Hypoxanthine Intrastriatal Administration Alters Neuroinflammatory Profile and Redox Status in Striatum of Infant and Young Adult Rats
- 294 Downloads
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.
KeywordsHypoxanthine Neuroinflammation Microglial and astrocyte markers DNA damage Lesch-Nyhan disease
This work was supported in part by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq-Brazil).
Compliance with Ethical Standards
Conflict of Interests
The authors declare that they have no conflict of interest.
- 3.Jinnah H, Friedmann T (2001) Lesch-Nyhan disease and its variants. In: Scriver C, Beaudet A, Sly W, Valle D (eds) Metabolic molecular bases of inherited disease. Mc Graw-Hill, New York, pp 2537–2569Google Scholar
- 10.Göttle M, Prudente CN, Fu R, Sutcliffe D, Pang H, Cooper D, Veledar E, Glass JD, Gearing M, Visser JE, Jinnah HA (2014) Loss of dopamine phenotype among midbrain neurons in Lesch-Nyhan disease. Ann Neurol. doi: 10.1002/ana.24191Google Scholar
- 21.Zugno AI, Scherer EBS, Mattos C, Ribeiro CAJ, Wannmacher CMD, Wajner M, Wyse ATS (2007) Evidence that the inhibitory effects of guanidinoacetate on the activities of the respiratory chain, Na+, K+-ATPase and creatine kinase can be differentially prevented by taurine and vitamins E and C administration in rat striatum in vivo. Biochim Biophys Acta 1772:563–569. doi: 10.1016/j.bbadis.2007.02.005 CrossRefPubMedGoogle Scholar
- 26.Scherer EBS, Loureiro SO, Vuaden FC, da Cunha AA, Schmitz F, Kolling J, Savio LEB, Bogo MR et al (2014) Mild hyperhomocysteinemia increases brain acetylcholinesterase and proinflammatory cytokine levels in different tissues. Mol Neurobiol 50:589–596. doi: 10.1007/s12035-014-8660-6 CrossRefPubMedGoogle Scholar
- 27.Da Cunha MJ, da Cunha AA, Loureiro SO, Machado FR, Schmitz F, Kolling J, Marques EP, Wyse ATS (2015) Experimental lung injury promotes changes in oxidative/nitrative status and inflammatory markers in cerebral cortex of rats. Mol Neurobiol 52:1590–1600. doi: 10.1007/s12035-014-8961-9 CrossRefPubMedGoogle Scholar
- 30.Schmitz F, Pierozan P, Rodrigues AF, Biasibetti H, Coelho DM, Mussulini BH, Pereira MSL, Parisi MM, Barbé-Tuana F, de Oliveira DL, Vargas CR, Wyse ATS (2015) Chronic treatment with a clinically relevant dose of methylphenidate increases glutamate levels in cerebrospinal fluid and impairs glutamatergic homeostasis in prefrontal cortex of juvenile rats. Mol Neurobiol. doi: 10.1007/s12035-015-9219-xGoogle Scholar
- 40.Morris KR, Lutz RD, Choi H-S, Kamitani T, Chmura K, Chan ED (2003) Role of the NF-kappaB signaling pathway and kappaB cis-regulatory elements on the IRF-1 and iNOS promoter regions in mycobacterial lipoarabinomannan induction of nitric oxide. Infect Immun 71:1442–1452CrossRefPubMedPubMedCentralGoogle Scholar
- 43.Torres RJ, Puig JG (2015) Hypoxanthine deregulates genes involved in early neuronal development. Implications in Lesch-Nyhan disease pathogenesis. J Inherit Metab Dis. doi: 10.1007/s10545-015-9854-4Google Scholar
- 59.Ribeiro BMM, do Carmo MRS, Freire RS, Rocha NFM, Borella VCM, de Menezes AT, Monte AS, Gomes PXL et al (2013) Evidences for a progressive microglial activation and increase in iNOS expression in rats submitted to a neurodevelopmental model of schizophrenia: reversal by clozapine. Schizophr Res 151:12–19. doi: 10.1016/j.schres.2013.10.040 CrossRefPubMedGoogle Scholar
- 60.Xu L, He D, Bai Y (2015) Microglia-mediated inflammation and neurodegenerative disease. Mol Neurobiol. doi: 10.1007/s12035-015-9593-4Google Scholar
- 62.Takeuchi H, Jin S, Wang J, Zhang G, Kawanokuchi J, Kuno R, Sonobe Y, Mizuno T et al (2006) Tumor necrosis factor-alpha induces neurotoxicity via glutamate release from hemichannels of activated microglia in an autocrine manner. J Biol Chem 281:21362–21368. doi: 10.1074/jbc.M600504200 CrossRefPubMedGoogle Scholar