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Glycine Administration Alters MAPK Signaling Pathways and Causes Neuronal Damage in Rat Brain: Putative Mechanisms Involved in the Neurological Dysfunction in Nonketotic Hyperglycinemia

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Abstract

High glycine (GLY) levels have been suggested to induce neurotoxic effects in the central nervous system of patients with nonketotic hyperglycinemia (NKH). Since the mechanisms involved in the neuropathophysiology of NKH are not totally established, we evaluated the effect of a single intracerebroventricular administration of GLY on the content of proteins involved in neuronal damage and inflammatory response, as well as on the phosphorylation of the MAPK p38, ERK1/2, and JNK in rat striatum and cerebral cortex. We also examined glial fibrillary acidic protein (GFAP) staining, a marker of glial reactivity. The parameters were analyzed 30 min or 24 h after GLY administration. GLY decreased Tau phosphorylation in striatum and cerebral cortex 30 min and 24 h after its administration. On the other hand, synaptophysin levels were decreased in striatum at 30 min and in cerebral cortex at 24 h after GLY injection. GLY also decreased the phosphorylation of p38, ERK1/2, and JNK 30 min after its administration in both brain structures. Moreover, GLY-induced decrease of p38 phosphorylation in striatum was attenuated by N-methyl-d-aspartate receptor antagonist MK-801. In contrast, synuclein, NF-κB, iκB, inducible nitric oxide synthase and nitrotyrosine content, and GFAP immunostaining were not altered by GLY infusion. It may be presumed that the decreased phosphorylation of MAPK associated with alterations of markers of neuronal injury induced by GLY may contribute to the neurological dysfunction observed in NKH.

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Acknowledgements

The authors declare that there is no conflict of interest. This work was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Programa de Apoio a Núcleos de Excelência (PRONEX II), Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS), Pró-Reitoria de Pesquisa/Universidade Federal do Rio Grande do Sul (PROPESQ/UFRGS), Financiadora de estudos e projetos (FINEP), Rede Instituto Brasileiro de Neurociência (IBN-Net) # 01.06.0842-00, and Instituto Nacional de Ciência e Tecnologia em Excitotoxicidade e Neuroproteção (INCT-EN).

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  1. Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

    Alana Pimentel Moura, Belisa Parmeggiani, Juciano Gasparotto, Mateus Grings, Gabriela Miranda Fernandez Cardoso & Bianca Seminotti

  2. Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal de Rio Grande do Sul, Rua Ramiro Barcelos N° 2600 – Attached, Porto Alegre, RS, CEP: 90035-003, Brazil

    José Cláudio Fonseca Moreira, Daniel Pens Gelain, Moacir Wajner & Guilhian Leipnitz

  3. Serviço de Genética Médica do Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil

    Moacir Wajner

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  1. Alana Pimentel Moura
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Correspondence to Guilhian Leipnitz.

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The experiments were approved by the local Animal Ethics Commission (Universidade Federal do Rio Grande do Sul) under the number 23787 and the National Animal Rights Regulations (Law 11.794/2008). The guidelines of National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH publication no. 80–23, revised 1996) and Directive 2010/63/EU were followed. All efforts were made to minimize the number of animals used and their suffering.

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Alana Pimentel Moura and Belisa Parmeggiani have contributed equally to this work.

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Moura, A.P., Parmeggiani, B., Gasparotto, J. et al. Glycine Administration Alters MAPK Signaling Pathways and Causes Neuronal Damage in Rat Brain: Putative Mechanisms Involved in the Neurological Dysfunction in Nonketotic Hyperglycinemia. Mol Neurobiol 55, 741–750 (2018). https://doi.org/10.1007/s12035-016-0319-z

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