The effects of cyclosporin-A on axonal conduction deficits following traumatic brain injury in adult rats

Abstract

Immunophilin ligands, including cyclosporin-A (CsA), have been shown to be neuroprotective in experimental models of traumatic brain injury (TBI), and to attenuate the severity of traumatic axonal injury. Prior studies have documented CsA treatment to reduce essential components of posttraumatic axonal pathology, including impaired axoplasmic transport, spectrin proteolysis, and axonal swelling. However, the effects of CsA administration on axonal function, following TBI, have not been evaluated. The present study assessed the effects of CsA treatment on compound action potentials (CAPs) evoked in corpus callosum of adult rats following midline fluid percussion injury. Rats received a 20 mg/Kg bolus of CsA, or cremaphor vehicle, at either 15 m or 1 h postinjury, and at 24 h postinjury CAP recording was conducted in coronal brain slices. To elucidate how injury and CsA treatments affect specific populations of axons, CAP waveforms generated largely by myelinated axons (N1) were analyzed separately from the CAP signal which predominantly reflects activity in unmyelinated axons (N2). CsA administration at 15 m postinjury resulted in significant protection of CAP area, and this effect was more pronounced in N1, than in the N2, CAP component. This treatment also significantly protected against TBI-induced reductions in high frequency responding of the N1 CAP signal. In contrast, CsA treatment at 1 h did not significantly protect CAPs, but was associated with atypical waveforms in N1 CAPs, including decreased CAP duration and reduced refractoriness. The present findings also support growing evidence that myelinated and unmyelinated axons respond differentially to injury and neuroprotective compounds.

Therapy Development for Diffuse Axonal Injury

“…42,51 In addition, Colley and coworkers, 177 showed that CsA treatment provided preserved compound action potentials in myelinated axons. This same effect, however, did not translate to the unmyelinated axons after injury.…”

“…This same effect, however, did not translate to the unmyelinated axons after injury. 177 Subsequently, FK506, another immunophilin ligand that attenuates calcineurin but does not affect mitochondrial permeability transition, was evaluated. Surprisingly, FK506 provided dramatic axonal protection after TAI with a reduction in axonal pathology and protection of electrophysiological function, particularly in unmyelinated axons.…”

PEG-PDLLA Micelle Treatment Improves Axonal Function of the Corpus Callosum following Traumatic Brain Injury

“…[21][22][23] CAPs evoked in the corpus callosum are dramatically suppressed in the fluid percussion model of TBI, 21,24 and are rescued by treatments with the immunophilin ligands cyclosporin-A (CsA) and FK506, or the calpain inhibitor MDL 28170. [25][26][27] In the controlled cortical impact model of TBI, our results indicated that micelles treatment improved the function of both the myelinated and unmyelinated axons in the corpus callosum in up to 4 h after TBI.…”

“…2). 25 Dextran dye-labeled cortical and hippocampal neurons (Fig. 4) were analyzed by using Student's t test.…”

“…27 In contrast, early administration of CsA, another immunophilin ligand, is shown to significantly improve the N 1 , but not the N 2 , component of the CAP in the corpus callosum after fluid percussion injury. 25 The efficacy of the micelles in improving the function of both types of axons may be explained by their ability to physically reseal the damaged axolemma of both myelinated and unmyelinated axons. 30 TBI also causes almost immediate membrane perturbation of neuronal somata in the brain, which is followed by abnormal ultrastructural changes such as plasma and nuclear membrane damages, nuclear chromatin condensation, and eventual necrosis.…”