NEUROPROTECTIVE STRATEGIES FOLLOWING EXPERIMENTAL TRAUMATIC BRAIN INJURY: LIPID PEROXIDATION-DERIVED ALDEHYDE SCAVENGING AND INHIBITION OF MITOCHONDRIAL PERMEABILITY TRANSITION

Traumatic brain injury (TBI) represents a significant health crisis. To date there are no FDA-approved pharmacotherapies available to prevent the neurologic deficits caused by TBI. Following TBI, dysfunctional mitochondria generate reactive oxygen and nitrogen species, initiating lipid peroxidation (LP) and the formation of LP-derived neurotoxic aldehydes, which bind mitochondrial proteins, exacerbating dysfunction and opening of the mitochondrial permeability pore (mPTP), resulting in extrusion of mitochondrial sequestered calcium into the cytosol, and initiating a downstream cascade of calpain activation, spectrin degradation, neurodegeneration and neurologic impairment. As central mediators of the TBI secondary injury cascade, mitochondria and LP-derived neurotoxic aldehydes make promising therapeutic targets. In fact, Cyclosporine A (CsA), an FDA-approved immunosuppressant capable of inhibiting mPTP has been shown to be neuroprotective in experimental TBI. Additionally, phenelzine (PZ), an FDA-approved non-selective irreversible monoamine oxidase inhibitor (MAOI) class antidepressant has also been shown to be neuroprotective in experimental TBI due to the presence of a hydrazine (-NH-NH2) moiety allowing for the scavenging of LP-derived neurotoxic aldehydes. The overall goal of this dissertation is to further examine the neuroprotective effects of the mPTP inhibitor, CsA, and the LP-derived neurotoxic aldehyde scavenger, PZ, using a severe controlled cortical impact injury (CCI) model in 3-month old male Sprague-Dawley rats. First, the effects of CsA on cortical synaptic and non-synaptic mitochondria, two heterogeneous populations, are examined. Our results indicate that compared to non-synaptic mitochondria, synaptic mitochondria sustain greater damage 24h following CCI and are protected to a greater degree by CsA. Second, the neuroprotective effects of a novel 72h continuous subcutaneous infusion of CsA combined with PZ are compared to monotherapy. Following CCI, our results indicate that individually both CsA and PZ attenuate modification of mitochondrial proteins by LP-derived neurotoxic aldehydes, PZ is able to maintain mitochondrial respiratory control ratio and cytoskeletal integrity, but together, PZ and CsA, are unable to improve and in some cases negate monotherapy neuroprotective effects. Finally, the effects of PZ (MAOI, aldehyde scavenger), pargyline (PG, MAOI, non-aldehyde scavenger) and hydralazine (HZ, non-MAOI, aldehyde scavenger) are compared. Our results indicate that PZ, PG, and HZ are unable to improve CCI-induced deficits to learning and memory as measured by Morris water maze (post-CCI D3-7). Of concern, PZ animals lost a significant amount of weight compared to all other group, possibly due to MAOI effects. In fact, in uninjured cortical tissue, PZ administration leads to a significant increase in norepinephrine and serotonin. Additionally, although PZ, PG, and HZ did not lead to a statistically significant improvement in cortical tissue sparing 8 days following CCI, the HZ group saw a 10% improvement over vehicle. Overall, these results indicate that pharmacotherapies which improve mitochondrial function and decrease lipid peroxidation should continue to be pursued as neuroprotective approaches to TBI. However, further pursuit of LP-derived aldehyde scavengers for clinical use in TBI may require the development of hydrazine (-NH-NH2)-compounds which lack additional confounding mechanisms of action