Background context: Calcium influx into cells is responsible for initiating the “final pathway” to cell death in neuronal tissue after traumatic or hypoxic injury. The specific pathways in this cascade are myriad, and the importance each one plays is controversial. It is clear, however, that blocking individual pathways confers protection to these tissues.Purpose: In the present study we examined the role of Cyclosporin A (CsA), FK506 and rapamycin modulating the effects of Ca2+ influx through their interactions with immunophilins and specifically the end result of calcineurin modulation.Study design: Dorsal columns were isolated from the spinal cord of adult rats and injured by exposure to hypoxic conditions for 60 minutes. The samples were monitored electrophysiologically in an in vitro recording chamber (maintained at 37 C) during injury, and the compound action potential (CAP) was monitored with glass microelectrodes. The dorsal column was exposed to ischemic Ringers solution alone or with the different immunosuppressants and compared with baseline readings. Functional recovery of the dorsal column was than assessed by recovery of the CAP.Results: The mean CAP decreased to about 20% of baseline control levels during hypoxia, and returned 53.8 ± 7.6% of baseline (p<.05) after reoxygenation. CsA, an immunosuppressant known to inhibit calcineurin, promoted a significantly greater recovery of CAP amplitude to 76.8 ± 5.2% and 72.1 ± 13.2% of control (p<.05) after hypoxic/ischemic injury and reoxygenation of dorsal column white matter when applied at concentrations of 1 μM and 10 μM, respectively. FK506, which also inhibits calcineurin, was applied at a concentration of (0.1 μM), and promoted CAP amplitude recovery to 82.6 ± 5.0% of control after hypoxic/ischemic injury and reoxygenation of dorsal column white matter. The addition of rapamycin (1 μM), which binds to the same immunophilin as FK506, to the FK506 (0.1 μM) solution during hypoxic/ischemic injury showed only recovery of CAP amplitudes to 56.9 ± 6.7% of control (p<.05). Electron microscopy revealed remarkable protection of axons and prevention of organelle disruption in segments treated with CsA and FK506 during hypoxia when compared with hypoxic controls.Conclusion: In conclusion, both CsA and FK506 confer in vitro protection to dorsal columns during hypoxic/ischemic injury at physiological temperatures, and rapamycin blocks the protective effect of FK506. Thus, calcineurin may play an important role in the physiology of neuronal injury.Disclosures: No disclosures.Conflicts of interest: No conflicts.