title: 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.
abstract: 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.
authors.affiliation: Spinal Cord & Brain Injury Research Center (SCoBIRC) and Department of Anatomy & Neurobiology, University of Kentucky College of Medicine , Lexington, Kentucky.
authors.forename: John E
authors.initials: JE
authors.lastname: Cebak
authors.affiliation: Spinal Cord & Brain Injury Research Center (SCoBIRC) and Department of Anatomy & Neurobiology, University of Kentucky College of Medicine , Lexington, Kentucky.
authors.forename: Indrapal N
authors.initials: IN
authors.lastname: Singh
authors.affiliation: Spinal Cord & Brain Injury Research Center (SCoBIRC) and Department of Anatomy & Neurobiology, University of Kentucky College of Medicine , Lexington, Kentucky.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Hill
authors.affiliation: Spinal Cord & Brain Injury Research Center (SCoBIRC) and Department of Anatomy & Neurobiology, University of Kentucky College of Medicine , Lexington, Kentucky.
authors.forename: Juan A
authors.initials: JA
authors.lastname: Wang
authors.affiliation: Spinal Cord & Brain Injury Research Center (SCoBIRC) and Department of Anatomy & Neurobiology, University of Kentucky College of Medicine , Lexington, Kentucky.
authors.forename: Edward D
authors.initials: ED
authors.lastname: Hall
mesh_terms: D000171:Acrolein / Q000378:metabolism*; D000447:Aldehydes / Q000378:metabolism*; D000818:Animals; D000070642:Brain Injuries, Traumatic / Q000188:drug therapy* / Q000378:metabolism*; D002540:Cerebral Cortex / Q000187:drug effects / Q000293:injuries / Q000378:metabolism; D004195:Disease Models, Animal; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010624:Phenelzine / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000447:Aldehydes; D008996:Monoamine Oxidase Inhibitors; D018696:Neuroprotective Agents; D000171:Acrolein; C027576:4-hydroxy-2-nonenal; D010624:Phenelzine
keywords: 4-hydroxynonenal; acrolein; brain mitochondria; lipid peroxidation; neuroprotection; phenelzine; traumatic brain injury