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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.
AuthorsAlana Pimentel Moura, Mateus Grings, Belisa Dos Santos Parmeggiani, Gustavo Flora Marcowich, Anelise Miotti Tonin, Carolina Maso Viegas, Angela Zanatta, César Augusto João Ribeiro, Moacir Wajner, Guilhian Leipnitz
JournalNeurotoxicity research (Neurotox Res) Vol. 24 Issue 4 Pg. 502-11 (Nov 2013) ISSN: 1476-3524 [Electronic] United States
PMID23640702 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Carbon Dioxide
  • Glycine
Topics
  • Animals
  • Carbon Dioxide (metabolism)
  • Cerebral Cortex (drug effects, enzymology, metabolism)
  • Corpus Striatum (drug effects, enzymology, metabolism)
  • Energy Metabolism (drug effects)
  • Glycine (administration & dosage, pharmacology)
  • Homeostasis (drug effects)
  • Infusions, Intraventricular
  • Mitochondria (drug effects, enzymology, metabolism)
  • Rats
  • Rats, Wistar

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