Adenosine, Glutamate and Neurodegeneration

腺苷、谷氨酸和神经变性

基本信息

批准号：
7418642
负责人：
Patricia K Sonsalla
金额：
$ 20.85万
依托单位：
UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-06-01 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7418642
关键词：
1-Methyl-4-phenylpyridinium 6-Cyano-7-nitroquinoxaline-2,3-dione Ablation Adenosine Afferent Neurons Agonist Attenuated Basal Ganglia Binding Brain Brain region Caffeine Cell Count Cell Death Condition Corpus striatum structure Data Dependency Detection Dialysis procedure Disease Dopamine Dose Effectiveness of Interventions Elevation Experimental Models Fluorescence Glutamate Receptor Glutamates High Pressure Liquid Chromatography Hypothalamic structure Immersion Investigative Technique Immunohistochemistry Impairment In Vitro Infusion procedures Intervention Lead Lesion Malonates Measures Mediating Metabolic Metabolic stress Metabotropic Glutamate Receptors Microdialysis Midbrain structure Mitochondria Motor N-Methyl-D-Aspartate Receptors N-Methylaspartate Nerve Nerve Degeneration Neurons Parkinson Disease Pathology Pathway interactions Patients Physical Dialysis Play Predisposition Proteins Quinolinic Acid Quinolinic Acids Rattus Reducing Agents Research Personnel Role Signal Transduction Source Stress Structure of subthalamic nucleus Substantia nigra structure Succinate dehydrogenase (ubiquinone)Techniques Testing Tetrodotoxin Thinking Time Tyrosine 3-Monooxygenase base dopaminergic neuron excitotoxicity extracellular hindbrain inhibitor/antagonist neurochemistry neurotoxicity presynaptic prevent programs receptor response stressor

项目摘要

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) 是一种使人衰弱的疾病，由多巴胺能 (DAergic) 黑质纹状体神经元逐渐丧失所致。这种神经变性的根本原因尚不清楚。我们目前的研究重点是了解腺苷和谷氨酸在介导 DAergic 神经变性中的关系，特别是在线粒体有缺陷的 PD 患者可能发生的代谢应激条件下。在初步研究中，在纹状体中施加代谢应激（通过注射丙二酸阻断电子传递链复合体 II）会提高黑质 (SN) 的细胞外谷氨酸水平。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，但不是纹状体，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 中谷氨酸释放，并且 A2a 拮抗剂或代谢性谷氨酸组 2/3 激动剂通过抑制实质黑质中突触前谷氨酸释放来防止应激诱导的神经元变性。该假设将在大鼠中进行测试，使用线粒体抑制剂的纹状体内输注并结合谷氨酸或腺苷能作用剂的施用。这些干预措施保护 DAergic 神经元免受纹状体代谢应激的能力将通过纹状体中的神经化学测量（酪氨酸羟化酶、多巴胺和代谢物的含量）和黑质中的免疫组织化学（TH+和 TH-/Nissl+ 的体视细胞计数）进行检查将评估这些干预措施改变 SN 中谷氨酸释放的能力。使用微透析技术（目标#1、2、3），将损害丘脑底核以确定从该大脑区域到 SN 的投射是否是谷氨酸升高的来源以及 A2a 受体是否位于这些 STN 上。 -黑质投影（目标#4,5）。