • DNA Fragmentation / drug effects
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Image Processing, Computer-Assisted
  • Neuroprotective Agents / administration & dosage*
  • Rats
  • Rats, Long-Evans
  • Spinal Cord Injuries / drug therapy*
  • Spinal Cord Injuries / pathology
  • Time

Substances

  • Neuroprotective Agents
  • Cyclosporine
  • Cytochromes c
  • (melle-4)cyclosporin