Neuronal and glial cell death caused by axonal injury sometimes contributes to whole brain pathology after traumatic brain injury (TBI). We show that neuroprotection by 2 types of immunosuppressants, cyclosporin A (CsA) and tacrolimus (FK506), in a cryogenic brain injury model results from inhibition of calcineurin and protection from mitochondrial damage caused by formation of a mitochondrial permeability transition pore induced by cyclophilin D (CyPD), one of the prolyl cis/trans isomerase family members. We evaluated why CsA is neuroprotective by microarray analysis of gene expression in the cryogenic brain injury rat model. Analyses of expression patterns demonstrated that expression of over 14,000 genes changed between the groups with and without CsA treatment, and about 350 genes among them were extracted showing a significant difference. We learned that the differential expression of several gene targets showed specific patterns in a time-dependent manner. These results may help elucidate the mechanisms of neuronal cell death after TBI and the neuroprotective effects of CsA after TBI.