title: Post-traumatic cytotoxic edema is directly related to mitochondrial function.
abstract: Cerebral edema represents a major threat following traumatic brain injury. However, therapeutic measures for control of intracranial pressure alone have failed to restore cerebral metabolism and improve neurological outcome. Since mitochondrial damage results in ATP depletion and deactivation of membrane ionic pumps, we hypothesized that modulation of ATP bioavailability may directly affect cytotoxic edema. Intracranial pressure measurements were performed in Sprague-Dawley rats treated by intraperitoneal injection of dimethylsulfoxide (vehicle), cyclosporine A (CsA), or Oligomycin B (OligB) following cortical contusion and further correlated with water content, mitochondrial damage, and electron microscopic assessment of neuronal and axonal edema. As hypothesized, ultra-structural figures of edema closely correlated with intracranial pressure elevation, increased water content and mitochondrial membrane permeabilization expressed by loss of transmembrane mitochondrial potential. Further, mitochondrial damage evidenced ultra-structurally by figures of swollen mitochondria with severely distorted cristae correlated with both cytotoxic edema and mitochondrial dysfunction. Importantly, cerebral edema and mitochondrial impairment were significantly worsened by treatment with OligB, whereas a noticeable improvement could be observed in animals that received injections of CsA. Since OligB and CsA are responsible for symmetrical and opposite effects on oxidative metabolism, these findings support the hypothesis of a causative relationship between edema and mitochondrial function.
authors.affiliation: Institute of Pathology, Rambam Medical Center, Haifa, Israel.|The Ruth & Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.
authors.forename: Eugene
authors.initials: E
authors.lastname: Vlodavsky
authors.affiliation: Eliachar Research Laboratory, Galilee Medical Center, Faculty of Medicine in the Galilee, University of Bar Ilan, Naharia, Israel.
authors.forename: Eilam
authors.initials: E
authors.lastname: Palzur
authors.affiliation: The Ruth & Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.
authors.forename: Mona
authors.initials: M
authors.lastname: Shehadeh
authors.affiliation: Eliachar Research Laboratory, Galilee Medical Center, Faculty of Medicine in the Galilee, University of Bar Ilan, Naharia, Israel jean.soustiel@naharia.health.gov.il.|Department of Neurosurgery, Galilee Medical Center, Faculty of Medicine in the Galilee, University of Bar Ilan, Naharia, Israel.
authors.forename: Jean F
authors.initials: JF
authors.lastname: Soustiel
mesh_terms: D000818:Animals; D001929:Brain Edema / Q000188:drug therapy / Q000209:etiology*; D000070642:Brain Injuries, Traumatic / Q000150:complications*; D016572:Cyclosporine / Q000008:administration & dosage / Q000494:pharmacology; D007427:Intracranial Pressure; D008928:Mitochondria / Q000473:pathology*; D051336:Mitochondrial Membranes / Q000378:metabolism / Q000473:pathology; D009840:Oligomycins / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D009840:Oligomycins; C048335:oligomycin B; D016572:Cyclosporine
keywords: Cerebral metabolism; cytotoxic edema; mitochondria; mitochondrial permeability transition; traumatic brain injury