Zeevalk Gail D, Manzino Lawrence, Sonsalla Patricia K
Department of Neurology, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey 08854, USA.
Exp Neurol. 2002 Jul;176(1):193-202. doi: 10.1006/exnr.2002.7917.
Previous work has shown that overstimulation of GABA(A) receptors can potentiate neuronal cell damage during excitotoxic or metabolic stress in vitro and that GABA(A) antagonists or GABA transport blockers are neuroprotective under these situations. Malonate, a reversible succinate dehydrogenase/mitochondrial complex II inhibitor, is frequently used in animals to model cell loss in neurodegenerative diseases such as Parkinson's and Huntington's diseases. To determine if GABA transporter blockade during mitochondrial impairment can protect neurons in vivo as compared with in vitro studies, rats received a stereotaxic infusion of malonate (2 micromol) into the left striatum to induce a metabolic stress. The nonsubstrate GABA transport blocker, NO711 (20 nmol) was infused in some rats 30 min before and 3 h following malonate infusion. After 1 week, dopamine and GABA levels in the striata were measured. Malonate caused a significant loss of striatal dopamine and GABA. Blockade of the GABA transporter significantly attenuated GABA, but not dopamine loss. In contrast with several in vitro reports, GABA(A) receptors were not a downstream mediator of protection by NO711. Intrastriatal infusion of malonate (2 micromol) plus or minus the GABA(A) receptor agonist muscimol (1 micromol), the GABA(A) Cl- binding site antagonist picrotoxin (50 nmol) or the GABA(B) receptor antagonist saclofen (33 nmol) did not modify loss of striatal dopamine or GABA when examined 1 week following infusion. These data show that GABA transporter blockade during mitochondrial impairment in the striatum provides protection to GABAergic neurons. GABA transporter blockade, which is currently a pharmacological strategy for the treatment of epilepsy, may thus also be beneficial in the treatment of acute and chronic conditions involving energy inhibition such as stroke/ischemia or Huntington's disease. These findings also point to fundamental differences between immature and adult neurons in the downstream involvement of GABA receptors during metabolic insult.
先前的研究表明，在体外兴奋性毒性或代谢应激期间，GABA(A)受体的过度刺激会增强神经元细胞损伤，并且在这些情况下，GABA(A)拮抗剂或GABA转运体阻滞剂具有神经保护作用。丙二酸是一种可逆的琥珀酸脱氢酶/线粒体复合物II抑制剂，常用于动物模型来模拟帕金森病和亨廷顿病等神经退行性疾病中的细胞损失。为了确定与体外研究相比，线粒体损伤期间GABA转运体阻断在体内是否能保护神经元，大鼠接受立体定向注射丙二酸（2微摩尔）至左侧纹状体以诱导代谢应激。在丙二酸注射前30分钟和注射后3小时，给一些大鼠注射非底物GABA转运体阻滞剂NO711（20纳摩尔）。1周后，测量纹状体中的多巴胺和GABA水平。丙二酸导致纹状体多巴胺和GABA显著损失。GABA转运体的阻断显著减轻了GABA的损失，但对多巴胺损失没有影响。与一些体外研究报告相反，GABA(A)受体不是NO711发挥保护作用的下游介质。纹状体内注射丙二酸（2微摩尔），加或不加GABA(A)受体激动剂蝇蕈醇（1微摩尔）、GABA(A)氯离子结合位点拮抗剂印防己毒素（50纳摩尔）或GABA(B)受体拮抗剂赛氯芬（33纳摩尔），在注射1周后检查时，并未改变纹状体多巴胺或GABA的损失。这些数据表明，纹状体线粒体损伤期间GABA转运体阻断对GABA能神经元具有保护作用。GABA转运体阻断目前是治疗癫痫的一种药理学策略，因此在治疗涉及能量抑制的急性和慢性疾病如中风/缺血或亨廷顿病时可能也有益处。这些发现还指出了在代谢损伤期间，未成熟神经元和成熟神经元在GABA受体下游参与方面的根本差异。
