DOPAMINE NERVES SUPRESS HYDROXYL RADICAL FORMATION IN NE

描述：(逐字摘自申请人的摘要)多巴胺(DA)是 儿茶酚胺最容易自动氧化成活性邻苯二酚，而且最 参与产生其他活性氧物种(ROS)，其中 羟基自由基活性最强。正是出于这个原因，DA是 疑似自体毒素，随着时间的推移，会破坏DA神经，包括实质 黑质部致密，导致帕金森氏症。与这种观点相反 作为一种自身毒素，他们发现当DA时，新纹状体中的基础羟基含量较低 新纹状体的神经支配是完整的，但DA使OH增加了几倍 神经支配抑制了新纹状体中OH的产生。不同程度的 新纹状体(15%-99%)的失神经首先将通过给予 6-羟基多巴胺对新生大鼠的影响。成年期体内微透析探头的研究 将被植入，探针尖端位于新纹状体；以及水杨酸盐 将包括在微透析液中，作为OH的自旋陷阱，检测到 HPLC/EC为2，5-二羟基苯甲酸和2，3-DHBA。淘汰其他 个体发育过程作为与增加羟基形成相关的因素 去神经大鼠，一组大鼠的新纹状体将被单侧 SNPC注射7-OHDA，8~10wk失神经。为了测试DA本身是 参与其中的一组大鼠将被a-甲基-p-酪氨酸耗尽DA。其他 测试DA主要作为抗氧化剂的作用的实验包括1) 亚慢性L多巴治疗对羟基磷灰石的影响；2)直接抑制羟基磷灰石 DA微透析液的形成；3)谷氨酸介导的羟基生成 在DA去神经支配的新纹状体。微透析液(神经细胞外隔室)和 将对整个纹状体(主要是神经元室)进行全面分析。 研究，以评估每个隔间中的DA影响并验证 神经衰弱。研究结果应该证实或驳斥DA的假设 神经支配主要是保护和抑制新纹状体中的OH。

DESCRIPTION: (Verbatim from the Applicant's Abstract) Dopamine (DA) is the catecholamine most easily auto-oxidized to reactive o-quinones and is most involved in generation of other reactive oxygen species (ROS), of which hydroxyl radical (OH) is the most reactive. It is for this reason that DA is suspect as an autotoxin, over time, destroys DA nerves, including substantia nigra pars compacta, resulting in Parkinson's disease. Counter to this view of DA as an autotoxin, they found that basal OH in neostriatum was low when DA innervation of neostriatum was intact, but that OH increased several fold if DA innervation suppresses OH generation in the neostriatum. Various degrees of DA-denervation of neostriatum (15-99%) first will be produced by giving 6-hydroxydopamine to neonatal rats. In adulthood an in vivo microdialysis probe will be implanted, with the probe tip residing in neostriatum; and salicylate will be included in microdialysates as a spin trap for OH, detected with HPLC/EC as 2,5-dihydroxybenzoic acid and 2,3-DHBA. To eliminate other ontogenetic processes as factors associated with increased OH formation in DA-denervated rats, the neostriatum of one group of rats will be unilaterally denervated at 8-10 wk by 7-OHDA injected into Snpc. To test that DA per se is involved, a group of rats will be DA depleted with a-methyl-p-tyrosine. Other experiments to test the role of DA primarily as an anti-oxidant include 1) effect of subchronic L-DOPA treatment on OH; 2) direct inhibition of OH formation by DA microdialysates; 3) mediation of OH generation by glutamic acid in DA-denervated neostriatum. Microdialysates (extraneuronal compartment) and whole striatum (mainly intraneuronal compartment) will be analyzed in all studies, to assess DA effects in each compartment and verify completeness of DA-denervation. Findings should validate or refute the hypothesis that DA innervation is primarily neuroprotectant and suppressive of OH in neostriatum.