Over five million people currently live with a disability resulting from a traumatic brain injury (TBI), with an associated economic burden of 60 billion dollars annually. Clinically there are limited treatment options for TBI, and single mechanism agents are unlikely to prevent its devastating neurologic consequences. Therefore, multi-mechanistic combinational therapies must be developed. Synaptic and non-synaptic mitochondrial dysfunction and lipid peroxidation (LP) induced oxidative damage are key contributors to the downstream pathology associated with TBI, including cytoskeletal degradation, neurodegeneration and behavioral impairments. Following injury, increased Ca++ is sequestered by mitochondria resulting in formation of the mitochondrial permeability transition pore (mPTP) and increased formation of reactive oxygen and nitrogen species. These reactive species initiate LP, leading to formation of the neurotoxic LP-breakdown products 4- HNE and acrolein, which covalently bind mitochondrial proteins causing oxidative damage, further enhancing mitochondrial respiratory dysfunction, generation of reactive species, and enhancing formation of mPTP, with synaptic mitochondria being particularly susceptible. Upon mPTP formation, the mitochondria stop producing ATP and lose their Ca++ buffering capacity. Ca++ is released back into the cytosol where it activates the protease calpain causing cytoskeletal degradation. Ultimately, synaptic dysregulation, neurodegeneration and neurologic impairment ensue. Individually, the aldehyde scavenger phenelzine (PZ) and the mPTP inhibitor cyclosporine A (CsA) partially attenuate mitochondrial dysfunction and neuronal damage following controlled cortical impact injury (CCI) in rats. Therefore, our overall hypothesis is that LP-induced neurotoxic aldehyde scavenging and inhibition of mPTP are complimentary and that combining these two mechanisms will additively or synergistically attenuate synaptic and non-synaptic mitochondrial respiratory dysfunction and LP- induced oxidative damage following severe controlled cortical impact (CCI) in rats, leading to decreased cytoskeletal degradation, decreased neurodegeneration, and improved motor and cognitive function.
Aim 1, a dose response, tests the hypothesis that early administration (15min.) of the combination, PZ & CsA, additively or synergistically attenuates synaptic and non-synaptic mitochondrial respiratory dysfunction and LP-induced oxidative damage, as well as neuronal cytoskeletal degradation following severe CCI.
Aim 2 tests the hypothesis that the combination, PZ & CsA, improves the therapeutic window for neuroprotection following severe CCI.
Aim 3 tests the hypothesis that the combination, PZ & CsA, additively or synergistically decreases neurodegeneration and improves motor and cognitive function over the first 28 days following severe CCI. This study will identify differential responses of synaptic and non-synaptic mitochondria to drug therapy following injury. It re-purposes two FDA approved drugs, which use complimentary neuroprotective mechanisms to ultimately identify a more neuroprotective combinational therapy that can successfully translate to human TBI.
Traumatic brain injury (TBI) represents a significant health crisis and affects millions of people worldwide. Currently there are no approved pharmacotherapies for the clinical treatment of TBI. This project combines two FDA approved drugs, phenelzine and cyclosporine A, to protect synaptic and non-synaptic mitochondria, prevent neuronal damage, and improve motor and cognitive function following experimental TBI.
|Kulbe, Jacqueline R; Singh, Indrapal N; Wang, Juan A et al. (2018) 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. J Neurotrauma 35:1280-1293|
|Kulbe, Jacqueline R; Hall, Edward D (2017) Chronic traumatic encephalopathy-integration of canonical traumatic brain injury secondary injury mechanisms with tau pathology. Prog Neurobiol 158:15-44|
|Kulbe, Jacqueline R; Hill, Rachel L; Singh, Indrapal N et al. (2017) Synaptic Mitochondria Sustain More Damage than Non-Synaptic Mitochondria after Traumatic Brain Injury and Are Protected by Cyclosporine A. J Neurotrauma 34:1291-1301|