title: Hypoxanthine Intrastriatal Administration Alters Neuroinflammatory Profile and Redox Status in Striatum of Infant and Young Adult Rats.
abstract: Hypoxanthine, the major oxypurine metabolite involved in purine's salvage pathway in the brain, is accumulated in Lesch-Nyhan disease, an inborn error of metabolism of purine. The purpose of this study was to investigate the effects of hypoxanthine intrastriatal administration on infant and young adult rats submitted to stereotactic surgery. We analyzed the effect of hypoxanthine on neuroinflammatory parameters, such as cytokine levels, immunocontent of NF-κB/p65 subunit, iNOS immunocontent, nitrite levels, as well as IBA1 and GFAP immunocontent in striatum of infant and young adult rats. We also evaluate some oxidative parameters, including reactive species production, superoxide dismutase, catalase, glutathione peroxidase activities, as well as DNA damage. Wistar rats of 21 and 60 days of life underwent stereotactic surgery and were divided into two groups: control (infusion of saline 0.9 %) and hypoxanthine (10 μM). Intrastriatal administration of hypoxanthine increased IL-6 levels in striatum of both ages of rats tested, while TNF-α increased only in 21-day-old rats. Hypoxanthine also increased nuclear immunocontent of NF-κB/p65 subunit in striatum of both ages of rats. Nitrite levels were decreased in striatum of 21-day-old rats; however, the immunocontent of iNOS was increased in striatum of hypoxanthine groups. Microglial and astrocyte activation was seen by the increase in IBA1 and GFAP immunocontent, respectively, in striatum of infant rats. All oxidative parameters were altered, suggesting a strong neurotoxic hypoxanthine role on oxidative stress. According to our results, hypoxanthine intrastriatal administration increases neuroinflammatory parameters perhaps through oxidative misbalance, suggesting that this process may be involved, at least in part, to neurological disorders found in patients with Lesch-Nyhan disease.
authors.affiliation: Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, ICBS, UFRGS, Rua Ramiro Barcelos, 2600-Anexo, CEP 90035-003, Porto Alegre, RS, Brazil.
authors.forename: Helena
authors.initials: H
authors.lastname: Biasibetti
authors.affiliation: Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, ICBS, UFRGS, Rua Ramiro Barcelos, 2600-Anexo, CEP 90035-003, Porto Alegre, RS, Brazil.
authors.forename: Paula
authors.initials: P
authors.lastname: Pierozan
authors.affiliation: Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, ICBS, UFRGS, Rua Ramiro Barcelos, 2600-Anexo, CEP 90035-003, Porto Alegre, RS, Brazil.
authors.forename: André Felipe
authors.initials: AF
authors.lastname: Rodrigues
authors.affiliation: Universidade Federal do Pampa, BR 472, Km 585, Caixa Postal 118, 97500-970, Uruguaiana, RS, Brazil.
authors.forename: Vanusa
authors.initials: V
authors.lastname: Manfredini
authors.affiliation: Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, ICBS, UFRGS, Rua Ramiro Barcelos, 2600-Anexo, CEP 90035-003, Porto Alegre, RS, Brazil. wyse@ufrgs.br.|Laboratório de Neuroproteção e Doenças Neurometabólicas. Departamento de Bioquímica, ICBS, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, CEP 90035-003, Porto Alegre, RS, Brazil. wyse@ufrgs.br.
authors.forename: Angela T S
authors.initials: ATS
authors.lastname: Wyse
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D019271:Hypoxanthine / Q000008:administration & dosage* / Q000494:pharmacology*; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D017208:Rats, Wistar
chemical_list: D016207:Cytokines; D009573:Nitrites; D019271:Hypoxanthine; D052247:Nitric Oxide Synthase Type II
keywords: DNA damage; Hypoxanthine; Lesch-Nyhan disease; Microglial and astrocyte markers; Neuroinflammation