Journal
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
Volume 29, Issue 1, Pages 87-97Publisher
SAGE PUBLICATIONS INC
DOI: 10.1038/jcbfm.2008.93
Keywords
calpain; alpha-spectrin; motor function; mitochondrial permeability transition pore; NIM811; traumatic brain injury
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Funding
- NIH [1R01 NS046566, 1P30 NS051220]
- Kentucky Spinal Cord and Head Injury Research Trust (KSCHIRT)
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [P30NS051220, R01NS046566] Funding Source: NIH RePORTER
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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, neuro-degeneration, 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 a-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.
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