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

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1865

Article

Marques, Eduardo Peil^1,2  Ferreira, Fernanda Silva^1,2  Santos, Tiago Marcon^1,2  Prezzi, Caroline Acauan^1,2  Martins, Leo A. M.²  Bobermin, Larissa Daniele²  Quincozes-Santos, Andre²  Wyse, Angela T. S.^1,2 

[1] Univ Fed Rio Grande do Sul, ICBS, Biochem Dept, Lab Neuroprotect & Neurometab Dis, St Ramiro Barcelos, BR-90035003 Porto Alegre, RS, Brazil

[2] Univ Fed Rio Grande do Sul, ICBS, Biochem Dept, Program Postgrad Biol Sci Biochem, St Ramiro Barcelos,2600 Annex, BR-90035003 Porto Alegre, RS, Brazil

关键词: Guanidinoacetate;    Mitochondria;    Inflammation;    Memory recognition;    Creatine;    Neuroprotection;   

DOI  :  10.1016/j.bbadis.2019.08.005

来源: Elsevier

【 摘 要 】

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 mu M 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 alpha 3 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.

【 授权许可】

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