Attenuation of acute mitochondrial dysfunction after traumatic brain injury in mice by NIM811, a non-immunosuppressive cyclosporin A analog

Exp Neurol. 2008 Jan;209(1):243-53. doi: 10.1016/j.expneurol.2007.09.025. Epub 2007 Oct 5.

Abstract

Following traumatic brain injury (TBI), mitochondrial function becomes compromised. Mitochondrial dysfunction is characterized by intra-mitochondrial Ca(2+) accumulation, induction of oxidative damage, and mitochondrial permeability transition (mPT). Experimental studies show that cyclosporin A (CsA) inhibits mPT. However, CsA also inhibits calcineurin. In the present study, we conducted a dose-response analysis of NIM811, a non-calcineurin inhibitory CsA analog, on mitochondrial dysfunction following TBI in mice, and compared the effects of the optimal dose of NIM811 (10 mg/kg i.p.) against an optimized dose of CsA (20 mg/kg i.p.). Male CF-1 mice were subjected to severe TBI utilizing the controlled cortical impact model. Mitochondrial respiration was assessed from animals treated with either NIM811, CsA, or vehicle 15 min post-injury. The respiratory control ratio (RCR) of mitochondria from vehicle-treated animals was significantly (p<0.01) lower at 3 or 12 h post-TBI, relative to shams. Treatment of animals with either NIM811 or CsA significantly (p<0.03) attenuated this reduction. Consistent with this finding, both NIM811 and CsA significantly reduced lipid peroxidative and protein nitrative damage to mitochondria at 12 h post-TBI. These results showing the ability of NIM811 to fully duplicate the mitochondrial protective efficacy of CsA supports the conclusion that inhibition of the mPT may be sufficient to explain CsA's protective effects.

Publication types

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

MeSH terms

  • Acute Disease
  • Aldehydes / pharmacology
  • Animals
  • Biomarkers
  • Brain Injuries / complications*
  • Cyclosporine / pharmacology*
  • Dose-Response Relationship, Drug
  • Immunoblotting
  • Lipid Peroxidation / drug effects
  • Male
  • Mice
  • Mitochondrial Diseases / drug therapy*
  • Mitochondrial Diseases / etiology*
  • Oxidative Stress / drug effects
  • Oxygen Consumption / drug effects
  • Structure-Activity Relationship
  • Tyrosine / analogs & derivatives
  • Tyrosine / pharmacology

Substances

  • Aldehydes
  • Biomarkers
  • 3-nitrotyrosine
  • Tyrosine
  • Cyclosporine
  • (melle-4)cyclosporin
  • 4-hydroxy-2-nonenal