Symptomatic and neuroprotective effects following activation of nigral group III metabotropic glutamate receptors in rodent models of Parkinson's disease
Symptomatic and neuroprotective effects following activation of nigral group III metabotropic glutamate receptors in rodent models of Parkinson's disease
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DOI：
10.1111/j.1476-5381.2010.00820.x
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发表时间：
2010-08-01
影响因子：
7.3
通讯作者：
Duty, S.
中科院分区：
文献类型：
--
作者：
Austin, P. J.;Betts, M. J.;Duty, S.
背景和目的：黑质网状部（SNpr）和延髓网状部（SNpc）的多巴胺能神经支配增加可能分别导致帕金森病（PD）的运动障碍和神经退行性变。本研究旨在确定突触前III组代谢型谷氨酸（mGlu）受体的激活是否会减少SN中的谷氨酸释放，并在PD动物模型中提供症状或神经保护缓解。实验方法：广谱III组mGlu受体激动剂O-磷酸-l-丝氨酸（l-SOP）和l-2-氨基-4-膦酰基丁酸（l-AP 4）使用微透析评估其抑制大鼠黑质棱镜中KCl诱发的[3 H]-d-天冬氨酸释放或抑制体内SNpr中KCl诱发的内源性谷氨酸释放的能力。在黑质内注射l-SOP和l-AP 4后，评估利血平处理的大鼠中运动不能的恢复。最后，在6-羟基多巴胺（6-OHDA）损伤的大鼠中检测了用l-AP 4进行7天的黑质上治疗的神经保护作用。这些作用被选择性III组mGlu拮抗剂（RS）-α-环丙基-4-膦酰基苯基甘氨酸（CPPG）阻断。L-SOP还使体内SNpr中的谷氨酸释放减少48%。向SNpr注射l-SOP和l-AP 4可逆转利血平诱导的运动不能。在SNpc上方施用后，I-AP 4提供针对黑质纹状体束的6-OHDA损伤的神经化学、组织学和功能保护。CPPG预处理抑制这些effects.Conclusions and implications：这些研究结果突出了第三组mGlu受体在SN作为潜在的目标，提供症状和神经保护缓解PD，并表明，抑制谷氨酸释放的SN可能是这些影响的基础。
Background and purpose:Increased glutamatergic innervation of the substantia nigra pars reticulata (SNpr) and pars compacta (SNpc) may contribute to the motor deficits and neurodegeneration, respectively, in Parkinson's disease (PD). This study aimed to establish whether activation of pre-synaptic group III metabotropic glutamate (mGlu) receptors reduced glutamate release in the SN, and provided symptomatic or neuroprotective relief in animal models of PD.Experimental approach:Broad-spectrum group III mGlu receptor agonists, O-phospho-l-serine (l-SOP) and l-2-amino-4-phosphonobutyrate (l-AP4), were assessed for their ability to inhibit KCl-evoked [3H]-d-aspartate release in rat nigral prisms or inhibit KCl-evoked endogenous glutamate release in the SNpr in vivo using microdialysis. Reversal of akinesia in reserpine-treated rats was assessed following intranigral injection of l-SOP and l-AP4. Finally, the neuroprotective effect of 7 days' supra-nigral treatment with l-AP4 was examined in 6-hydroxydopamine (6-OHDA)-lesioned rats.Key results:l-SOP and l-AP4 inhibited [3H]-d-aspartate release by 33 and 44% respectively. These effects were blocked by the selective group III mGlu antagonist (RS)-alpha-cyclopropyl-4-phosphonophenylglycine (CPPG). l-SOP also reduced glutamate release in the SNpr in vivo by 48%. Injection of l-SOP and l-AP4 into the SNpr reversed reserpine-induced akinesia. Following administration above the SNpc, l-AP4 provided neurochemical, histological and functional protection against 6-OHDA lesion of the nigrostriatal tract. Pretreatment with CPPG inhibited these effects.Conclusions and implications:These findings highlight group III mGlu receptors in the SN as potential targets for providing both symptomatic and neuroprotective relief in PD, and indicate that inhibition of glutamate release in the SN may underlie these effects.