Adenosine, Glutamate and Neurodegeneration

腺苷、谷氨酸和神经变性

• 批准号: 7071273
• 负责人: Patricia K Sonsalla
• 金额: $ 26.39万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7071273
• 关键词: Parkinson' s disease; adenosine; autoradiography; corpus striatum; glutamates; high performance liquid chromatography; immunocytochemistry; laboratory rat; malonates; microdialysis; mitochondrial disease /disorder; neural degeneration; neurochemistry; neurons; neuropathology; neuroregulation; neurotoxicology; neurotransmitter antagonist; neurotransmitter transport; protein localization; purinergic receptor; receptor binding; substantia nigra; subthalamus; tyrosine 3 monooxygenase

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a debilitating disorder that results from the progressive loss of dopaminergic (DAergic) nigrostriatal neurons. Underlying causes of this neurodegeneration are not known. Our current studies focus on understanding the relationship between adenosine and glutamate in mediating DAergic neurodegeneration, particularly under conditions of a metabolic stress as may occur in PD patients with defective mitochondria. In preliminary studies, the imposition of a metabolic stress in the striatum (via an infusion of malonate which blocks complex II of the electron transport chain) elevated extracellular glutamate levels in the substantia nigra (SN). Furthermore, blockade of glutamate N-methyl-D-aspartate (NMDA) or adenosine A2a receptors in the SN, but not the striatum, protected DAergic neurons against the mitochondrial stress. Based on these findings, we hypothesize that a striatal metabolic stress causes glutamate release in the SN and that A2a antagonists or metabotrobic glutamate group 2/3 agonists protect against stress-induced neuronal degeneration by inhibiting presynaptic glutamate release in the substantial nigra. This hypothesis will be tested in rats using intrastriatal infusion of a mitochondrial inhibitor in conjunction with the administration of either glutamatergic- or adenosinergic-acting agents. The ability of these interventions to protect DAergic neurons against a striatal metabolic stress will be examined by neurochemical measures in the striatum (content of tyrosine hydroxylase, dopamine and metabolites) and immunohistochemistry in the substantia nigra (stereological cell counts of TH+ and TH-/Nissl+ neurons (Aims #2,3,4). The ability of these interventions to modify glutamate release in the SN will be assessed using microdialysis techniques (Aims #1,2,3). In other studies, the subthalamic nucleus will be lesioned to determine if projections from this brain region to the SN are the source of the elevated glutamate and if A2a receptors are located on these STN-nigral projections (Aims #4,5).

描述（由申请人提供）：帕金森病（PD）是一种衰弱性疾病，由多巴胺能（DAergic）黑质纹状体神经元的进行性丧失引起。这种神经变性的潜在原因尚不清楚。我们目前的研究重点是了解腺苷和谷氨酸在介导能性神经退行性变中的关系，特别是在线粒体缺陷的PD患者可能发生代谢应激的情况下。在初步研究中，纹状体中施加代谢应激（通过注入阻断电子传递链复合体II的丙二酸盐）可提高黑质（SN）中细胞外谷氨酸水平。此外，阻断SN中的谷氨酸n -甲基- d -天冬氨酸（NMDA）或腺苷A2a受体，而不是纹状体，可以保护DAergic神经元免受线粒体应激。基于这些发现，我们假设纹状体代谢应激导致SN中的谷氨酸释放，A2a拮抗剂或代谢谷氨酸2/3组激动剂通过抑制实质黑质中突触前谷氨酸释放来保护应激诱导的神经元变性。这一假设将在大鼠中进行验证，使用线粒体抑制剂与谷氨酸能或腺苷能作用药物联合注入。这些干预措施保护能神经元免受纹状体代谢应激的能力将通过纹状体的神经化学测量（酪氨酸羟化酶、多巴胺和代谢物的含量）和黑质的免疫组织化学（TH+和TH-/Nissl+神经元的体视细胞计数）来检验（目的#2,3,4）。这些干预措施对谷氨酸释放的影响将通过微透析技术进行评估（目的1、2、3）。在其他研究中，将对丘脑下核进行损伤，以确定从该脑区到SN的突起是否为谷氨酸升高的来源，以及A2a受体是否位于这些stn -黑质突起上（Aims #4,5）。