Continuous Infusion of Phenelzine, Cyclosporine A, or Their Combination: Evaluation of Mitochondrial Bioenergetics, Oxidative Damage, and Cytoskeletal Degradation following Severe Controlled Cortical Impact Traumatic Brain Injury in Rats.

Abstract

To date, all monotherapy clinical traumatic brain injury (TBI) trials have failed, and there are currently no Food and Drug Administration (FDA)-approved pharmacotherapies for the acute treatment of severe TBI. Due to the complex secondary injury cascade following injury, there is a need to develop multi-mechanistic combinational neuroprotective approaches for the treatment of acute TBI. As central mediators of the TBI secondary injury cascade, both mitochondria and lipid peroxidation-derived aldehydes make promising therapeutic targets. Cyclosporine A (CsA), an FDA-approved immunosuppressant capable of inhibiting the mitochondrial permeability transition pore, and phenelzine (PZ), an FDA-approved monoamine oxidase inhibitor capable of scavenging neurotoxic lipid peroxidation-derived aldehydes, have both been shown to be partially neuroprotective following experimental TBI. Therefore, it follows that the combination of PZ and CsA may enhance neuroprotection over either agent alone through the combining of distinct but complementary mechanisms of action. Additionally, as the first 72 h represents a critical time period following injury, it follows that continuous drug infusion over the first 72 h following injury may also lead to optimal neuroprotective effects. This is the first study to examine the effects of a 72 h subcutaneous continuous infusion of PZ, CsA, and the combination of these two agents on mitochondrial respiration, mitochondrial bound 4-hydroxynonenal (4-HNE), and acrolein, and α-spectrin degradation 72 h following a severe controlled cortical impact injury in rats. Our results indicate that individually, both CsA and PZ are able to attenuate mitochondrial 4-HNE and acrolein, PZ is able to maintain mitochondrial respiratory control ratio and cytoskeletal integrity but together, PZ and CsA are unable to maintain neuroprotective effects.