Our laboratory has documented that generation of the potent reactive nitrogen species (RNS) peroxynitrite (PN) is responsible for oxidative damage by lipid peroxidation (LP) and neurotoxic protein modification by binding of LP-derived carbonyl-containing aldehydes such as 4-hydroxynoneal (4-HNE) and acrolein to mitochondrial and other cellular elements during the first 72 hrs after traumatic brain injury (TBI). This oxidative damage causes brain mitochondrial respiratory compromise and decreased calcium (Ca++) buffering which worsens post-TBI neuronal intracellular Ca++ overload, calpain-mediated neuronal cytoskeletal degradation, neurodegeneration and neurological impairment. Recently, a novel antioxidant approach for post-central nervous system (CNS) injury for decreasing, and possibly reversing, oxidative damage has been identified that involves scavenging the LP-derived carbonyl compounds ("carbonyl scavenging") preventing their neurotoxic effects. Preliminary support from other laboratories and our own has shown that certain clinically used drugs that contain hydrazine function groups can covalently bind to 4-HNE or acrolein and prevent their neurotoxicity. The proposed 3 Aim project will employ phenelzine, a long used hydrazine-containing anti-depressant that contains has been found to be an effective carbonyl scavenger, as a tool to investigate the antioxidant neuroprotective effects of carbonyl scavenging in isolated rat brain mitochondria and the rat controlled cortical impact TBI model. Specifcally, the project will define the neuroprotective pharmacology (e.g. mechanism of action, dose-response and therapeutic window) of phenelzine's "carbonyl scavenging" in terms of neuronal mitochondrial and cytoskeletal protection along with the ability to improve chronic motor and cognitive recovery and to decrease post-traumatic neurodegeneration. Since phenelzine has a long history of clinical use and a well understood human safety profile, the translation of the drug's use into clinical TBI trials would be facilitated.
This project will examine the neuroprotective effects of phenelzine, a long-used anti-depressant compound that has recently been discovered to also be a scavenger of lipid peroxidation-derived carbonyl-containing aldehydes such as 4-hydroxynonenal and acrolein, in the rat controlled cortical impact traumatic brain injury model (CCI-TBI). Preliminary data has demonstrated that phenelzine can protect brain mitochchondria from impairment of their function, an effect that is correlated with a lessened 4-hydroxynonenal modification of mitochondrial proteins, and to decrease post-TBI brain damage. This proposal will expand our understanding of the neuroprotective pharmacology (e.g. mechanism of action, dose-response and therapeutic window) of phenelzine's carbonyl scavenging in terms of neuronal mitochondrial and cytoskeletal protection along with the ability to improve chronic motor and cognitive recovery and to decrease post-traumatic neurodegeneration.
|Hall, Edward D; Wang, Juan A; Bosken, Jeffrey M et al. (2016) Lipid peroxidation in brain or spinal cord mitochondria after injury. J Bioenerg Biomembr 48:169-74|
|Cebak, John E; Singh, Indrapal N; Hill, Rachel L et al. (2016) Phenelzine Protects Brain Mitochondrial Function In Vitro and In Vivo following Traumatic Brain Injury by Scavenging the Reactive Carbonyls 4-Hydroxynonenal and Acrolein Leading to Cortical Histological Neuroprotection. J Neurotrauma :|