Cross-talk between guanidinoacetate neurotoxicity, memory and possible neuroprotective role of creatine.

Abstract

Guanidinoacetate Methyltransferase deficiency is an inborn error of metabolism that results in decreased creatine and increased guanidinoacetate (GAA) levels. Patients present neurological symptoms whose mechanisms are unclear. We investigated the effects of an intrastriatal administration of 10 μM of GAA (0.02 nmol/striatum) on energy metabolism, redox state, inflammation, glutamate homeostasis, and activities/immunocontents of acetylcholinesterase and Na+,K+-ATPase, as well as on memory acquisition. The neuroprotective role of creatine was also investigated. Male Wistar rats were pretreated with creatine (50 mg/kg) or saline for 7 days underwenting stereotactic surgery. Forty-eight hours after surgery, the animals (then sixty-days-old) were divided into groups: Control, GAA, GAA + Creatine, and Creatine. Experiments were performed 30 min after intrastriatal infusion. GAA decreased SDH, complexes II and IV activities, and ATP levels, but had no effect on mitochondrial mass/membrane potential. Creatine totally prevented SDH and complex II, and partially prevented COX and ATP alterations. GAA increased dichlorofluorescein levels and decreased superoxide dismutase and catalase activities. Creatine only prevented catalase and dichlorofluorescein alterations. GAA increased cytokines, nitrites levels and acetylcholinesterase activity, but not its immunocontent. Creatine prevented such effects, except nitrite levels. GAA decreased glutamate uptake, but had no effect on the immunocontent of its transporters. GAA decreased Na+,K+-ATPase activity and increased the immunocontent of its α3 subunit. The performance on the novel object recognition task was also impaired. Creatine partially prevented the changes in glutamate uptake and Na+,K+-ATPase activity, and completely prevented the memory impairment. This study helps to elucidate the protective effects of creatine against the damage caused by GAA.

• Authors: Eduardo Peil Marques, Fernanda Silva Ferreira, Tiago Marcon Santos, Caroline Acauan Prezzi, Leo A M Martins, Larissa Daniele Bobermin, André Quincozes-Santos, Angela T S Wyse
• Journal: Biochimica et biophysica acta. Molecular basis of disease (Biochim Biophys Acta Mol Basis Dis) Vol. 1865 Issue 11 Pg. 165529 (11 01 2019) ISSN: 1879-260X [Electronic] Netherlands
• PMID: 31398469 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019. Published by Elsevier B.V.

Chemical References

• Cholinesterase Inhibitors
• Neuroprotective Agents
• Acetylcholinesterase
• Sodium-Potassium-Exchanging ATPase
• glycocyamine
• Creatine
• Glycine

Topics

• Acetylcholinesterase (metabolism)
• Animals
• Cholinesterase Inhibitors (administration & dosage, toxicity)
• Creatine (pharmacology, therapeutic use)
• Energy Metabolism (drug effects)
• Glycine (administration & dosage, analogs & derivatives, toxicity)
• Male
• Memory (drug effects)
• Neuroprotective Agents (pharmacology, therapeutic use)
• Neurotoxicity Syndromes (drug therapy, metabolism, physiopathology)
• Oxidative Stress (drug effects)
• Rats, Wistar
• Sodium-Potassium-Exchanging ATPase (antagonists & inhibitors, metabolism)