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

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.

• Authors: Alana Pimentel Moura, Belisa Parmeggiani, Juciano Gasparotto, Mateus Grings, Gabriela Miranda Fernandez Cardoso, Bianca Seminotti, José Cláudio Fonseca Moreira, Daniel Pens Gelain, Moacir Wajner, Guilhian Leipnitz
• Journal: Molecular neurobiology (Mol Neurobiol) Vol. 55 Issue 1 Pg. 741-750 (01 2018) ISSN: 1559-1182 [Electronic] United States
• PMID: 28050793 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Glial Fibrillary Acidic Protein
• I-kappa B Proteins
• NF-kappa B
• Synaptophysin
• tau Proteins
• 3-nitrotyrosine
• Tyrosine
• Dizocilpine Maleate
• Nitric Oxide Synthase Type II
• p38 Mitogen-Activated Protein Kinases
• Glycine

Topics

• Animals
• Brain (pathology)
• Corpus Striatum (drug effects, enzymology, pathology, physiopathology)
• Dizocilpine Maleate (pharmacology)
• Glial Fibrillary Acidic Protein (metabolism)
• Glycine (administration & dosage)
• Hyperglycinemia, Nonketotic (pathology, physiopathology)
• I-kappa B Proteins (metabolism)
• Injections, Intraventricular
• MAP Kinase Signaling System (drug effects)
• NF-kappa B (metabolism)
• Neurons (metabolism, pathology)
• Nitric Oxide Synthase Type II (metabolism)
• Phosphorylation (drug effects)
• Rats, Wistar
• Synaptophysin (metabolism)
• Tyrosine (analogs & derivatives, metabolism)
• p38 Mitogen-Activated Protein Kinases (metabolism)
• tau Proteins (metabolism)