Laboratory of Neuroprotection and Neurometabolic Diseases, Biochemistry Department, ICBS, Universidade Federal do Rio Grande do Sul, Street Ramiro Barcelos, 2600-Annex, CEP 90035-003 Porto Alegre, RS, Brazil; Program of Post-graduation in Biological Sciences-Biochemistry, Biochemistry Department, ICBS, Universidade Federal do Rio Grande do Sul, Street Ramiro Barcelos, 2600-Annex, CEP 90035-003 Porto Alegre, RS, Brazil.
Program of Post-graduation in Biological Sciences-Biochemistry, Biochemistry Department, ICBS, Universidade Federal do Rio Grande do Sul, Street Ramiro Barcelos, 2600-Annex, CEP 90035-003 Porto Alegre, RS, Brazil.
Biochim Biophys Acta Mol Basis Dis. 2019 Nov 1;1865(11):165529. doi: 10.1016/j.bbadis.2019.08.005. Epub 2019 Aug 6.
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.
胍基乙酸甲基转移酶缺乏症是一种代谢性先天缺陷，导致肌酸减少和胍基乙酸（GAA）水平升高。患者表现出神经系统症状，但其机制尚不清楚。我们研究了纹状体腔内给予 10μM GAA（0.02nmol/纹状体）对能量代谢、氧化还原状态、炎症、谷氨酸稳态以及乙酰胆碱酯酶和 Na，K-ATP 酶的活性/免疫含量的影响，以及对记忆获得的影响。还研究了肌酸的神经保护作用。雄性 Wistar 大鼠用肌酸（50mg/kg）或生理盐水预处理 7 天，然后进行立体定向手术。手术后 48 小时，动物（60 天大）分为对照组、GAA 组、GAA+肌酸组和肌酸组。纹状体腔内输注 30min 后进行实验。GAA 降低 SDH、复合物 II 和 IV 的活性以及 ATP 水平，但对线粒体质量/膜电位没有影响。肌酸完全阻止了 SDH 和复合物 II 的改变，部分阻止了 COX 和 ATP 的改变。GAA 增加二氯荧光素水平并降低超氧化物歧化酶和过氧化氢酶的活性。肌酸仅阻止了过氧化氢酶和二氯荧光素的改变。GAA 增加细胞因子、亚硝酸盐水平和乙酰胆碱酯酶的活性，但不影响其免疫含量。肌酸防止了这种作用，除了亚硝酸盐水平。GAA 降低了谷氨酸摄取，但对其转运体的免疫含量没有影响。GAA 降低了 Na，K-ATP 酶的活性并增加了其α3 亚基的免疫含量。在新物体识别任务中的表现也受到损害。肌酸部分阻止了谷氨酸摄取和 Na，K-ATP 酶活性的变化，并完全防止了记忆障碍。这项研究有助于阐明肌酸对 GAA 引起的损伤的保护作用。
