title: Guanosine Exerts Neuroprotective Effect in an Experimental Model of Acute Ammonia Intoxication.
abstract: The nucleoside guanosine (GUO) increases glutamate uptake by astrocytes and acts as antioxidant, thereby providing neuroprotection against glutamatergic excitotoxicity, as we have recently demonstrated in an animal model of chronic hepatic encephalopathy. Here, we investigated the neuroprotective effect of GUO in an acute ammonia intoxication model. Adult male Wistar rats received an intraperitoneal (i.p.) injection of vehicle or GUO 60 mg/kg, followed 20 min later by an i.p. injection of vehicle or 550 mg/kg of ammonium acetate. Afterwards, animals were observed for 45 min, being evaluated as normal, coma (i.e., absence of corneal reflex), or death status. In a second cohort of rats, video-electroencephalogram (EEG) recordings were performed. In a third cohort of rats, the following were measured: (i) plasma levels of glucose, transaminases, and urea; (ii) cerebrospinal fluid (CSF) levels of ammonia, glutamine, glutamate, and alanine; (iii) glutamate uptake in brain slices; and (iv) brain redox status and glutamine synthetase activity in cerebral cortex. GUO drastically reduced the lethality rate and the duration of coma. Animals treated with GUO had improved EEG traces, decreased CSF levels of glutamate and alanine, lowered oxidative stress in the cerebral cortex, and increased glutamate uptake by astrocytes in brain slices compared with animals that received vehicle prior to ammonium acetate administration. This study provides new evidence on mechanisms of guanine-derived purines in their potential modulation of glutamatergic system, contributing to GUO neuroprotective effects in a rodent model of by acute ammonia intoxication.
authors.affiliation: Postgraduate Program in Biological Sciences: Biochemistry, ICBS, Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil.
authors.forename: G F
authors.initials: GF
authors.lastname: Cittolin-Santos
authors.affiliation: Postgraduate Program in Biological Sciences: Biochemistry, ICBS, Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil.
authors.forename: A M
authors.initials: AM
authors.lastname: de Assis
authors.affiliation: Postgraduate Program in Biological Sciences: Biochemistry, ICBS, Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil.
authors.forename: P A
authors.initials: PA
authors.lastname: Guazzelli
authors.affiliation: Postgraduate Program in Biological Sciences: Biochemistry, ICBS, Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil.
authors.forename: L G
authors.initials: LG
authors.lastname: Paniz
authors.affiliation: Postgraduate Program in Biological Sciences: Biochemistry, ICBS, Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil.
authors.forename: J S
authors.initials: JS
authors.lastname: da Silva
authors.affiliation: Postgraduate Program in Biological Sciences: Biochemistry, ICBS, Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil.|Department of Biochemistry, Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil.
authors.forename: M E
authors.initials: ME
authors.lastname: Calcagnotto
authors.affiliation: Postgraduate Program in Biological Sciences: Biochemistry, ICBS, Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil.
authors.forename: G
authors.initials: G
authors.lastname: Hansel
authors.affiliation: Postgraduate Program in Biological Sciences: Biochemistry, ICBS, Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil.|Department of Physiology, Federal University of Sergipe, São Cristovão, SE, 49100-000, Brazil.
authors.forename: K C
authors.initials: KC
authors.lastname: Zenki
authors.affiliation: Postgraduate Program in Biological Sciences: Biochemistry, ICBS, Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil.|Department of Physiology, Federal University of Sergipe, São Cristovão, SE, 49100-000, Brazil.
authors.forename: E
authors.initials: E
authors.lastname: Kalinine
authors.affiliation: Health Sciences Center, Lutheran University of Brazil (ULBRA), Campus Santa Maria, Santa Maria, RS, 97020-001, Brazil.
authors.forename: M M
authors.initials: MM
authors.lastname: Duarte
authors.affiliation: Postgraduate Program in Biological Sciences: Biochemistry, ICBS, Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil. diogo@ufrgs.br.|Department of Biochemistry, Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil. diogo@ufrgs.br.
authors.forename: D O
authors.initials: DO
authors.lastname: Souza
mesh_terms: D000641:Ammonia / Q000633:toxicity*; D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000134:cerebrospinal fluid; D001921:Brain / Q000378:metabolism; D003128:Coma / Q000097:blood / Q000134:cerebrospinal fluid / Q000139:chemically induced / Q000188:drug therapy; D004195:Disease Models, Animal; D004569:Electroencephalography; D006151:Guanosine / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D017208:Rats, Wistar
chemical_list: D015415:Biomarkers; D018696:Neuroprotective Agents; D006151:Guanosine; D000641:Ammonia
keywords: Acute ammonia intoxication; Glutamate excitotoxicity; Guanosine; Hyperammonemia