title: Glycine intracerebroventricular administration disrupts mitochondrial energy homeostasis in cerebral cortex and striatum of young rats.
abstract: High tissue levels of glycine (GLY) are the biochemical hallmark of nonketotic hyperglycinemia (NKH), an inherited metabolic disease clinically characterized by severe neurological symptoms and brain abnormalities. Considering that the mechanisms underlying the neuropathology of this disease are not fully established, the present work investigated the in vivo effects of intracerebroventricular administration of GLY on important parameters of energy metabolism in cerebral cortex and striatum from young rats. Our results show that GLY reduced CO₂ production using glucose as substrate and inhibited the activities of citrate synthase and isocitrate dehydrogenase in striatum, whereas no alterations of these parameters were verified in cerebral cortex 30 min after GLY injection. We also observed that GLY diminished the activities of complex IV in cerebral cortex and complex I-III in striatum at 30 min and inhibited complex I-III activity in striatum at 24 h after its injection. Furthermore, GLY reduced the activity of total and mitochondrial creatine kinase in both brain structures 30 min and 24 h after its administration. In contrast, the activity of Na⁺, K⁺-ATPase was not altered by GLY. Finally, the antioxidants N-acetylcysteine and creatine, and the NMDA receptor antagonist MK-801 attenuated or fully prevented the inhibitory effects of GLY on creatine kinase and respiratory complexes in cerebral cortex and striatum. Our data indicate that crucial pathways for energy production and intracellular energy transfer are severely compromised by GLY. It is proposed that bioenergetic impairment induced by GLY in vivo may contribute to the neurological dysfunction found in patients affected by NKH.
authors: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal de Rio Grande do Sul, Rua Ramiro Barcelos N° 2600-Anexo, Porto Alegre, RS, CEP 90035-003, Brazil.
authors: Alana Pimentel
authors: AP
authors: Moura
authors: Mateus
authors: M
authors: Grings
authors: Belisa
authors: B
authors: Dos Santos Parmeggiani
authors: Gustavo Flora
authors: GF
authors: Marcowich
authors: Anelise Miotti
authors: AM
authors: Tonin
authors: Carolina Maso
authors: CM
authors: Viegas
authors: Angela
authors: A
authors: Zanatta
authors: César Augusto João
authors: CA
authors: Ribeiro
authors: Moacir
authors: M
authors: Wajner
authors: Guilhian
authors: G
authors: Leipnitz
mesh_terms: D000818:Animals; D002245:Carbon Dioxide / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D004734:Energy Metabolism / Q000187:drug effects*; D005998:Glycine / Q000008:administration & dosage / Q000494:pharmacology*; D006706:Homeostasis / Q000187:drug effects; D057967:Infusions, Intraventricular; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D002245:Carbon Dioxide; D005998:Glycine
references: Free Radic Biol Med. 2006 Mar 1;40(5):837-49
references: 16520236
references: J Neurochem. 2006 Dec;99(6):1531-42
references: 17230642
references: Life Sci. 2011 Aug 15;89(7-8):276-81
references: 21762704
references: Toxicology. 2000 Dec 7;156(1):47-55
references: 11162875
references: Clin Chim Acta. 1962 Sep;7:597-603
references: 13955534
references: Biochem Soc Trans. 1995 May;23(2):228S
references: 7672249
references: J Cereb Blood Flow Metab. 2011 Mar;31(3):976-85
references: 21081956
references: J Biol Chem. 2006 Dec 8;281(49):37361-71
references: 17028195
references: Life Sci. 2007 Aug 9;81(9):740-9
references: 17698151
references: Neurochem Int. 2004 Jan;44(1):45-52
references: 12963087
references: AJNR Am J Neuroradiol. 1993 May-Jun;14(3):629-35
references: 8517351
references: Biochem J. 1954 Dec;58(4):685-92
references: 13230022
references: J Biol Chem. 1990 Sep 25;265(27):16330-6
references: 2168888
references: Anal Biochem. 1986 Sep;157(2):375-80
references: 2946250
references: Biochem J. 1984 May 15;220(1):301-7
references: 6331412
references: J Pediatr. 1996 Feb;128(2):243-6
references: 8636821
references: J Inherit Metab Dis. 2009 Dec;32(6):720-727
references: 19816787
references: Brain Dev. 2012 Jan;34(1):72-5
references: 21316884
references: Cell Mol Neurobiol. 2009 Sep;29(6-7):1063-71
references: 19350381
references: Mitochondrion. 2012 Jan;12(1):46-56
references: 21640202
references: Eur J Neurosci. 2007 Mar;25(6):1748-56
references: 17408431
references: J Neurochem. 1990 Dec;55(6):2142-5
references: 2121905
references: Am J Dis Child. 1978 Aug;132(8):777-81
references: 80128
references: Clin Chim Acta. 1985 Nov 29;153(1):23-36
references: 3000647
references: Neuroradiology. 2001 Sep;43(9):792-3
references: 11594434
references: Pediatrics. 2000 Jan;105(1):e10
references: 10617747
references: Clin Chim Acta. 1994 Jul;228(1):35-51
references: 7955428
references: Prog Neurobiol. 1993 Jun;40(6):645-70
references: 8484006
references: J Neurosci Res. 2011 Dec;89(12):2068-82
references: 21598289
references: Biochem Biophys Res Commun. 1988 Dec 30;157(3):1423-8
references: 3061381
references: J Neurol Sci. 2006 May 15;244(1-2):23-9
references: 16457851
references: J Biol Chem. 2000 Mar 10;275(10):6937-44
references: 10702255
references: Jpn J Hum Genet. 1997 Mar;42(1):13-22
references: 9183995
references: Cell Mol Neurobiol. 2009 Mar;29(2):253-61
references: 18830815
references: J Inherit Metab Dis. 2012 Mar;35(2):253-61
references: 22002442
references: Neurochem Int. 2010 Jul;56(8):948-54
references: 20394787
references: J Biol Chem. 1998 Jul 3;273(27):16694-9
references: 9642223
references: J Neurochem. 2005 Sep;94(6):1594-603
references: 16045441
references: Mol Genet Metab. 2001 Sep-Oct;74(1-2):139-46
references: 11592811
references: Biochim Biophys Acta. 2002 Jan 2;1586(1):81-91
references: 11781152
references: Biochim Biophys Acta. 1974 Aug 9;356(3):276-87
references: 4367725
references: Neurotox Res. 2011 Jul;20(1):1-14
references: 20734249
references: J Biol Chem. 1951 Nov;193(1):265-75
references: 14907713