Comparative neuroprotective effects of cyclosporin A and NIM811, a nonimmunosuppressive cyclosporin A analog, following traumatic brain injury

J Cereb Blood Flow Metab. 2009 Jan;29(1):87-97. doi: 10.1038/jcbfm.2008.93. Epub 2008 Aug 20.


Earlier experiments have shown that cyclosporin A (CsA) and its non-calcineurin inhibitory analog NIM811 attenuate mitochondrial dysfunction after experimental traumatic brain injury (TBI). Presently, we compared the neuroprotective effects of previously determined mitochondrial protective doses of CsA (20 mg/kg intraperitoneally) and NIM811 (10 mg/kg intraperitoneally) when administered at 15 mins postinjury in preventing cytoskeletal (alpha-spectrin) degradation, neurodegeneration, and neurological dysfunction after severe (1.0 mm) controlled cortical impact (CCI) TBI in mice. In a first set of experiments, we analyzed calpain-mediated alpha-spectrin proteolysis at 24 h postinjury. Both NIM811 and CsA significantly attenuated the increased alpha-spectrin breakdown products observed in vehicle-treated animals (P<0.005). In a second set of experiments, treatment of animals with either NIM811 or CsA at 15 mins and again at 24 h postinjury attenuated motor function impairment at 48 h and 7 days (P<0.005) and neurodegeneration at 7 days postinjury (P<0.0001). Delayed administration of NIM811 out to 12 h was still able to significantly reduce alpha-spectrin degradation. These results show that the neuroprotective mechanism of CsA involves maintenance of mitochondrial integrity and that calcineurin inhibition plays little or no role because the non-calcineurin inhibitory analog, NIM811, is as effective as CsA.

Publication types

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

MeSH terms

  • Animals
  • Brain Injuries / metabolism
  • Brain Injuries / pathology
  • Brain Injuries / prevention & control*
  • Calpain / metabolism
  • Cyclosporine / chemistry*
  • Cyclosporine / pharmacology*
  • Cytoskeleton / drug effects
  • Cytoskeleton / enzymology
  • Immunosuppressive Agents / chemistry
  • Immunosuppressive Agents / pharmacology
  • Male
  • Mice
  • Motor Activity / drug effects
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology*
  • Physical Conditioning, Animal
  • Spectrin / metabolism


  • Immunosuppressive Agents
  • Neuroprotective Agents
  • Spectrin
  • Cyclosporine
  • Calpain