Comparative neuroprotective effects of cyclosporin A and NIM811, a nonimmunosuppressive cyclosporin A analog, following traumatic brain injury.
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.
Mbye
Lamin H A N
LH
Spinal Cord and Brain Injury Research Center, University of Kentucky College of Medicine, Lexington, Kentucky 40536, USA.
Singh
Indrapal N
IN
Carrico
Kimberly M
KM
Saatman
Kathryn E
KE
Hall
Edward D
ED
D000818:Animals; D001930:Brain Injuries / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002154:Calpain / Q000378:metabolism; D016572:Cyclosporine / Q000737:chemistry* / Q000494:pharmacology*; D003599:Cytoskeleton / Q000187:drug effects / Q000201:enzymology; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D010805:Physical Conditioning, Animal; D013049:Spectrin / Q000378:metabolism
D007166:Immunosuppressive Agents; D018696:Neuroprotective Agents; D013049:Spectrin; D016572:Cyclosporine; D002154:Calpain