Inactivation of neuronal forebrain A2A receptors protects dopaminergic neurons in a mouse model of Parkinson's disease
Inactivation of neuronal forebrain A2A receptors protects dopaminergic neurons in a mouse model of Parkinson's disease
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DOI：
10.1111/j.1471-4159.2009.06425.x
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发表时间：
2009-12-01
影响因子：
4.7
通讯作者：
Morelli, Micaela
中科院分区：
文献类型：
--
作者：
Carta, Anna R.;Kachroo, Anil;Morelli, Micaela
腺苷 A(2A) 受体拮抗剂在帕金森病 (PD) 动物模型中产生神经保护作用。由于神经炎症参与 PD 发病机制，神经元和胶质 A(2A) 受体可能参与神经保护。我们在 PD 的多 MPTP 小鼠模型中采用互补的药理学和遗传学方法来灭活 A(2A) 受体，以研究 A(2A) 拮抗作用的神经保护的细胞基础。在用 A(2A) 拮抗剂 SCH58261 治疗的小鼠或前脑神经元上缺乏 A(2A) 受体的条件敲除小鼠（fbnA(2A)KO 小鼠）中给予 MPTP 中心点 HCl（每天 20 mg/kg，持续 4 天）。 MPTP 诱导黑质致密部 (SNc) 和纹状体 (Str) 多巴胺神经元部分丧失，与这些区域星形胶质细胞和小胶质细胞免疫反应性增加相关。 MPTP 给药后 1、3 和 7 天星形胶质细胞类似地被激活，而在第 1 天检测到最大小胶质细胞反应性，并在 MPTP 给药后 7 天恢复到基线。 SCH58261 减轻 SNc 和 Str 中的多巴胺细胞损失和神经胶质增生。选择性耗尽 fbnA(2A)KO 小鼠中的 A(2A) 受体完全阻止了 MPTP 诱导的 SNc 中的多巴胺神经元变性和神经胶质增生，并部分抵消了 Str 中的神经胶质增生。结果证明，在 PD 多次 MPTP 注射模型中，神经元 A(2A) 受体在 A(2A) 拮抗剂的神经保护作用中发挥主要作用。随着临床试验中对几种 A(2A) 受体拮抗剂的症状性抗帕金森病潜力的研究，这项研究为更广泛的临床获益和在帕金森病治疗早期使用这些药物提供了理论基础。
Adenosine A(2A) receptors antagonists produce neuroprotective effects in animal models of Parkinson's disease (PD). As neuroinflammation is involved in PD pathogenesis, both neuronal and glial A(2A) receptors might participate to neuroprotection. We employed complementary pharmacologic and genetic approaches to A(2A) receptor inactivation, in a multiple MPTP mouse model of PD, to investigate the cellular basis of neuroprotection by A(2A) antagonism. MPTP center dot HCl (20 mg/kg daily for 4 days) was administered in mice treated with the A(2A) antagonist SCH58261, or in conditional knockout mice lacking A(2A) receptors on forebrain neurons (fbnA(2A)KO mice). MPTP-induced partial loss of dopamine neurons in substantia nigra pars compacta (SNc) and striatum (Str), associated with increased astroglial and microglial immunoreactivity in these areas. Astroglia was similarly activated 1, 3, and 7 days after MPTP administration, whereas maximal microglial reactivity was detected on day 1, returning to baseline 7 days after MPTP administration. SCH58261 attenuated dopamine cell loss and gliosis in SNc and Str. Selective depletion of A(2A) receptors in fbnA(2A)KO mice completely prevented MPTP-induced dopamine neuron degeneration and gliosis in SNc, and partially counteracted gliosis in Str. Results provide evidence of a primary role played by neuronal A(2A) receptors in neuroprotective effects of A(2A) antagonists in a multiple MPTP injections model of PD. With the symptomatic antiparkinsonian potential of several A(2A) receptor antagonists being pursued in clinical trials, this study adds to the rationale for broader clinical benefit and use of these drugs early in the treatment of PD.