title: Phenelzine mitochondrial functional preservation and neuroprotection after traumatic brain injury related to scavenging of the lipid peroxidation-derived aldehyde 4-hydroxy-2-nonenal.
abstract: Phenelzine (PZ) is a scavenger of the lipid peroxidation (LP)-derived reactive aldehyde 4-hydroxynonenal (4-HNE) due to its hydrazine functional group, which can covalently react with 4-HNE. In this study, we first examined the ability of PZ to prevent the respiratory depressant effects of 4-HNE on normal isolated brain cortical mitochondria. Second, in rats subjected to controlled cortical impact traumatic brain injury (CCI-TBI), we evaluated PZ (10 mg/kg subcutaneously at 15 minutes after CCI-TBI) to attenuate 3-hour post-TBI mitochondrial respiratory dysfunction, and in separate animals, to improve cortical tissue sparing at 14 days. While 4-HNE exposure inhibited mitochondrial complex I and II respiration in a concentration-dependent manner, pretreatment with equimolar concentrations of PZ antagonized these effects. Western blot analysis demonstrated a PZ decrease in 4-HNE in mitochondrial proteins. Mitochondria isolated from peri-contusional brain tissue of CCI-TBI rats treated with vehicle at 15 minutes after injury showed a 37% decrease in the respiratory control ratio (RCR) relative to noninjured mitochondria. In PZ-treated rats, RCR suppression was prevented (P<0.05 versus vehicle). In another cohort, PZ administration increased spared cortical tissue from 86% to 97% (P<0.03). These results suggest that PZ's neuroprotective effect is due to mitochondrial protection by scavenging of LP-derived 4-HNE.
authors: Spinal Cord and Brain Injury Research Center (SCoBIRC), Department of Anatomy and Neurobiology, University of Kentucky College of Medicine, Lexington, KY, USA.
authors: Indrapal N
authors: IN
authors: Singh
authors: Lesley K
authors: LK
authors: Gilmer
authors: Darren M
authors: DM
authors: Miller
authors: John E
authors: JE
authors: Cebak
authors: Juan A
authors: JA
authors: Wang
authors: Edward D
authors: ED
authors: Hall
mesh_terms: D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D001930:Brain Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D042967:Electron Transport Complex I / Q000378:metabolism; D042963:Electron Transport Complex II / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010101:Oxygen Consumption / Q000187:drug effects; D010624:Phenelzine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000447:Aldehydes; D024101:Mitochondrial Proteins; D008996:Monoamine Oxidase Inhibitors; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D042963:Electron Transport Complex II; D042967:Electron Transport Complex I; C027576:4-hydroxy-2-nonenal; D010624:Phenelzine