The protective effect of cyclosporin A upon N-acetylaspartate and mitochondrial dysfunction following experimental diffuse traumatic brain injury

J Neurotrauma. 2004 Sep;21(9):1154-67. doi: 10.1089/neu.2004.21.1154.

Abstract

Pre- and post-injury Cyclosporin A (CsA) administration has shown neuroprotective properties by ameliorating mitochondrial damage. The aim of this study was to assess the effect of CsA upon N-acetylaspartate (NAA) reduction and ATP loss, two sensitive markers of mitochondrial dysfunction and bioenergetic impairment. Adult male Sprague-Dawley rats were exposed to impact acceleration traumatic brain injury (2 m/450 g) and randomized into the following experimental groups: intrathecal CsA/vehicle treated (n = 12), intravenous CsA/vehicle treated (n = 18) and sham (n = 12). Intrathecal treatment consisted of post-injury (30 min) cisternal bolus of CsA or Vehicle (0.15 mL, 10 mg/kg). Intravenous administration consisted of 30 min post-injury continuous 1 hour infusion of either 20 or 35 mg/kg CsA or Vehicle. Quantitative HPLC analysis of whole brain samples was performed 6 h post-injury for levels of NAA and ATP. Following intrathecal delivery CsA demonstrated significant neuroprotection blunting a 30% NAA reduction (p < 0.001) and restoring 26% of the ATP loss (p < 0.005). The 20 mg/kg intravenous dose failed to ameliorate the biochemical damages while the 35 mg/kg dosage showed 36% NAA recovery and 39% ATP restoration (p < 0.001). In conclusion, CsA is capable of restoring ATP and blunting NAA reduction. Intravenous infusion of 35 mg/kg appears to be the optimal therapeutic strategy in this model. These findings contribute to the notion that CsA achieves neuroprotection, preserving mitochondrial function, and provides a rationale for the assessment of CsA in the clinical setting where MR spectroscopy can monitor NAA and ATP in brain-injured patients.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Aspartic Acid / analogs & derivatives*
  • Aspartic Acid / metabolism*
  • Brain Injuries / drug therapy*
  • Brain Injuries / metabolism
  • Brain Injuries / physiopathology
  • Cyclosporine / administration & dosage
  • Cyclosporine / therapeutic use*
  • Drug Administration Schedule
  • Infusions, Intravenous
  • Injections, Spinal
  • Male
  • Mitochondria / drug effects*
  • Mitochondria / pathology*
  • Neuroprotective Agents / administration & dosage
  • Neuroprotective Agents / therapeutic use*
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Neuroprotective Agents
  • Aspartic Acid
  • Cyclosporine
  • N-acetylaspartate