title: Post-Injury Administration of Mitochondrial Uncouplers Increases Tissue Sparing and Improves Behavioral Outcome following Traumatic Brain Injury in Rodents.
abstract: Following experimental traumatic brain injury (TBI), a rapid and significant necrosis occurs at the site of injury which coincides with significant mitochondrial dysfunction. The present study is driven by the hypothesis that TBI-induced glutamate release increases mitochondrial Ca(2+)cycling/overload, ultimately leading to mitochondrial dysfunction. Based on this premise, mitochondrial uncoupling during the acute phases of TBI-induced excitotoxicity should reduce mitochondrial Ca(2+) uptake (cycling) and reactive oxygen species (ROS) production since both are mitochondrial membrane potential dependent. In the present study, we utilized a cortical impact model of TBI to assess the potential use of mitochondrial uncouplers (2,4-DNP, FCCP) as a neuroprotective therapy. Young adult male rats were intraperitoneally administered vehicle (DMSO), 2,4-DNP (5 mg/kg), or FCCP (2.5 mg/kg) at 5 min post-injury. All animals treated with the uncouplers demonstrated a significant reduction in the amount of cortical damage and behavioral improvement following TBI. In addition, mitochondria isolated from the injured cortex at 3 or 6 h post-injury demonstrated that treatment with the uncouplers significantly improved several parameters of mitochondrial bioenergetics. These results demonstrate that post-injury treatment with mitochondrial uncouplers significantly (p < 0.01) increases cortical tissue sparing ( approximately 12%) and significantly (p< 0.01) improves behavioral outcome following TBI. The mechanism of neuroprotection most likely involves the maintenance of mitochondrial homeostasis by reducing mitochondrial Ca(2+) loading and subsequent mitochondrial dysfunction. These results further implicate mitochondrial dysfunction as an early event in the pathophysiology of TBI and that targeting acute mitochondrial events can result in long-term neuroprotection and improve behavioral outcome following brain injury.
authors.affiliation: Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, Kentucky 40536-0305, USA.
authors.forename: Jignesh D
authors.initials: JD
authors.lastname: Pandya
authors.forename: James R
authors.initials: JR
authors.lastname: Pauly
authors.forename: Vidya N
authors.initials: VN
authors.lastname: Nukala
authors.forename: Andrea H
authors.initials: AH
authors.lastname: Sebastian
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Day
authors.forename: Amit S
authors.initials: AS
authors.lastname: Korde
authors.forename: William F
authors.initials: WF
authors.lastname: Maragos
authors.forename: Edward D
authors.initials: ED
authors.lastname: Hall
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Sullivan
mesh_terms: D019297:2,4-Dinitrophenol / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D001930:Brain Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology / Q000627:therapeutic use; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000209:etiology / Q000517:prevention & control; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D016896:Treatment Outcome; D014475:Uncoupling Agents / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D014475:Uncoupling Agents; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D019297:2,4-Dinitrophenol