title: Regulation of Mitochondrial Function and Glutamatergic System Are the Target of Guanosine Effect in Traumatic Brain Injury.
abstract: Traumatic brain injury (TBI) is a highly complex multi-factorial disorder. Experimental trauma involves primary and secondary injury cascades that underlie delayed neuronal dysfunction and death. Mitochondrial dysfunction and glutamatergic excitotoxicity are the hallmark mechanisms of damage. Accordingly, a successful pharmacological intervention requires a multi-faceted approach. Guanosine (GUO) is known for its neuromodulator effects in various models of brain pathology, specifically those that involve the glutamatergic system. The aim of the study was to investigate the GUO effects against mitochondrial damage in hippocampus and cortex of rats subjected to TBI, as well as the relationship of this effect with the glutamatergic system. Adult male Wistar rats were subjected to a unilateral moderate fluid percussion brain injury (FPI) and treated 15 min later with GUO (7.5 mg/kg) or vehicle (saline 0.9%). Analyses were performed in hippocampus and cortex 3 h post-trauma and revealed significant mitochondrial dysfunction, characterized by a disrupted membrane potential, unbalanced redox system, decreased mitochondrial viability, and complex I inhibition. Further, disruption of Ca2+homeostasis and increased mitochondrial swelling was also noted. Our results showed that mitochondrial dysfunction contributed to decreased glutamate uptake and levels of glial glutamate transporters (glutamate transporter 1 and glutamate aspartate transporter), which leads to excitotoxicity. GUO treatment ameliorated mitochondrial damage and glutamatergic dyshomeostasis. Thus, GUO might provide a new efficacious strategy for the treatment acute physiological alterations secondary to TBI.
authors.affiliation: 1 Departamento de Bioquímica e Biologia Molecular, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria , Santa Maria, RS, Brasil .|5 CNC-Centro de Neurociências e Biologia Celular, Faculdade de Medicina, Universidade de Coimbra , Coimbra, Portugal .
authors.forename: Fernando
authors.initials: F
authors.lastname: Dobrachinski
authors.affiliation: 1 Departamento de Bioquímica e Biologia Molecular, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria , Santa Maria, RS, Brasil .|2 Laboratório de Bioquímica do Exercício, Universidade Federal de Santa Maria , Santa Maria, RS, Brasil .
authors.forename: Rogério
authors.initials: R
authors.lastname: da Rosa Gerbatin
authors.affiliation: 1 Departamento de Bioquímica e Biologia Molecular, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria , Santa Maria, RS, Brasil .
authors.forename: Gláubia
authors.initials: G
authors.lastname: Sartori
authors.affiliation: 1 Departamento de Bioquímica e Biologia Molecular, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria , Santa Maria, RS, Brasil .
authors.forename: Naiani
authors.initials: N
authors.lastname: Ferreira Marques
authors.affiliation: 1 Departamento de Bioquímica e Biologia Molecular, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria , Santa Maria, RS, Brasil .
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Zemolin
authors.affiliation: 1 Departamento de Bioquímica e Biologia Molecular, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria , Santa Maria, RS, Brasil .
authors.forename: Luiz Fernando
authors.initials: LF
authors.lastname: Almeida Silva
authors.affiliation: 1 Departamento de Bioquímica e Biologia Molecular, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria , Santa Maria, RS, Brasil .|4 Programa de Pós-Graduação em Ciências Biológicas, Universidade Federal do Pampa , Campus São Gabriel, São Gabriel, RS, Brasil .
authors.forename: Jeferson Luis
authors.initials: JL
authors.lastname: Franco
authors.affiliation: 1 Departamento de Bioquímica e Biologia Molecular, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria , Santa Maria, RS, Brasil .|2 Laboratório de Bioquímica do Exercício, Universidade Federal de Santa Maria , Santa Maria, RS, Brasil .
authors.forename: Luiz Fernando
authors.initials: LF
authors.lastname: Freire Royes
authors.affiliation: 1 Departamento de Bioquímica e Biologia Molecular, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria , Santa Maria, RS, Brasil .|3 Departamento de Neuropsiquiatria, Centro de Ciências da Saúde, Universidade Federal de Santa Maria , Santa Maria, RS, Brasil .
authors.forename: Michele
authors.initials: M
authors.lastname: Rechia Fighera
authors.affiliation: 1 Departamento de Bioquímica e Biologia Molecular, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria , Santa Maria, RS, Brasil .
authors.forename: Félix Alexandre
authors.initials: FA
authors.lastname: Antunes Soares
mesh_terms: D027322:Amino Acid Transport System X-AG / Q000378:metabolism*; D000818:Animals; D000070642:Brain Injuries, Traumatic / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D004195:Disease Models, Animal; D018698:Glutamic Acid / Q000378:metabolism*; D006151:Guanosine / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D028361:Mitochondrial Diseases / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D010084:Oxidation-Reduction / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
chemical_list: D027322:Amino Acid Transport System X-AG; D006151:Guanosine; D018698:Glutamic Acid
keywords: fluid percussion injury; glutamate; glutamate transporters; mitochondria redox system; purinergic nucleoside