Lipid peroxidation (LP) is a key contributor to the pathophysiology of
traumatic brain injury (TBI). Traditional
antioxidant therapies are intended to scavenge the
free radicals responsible for either initiation or propagation of LP. A more recently explored approach involves scavenging the terminal LP breakdown products that are highly reactive and neurotoxic carbonyl compounds,
4-hydroxynonenal (4-HNE) and
acrolein (ACR), to prevent their covalent modification and rendering of cellular
proteins nonfunctional leading to loss of ionic homeostasis, mitochondrial failure, and subsequent neuronal death.
Phenelzine (PZ) is a U.S. Food and Drug Administration-approved
monoamine oxidase (
MAO) inhibitor (
MAO-I) used for treatment of
refractory depression that possesses a
hydrazine functional group recently discovered by other investigators to scavenge reactive carbonyls. We hypothesized that PZ will protect mitochondrial function and reduce markers of oxidative damage by scavenging LP-derived
aldehydes. In a first set of in vitro studies, we found that exogenous application of 4-HNE or ACR significantly reduced respiratory function and increased markers of oxidative damage (p < 0.05) in isolated noninjured rat brain cortical mitochondria, whereas PZ pre-treatment significantly prevented
mitochondrial dysfunction and oxidative modification of
mitochondrial proteins in a concentration-related manner (p < 0.05). This effect was not shared by a structurally similar
MAO-I,
pargyline, which lacks the
hydrazine group, confirming that the mitochondrial protective effects of PZ were related to its carbonyl scavenging and not to
MAO inhibition. In subsequent in vivo studies, we documented that PZ treatment begun at 15 min after controlled cortical impact TBI significantly attenuated 72-h post-injury mitochondrial respiratory dysfunction. The cortical mitochondrial respiratory protection occurred together with a significant increase in cortical tissue sparing.