Intrastriatal administration of guanidinoacetate inhibits Na+, K+-ATPase and creatine kinase activities in rat striatum.
Guanidinoacetate methyltransferase deficiency (GAMT deficiency) is an inherited neurometabolic disorder clinically characterized by epilepsy and mental retardation and biochemically by accumulation of guanidinoacetate (GAA) and depletion of creatine. Although this disease is predominantly characterized by severe neurological findings, the underlying mechanisms of brain injury are not yet established. In the present study, we investigated the effect of intrastriatal administration of GAA on Na+, K+-ATPase activity, total (tCK), cytosolic (Cy-CK), and mitochondrial (Mi-CK) creatine kinase (CK) activities in rat striatum. We verified that Na+, K+-ATPase, tCK, and Mi-CK activities were significantly inhibited by GAA, in contrast to Cy-CK which was not affected by this guanidino compound. Since these enzyme activities can be affected by reactive species, we also investigated the effect of intrastriatal administration of GAA on thiobarbituric acid reactive substances (TBARS), an index of lipid peroxidation in rats. We found that this metabolite significantly increased this oxidative stress parameter. Considering the importance of Na+, K+-ATPase and CK activities for brain metabolism homeostasis, our results suggest that the inhibition of these enzymes by increased intracerebral levels of GAA may contribute to the neuropathology observed in patients with GAMT-deficiency.
Zugno
Alexandra I
AI
Departamento de Bioquímica, ICBS, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, CEP 90035-003, Porto Alegre, RS, Brazil.
Scherer
Emilene B S
EB
Schuck
Patrícia F
PF
Oliveira
Diogo L
DL
Wofchuk
Suzana
S
Wannmacher
Clovis M D
CM
Wajner
Moacir
M
Wyse
Angela T S
AT
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000201:enzymology*; D003402:Creatine Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D050937:Guanidinoacetate N-Methyltransferase / Q000172:deficiency; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D008845:Microinjections; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
D017392:Thiobarbituric Acid Reactive Substances; D050937:Guanidinoacetate N-Methyltransferase; D003402:Creatine Kinase; D000254:Sodium-Potassium-Exchanging ATPase; C004946:glycocyamine; D005998:Glycine