Glycine Intracerebroventricular Administration Disrupts Mitochondrial Energy Homeostasis in Cerebral Cortex and Striatum of Young Rats
Glycine Intracerebroventricular Administration Disrupts Mitochondrial Energy Homeostasis in Cerebral Cortex and Striatum of Young Rats
复制标题
甘氨酸脑室内给药破坏幼鼠大脑皮层和纹状体的线粒体能量稳态
DOI：
10.1007/s12640-013-9396-1
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发表时间：
2013
影响因子：
3.7
通讯作者：
G. Leipnitz
中科院分区：
文献类型：
--
作者：
A. P. Moura;M. Grings;Belisa Santos Parmeggiani;Gustavo Flora Marcowich;A. Tonin;C. M. Viegas;Â. Zanatta;C. Ribeiro;M. Wajner;G. Leipnitz
高组织甘氨酸 (GLY) 水平是非酮性高甘氨酸血症 (NKH) 的生化标志，这是一种遗传性代谢疾病，临床特征为严重的神经系统症状和大脑异常。考虑到该疾病的神经病理学机制尚未完全确定，目前的工作研究了脑室内注射 GLY 对年轻大鼠大脑皮层和纹状体能量代谢重要参数的影响。我们的结果表明，GLY 以葡萄糖为底物减少 CO2 产生，并抑制纹状体中柠檬酸合酶和异柠檬酸脱氢酶的活性，而注射 GLY 30 分钟后，在大脑皮层中未证实这些参数发生变化。我们还观察到，GLY 在注射后 30 分钟降低了大脑皮层中复合物 IV 和纹状体中复合物 I-III 的活性，并在注射后 24 小时抑制了纹状体中复合物 I-III 的活性。此外，GLY 在给药后 30 分钟和 24 小时降低了大脑结构中总肌酸激酶和线粒体肌酸激酶的活性。相反，GLY 不会改变 Na+、K+-ATP 酶的活性。最后，抗氧化剂N-乙酰半胱氨酸和肌酸以及NMDA受体拮抗剂MK-801减弱或完全阻止GLY对大脑皮层和纹状体中肌酸激酶和呼吸复合物的抑制作用。我们的数据表明，GLY 严重损害了能量产生和细胞内能量转移的关键途径。有人提出，GLY 在体内引起的生物能损伤可能会导致 NKH 患者的神经功能障碍。
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 CO2production 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 antioxidantsN-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.
非酮症高甘氨酸血症患者服用丙戊酸钠后癫痫发作频率反而增加
DOI：
10.1016/j.braindev.2011.01.005
发表时间：
2012
期刊：
Brain Dev
影响因子：
--
作者：
Morita M;Kuba K;Ichikawa A;Nakayama M;Katahira J;Iwamoto R;Watanebe T;Sakabe S;Daidoji T;Nakamura S;Kadowaki A;Ohto T;Nakanishi H;Taguchi R;Nakaya T;Murakami M;Yoneda Y;Arai H;Kawaoka Y;Penninger JM;Arita M;Imai Y.;Tsuyusaki Y
通讯作者：
Tsuyusaki Y