Pretreatment with the cyclosporin derivative, NIM811, improves the function of synaptic mitochondria following spinal cord contusion in rats

J Neurotrauma. 2007 Apr;24(4):613-24. doi: 10.1089/neu.2006.9969.

Abstract

Trauma to the spinal cord causes a cascade of secondary events, such as mitochondrial dysfunction, which disrupts cellular functions and ultimately leads to cell death. Cyclosporin A (CsA) is a potent immunosuppressant that promotes mitochondrial function by inhibiting mitochondrial permeability transition (mPT). Clinical trials examining CsA in traumatic brain injury are currently under-way, but CsA is potentially neurotoxic. NIM811 is a non-immunosuppressive CsA derivative that inhibits mPT at nanomolar concentrations and with significantly less cytotoxicity than CsA. In the present study, we investigated the effects of NIM811 treatment on mitochondrial bioenergetics and the production of reactive oxygen species following spinal cord injury (SCI) in rats. Rats were pretreated with NIM811 or vehicle, and after 15 min the rats received a "mild/moderate" spinal cord contusion. After 24 h, the spinal cords were rapidly removed and synaptosomal mitochondria were isolated. NIM811 pretreatment significantly improved mitochondrial respiratory control ratios, and the maximal electron transport capacity of complex I and II, as well as their ATP-producing capacity. Consistent with the improvements in mitochondrial function, NIM811 pretreatment significantly decreased free radical production in isolated mitochondria. These studies are the first to demonstrate the therapeutic potential of CsA derivatives in a model of SCI, and support the need for continued investigation of compounds like NIM811 as an acute treatment for human SCI.

Publication types

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

MeSH terms

  • Animals
  • Biomechanical Phenomena
  • Chromatography, High Pressure Liquid
  • Contusions / drug therapy*
  • Contusions / metabolism
  • Cyclosporine / pharmacology*
  • Female
  • Mass Spectrometry
  • Mitochondria / chemistry
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Oxygen Consumption / drug effects
  • Rats
  • Rats, Long-Evans
  • Reactive Oxygen Species / metabolism
  • Spinal Cord Injuries / drug therapy*
  • Spinal Cord Injuries / metabolism
  • Synapses / chemistry
  • Synapses / drug effects*
  • Synapses / metabolism

Substances

  • Reactive Oxygen Species
  • Cyclosporine
  • (melle-4)cyclosporin