title: Erythropoietin and Its Derivates Modulate Mitochondrial Dysfunction after Diffuse Traumatic Brain Injury.
abstract: Inhibiting the opening of mitochondrial permeability transition pore (mPTP), thereby maintaining the mitochondrial membrane potential and calcium homeostasis, could reduce the induction of cell death. Although recombinant human erythropoietin (rhEpo) and carbamylated erythropoietin (Cepo) were shown to prevent apoptosis after traumatic brain injury (TBI), their impact on mPTP is yet unknown. Thirty minutes after diffuse TBI (impact-acceleration model), rats were intravenously administered a saline solution (TBI-saline), 5000 UI/kg rhEpo (TBI-rhEpo) or 50 μg/kg Cepo (TBI-Cepo). A fourth group received no TBI insult (sham-operated) (n = 11 rats per group). Post-traumatic brain edema was measured using magnetic resonance imaging. A first series of experiments was conducted 2 h after TBI (or equivalent) to investigate the mitochondrial function with the determination of thresholds for mPTP opening and ultrastructural mitochondrial changes. In addition, the intramitochondrial calcium content [Caim] was measured. In a second series of experiments, brain cell apoptosis was assessed at 24 h post-injury. TBI-rhEpo and TBI-Cepo groups had a reduced brain edema compared with TBI-saline. They had higher threshold for mPTP opening with succinate as substrate: 120 (120-150) (median, interquartiles) and 100 (100-120) versus 80 (60-90) nmol calcium/mg protein in TBI-saline, respectively (p < 0.05). Similar findings were shown with glutamate-malate as substrate. TBI-rhEpo and Cepo groups had less morphological mitochondrial disruption in astrocytes. The elevation in [Caim] after TBI was not changed by rhEpo and Cepo treatment. Finally, rhEpo and Cepo reduced caspase-3 expression at 24 h post-injury. These results indicate that rhEpo and Cepo could modulate mitochondrial dysfunction after TBI. The mechanisms involved are discussed.
authors.affiliation: 1 INSERM , U1216, Grenoble, France .|2 Grenoble Institut des Neurosciences, Université Grenoble Alpes , Grenoble, France .|3 Département de Réanimation Pédiatrique et Néonatale, Hôpital Couple Enfant , Grenoble, France .
authors.forename: Anne
authors.initials: A
authors.lastname: Millet
authors.affiliation: 1 INSERM , U1216, Grenoble, France .|2 Grenoble Institut des Neurosciences, Université Grenoble Alpes , Grenoble, France .|4 Pôle d'Anesthésie Réanimation, CHU Grenoble Alpes , Grenoble, France .
authors.forename: Pierre
authors.initials: P
authors.lastname: Bouzat
authors.affiliation: 1 INSERM , U1216, Grenoble, France .|2 Grenoble Institut des Neurosciences, Université Grenoble Alpes , Grenoble, France .|4 Pôle d'Anesthésie Réanimation, CHU Grenoble Alpes , Grenoble, France .
authors.forename: Thibaut
authors.initials: T
authors.lastname: Trouve-Buisson
authors.affiliation: 5 INSERM, U1055, Laboratoire de Biologie Fondamentale et Appliquée, Université Joseph Fourier , Grenoble, France .
authors.forename: Cécile
authors.initials: C
authors.lastname: Batandier
authors.affiliation: 1 INSERM , U1216, Grenoble, France .|2 Grenoble Institut des Neurosciences, Université Grenoble Alpes , Grenoble, France .
authors.forename: Karin
authors.initials: K
authors.lastname: Pernet-Gallay
authors.affiliation: 1 INSERM , U1216, Grenoble, France .|2 Grenoble Institut des Neurosciences, Université Grenoble Alpes , Grenoble, France .|4 Pôle d'Anesthésie Réanimation, CHU Grenoble Alpes , Grenoble, France .
authors.forename: Lucie
authors.initials: L
authors.lastname: Gaide-Chevronnay
authors.affiliation: 1 INSERM , U1216, Grenoble, France .
authors.forename: Emmanuel L
authors.initials: EL
authors.lastname: Barbier
authors.affiliation: 3 Département de Réanimation Pédiatrique et Néonatale, Hôpital Couple Enfant , Grenoble, France .
authors.forename: Thierry
authors.initials: T
authors.lastname: Debillon
authors.affiliation: 5 INSERM, U1055, Laboratoire de Biologie Fondamentale et Appliquée, Université Joseph Fourier , Grenoble, France .|6 Unité de Nutrition Parentérale, Pôle de médecin Aigue Spécialisée, CHU Grenoble Alpes , Grenoble, France .
authors.forename: Eric
authors.initials: E
authors.lastname: Fontaine
authors.affiliation: 1 INSERM , U1216, Grenoble, France .|2 Grenoble Institut des Neurosciences, Université Grenoble Alpes , Grenoble, France .|4 Pôle d'Anesthésie Réanimation, CHU Grenoble Alpes , Grenoble, France .
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Payen
mesh_terms: D000818:Animals; D000070642:Brain Injuries, Traumatic / Q000503:physiopathology*; D004921:Erythropoietin / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000187:drug effects*; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects*; D000083162:Mitochondrial Permeability Transition Pore; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D018696:Neuroprotective Agents; D004921:Erythropoietin
keywords: brain edema; erythropoietin; mitochondrial permeability; transition pore; traumatic brain injury