The Neuroprotective Effects of the CB2 Agonist GW842166x in the 6-OHDA Mouse Model of Parkinson's Disease.
The Neuroprotective Effects of the CB2 Agonist GW842166x in the 6-OHDA Mouse Model of Parkinson's Disease.
复制标题
CB 2激动剂GW 842166 x在帕金森病的6-OHDA小鼠模型中的神经保护作用。
作者：
Yu H;Liu X;Chen B;Vickstrom CR;Friedman V;Kelly TJ;Bai X;Zhao L;Hillard CJ;Liu QS
帕金森病（PD）是一种慢性神经退行性疾病，与多巴胺神经元丢失和运动功能障碍有关。防止多巴胺神经元死亡的神经保护剂在减缓疾病进展方面有很大的希望。大麻素（CB）受体的激活已在神经退行性疾病、创伤性脑损伤和中风的临床前模型中显示出神经保护作用，并可提供针对PD的神经保护。在这里，我们报告说，选择性CB 2激动剂GW 842166 x对小鼠中6-羟基多巴胺（6-OHDA）诱导的多巴胺神经元损失及其相关运动功能缺陷具有保护作用，平衡木行走、撑杆、握力、旋转棒和安非他明诱导的旋转测试的改善就表明了这一点。GW 842166 x的神经保护作用被CB 2受体拮抗剂AM 630阻止，表明CB 2依赖性机制。为了研究GW 842166 x的神经保护作用的潜在机制，我们对从药物未处理小鼠制备的离体中脑切片中的黑质腹侧部（SNc）多巴胺神经元进行了电生理记录。我们发现，浴应用GW 842166 x导致动作电位放电减少，可能是由于超极化激活电流（Ih）减少和Ih的半激活电位（V1/2）向更超极化水平移动。总之，CB 2激动剂GW 842166 x可以通过降低这些神经元的动作电位放电和相关的钙负荷来降低多巴胺神经元对6-OHDA的脆弱性。
Parkinson’s disease (PD) is a chronic neurodegenerative disorder associated with dopamine neuron loss and motor dysfunction. Neuroprotective agents that prevent dopamine neuron death hold great promise for slowing the disease’s progression. The activation of cannabinoid (CB) receptors has shown neuroprotective effects in preclinical models of neurodegenerative disease, traumatic brain injury, and stroke, and may provide neuroprotection against PD. Here, we report that the selective CB2 agonist GW842166x exerted protective effects against the 6-hydroxydopamine (6-OHDA)-induced loss of dopamine neurons and its associated motor function deficits in mice, as shown by an improvement in balance beam walking, pole, grip strength, rotarod, and amphetamine-induced rotation tests. The neuroprotective effects of GW842166x were prevented by the CB2 receptor antagonist AM630, suggesting a CB2-dependent mechanism. To investigate potential mechanisms for the neuroprotective effects of GW842166x, we performed electrophysiological recordings from substantia nigra pars compacta (SNc) dopamine neurons in ex vivo midbrain slices prepared from drug-naïve mice. We found that the bath application of GW842166x led to a decrease in action potential firing, likely due to a decrease in hyperpolarization-activated currents (Ih) and a shift of the half-activation potential (V1/2) of Ih to a more hyperpolarized level. Taken together, the CB2 agonist GW842166x may reduce the vulnerability of dopamine neurons to 6-OHDA by decreasing the action potential firing of these neurons and the associated calcium load.
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影响因子：
7.3
作者：
Giblin, Gerard M. P.;O'Shaughnessy, Celestine T.;Green, Richard
通讯作者：
Green, Richard
影响因子：
8.6
作者：
Fox, SH;Henry, B;Brotchie, J
通讯作者：
Brotchie, J
DOI：
10.1111/j.1749-6632.1992.tb24523.x
发表时间：
1992-05-11
影响因子：
5.2
作者：
GERMAN, DC;MANAYE, KF;BROOKS, BA
通讯作者：
BROOKS, BA
DOI：
10.1523/jneurosci.2519-09.2009
发表时间：
2009-09-02
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Guzman JN;Sánchez-Padilla J;Chan CS;Surmeier DJ
通讯作者：
Surmeier DJ
影响因子：
4.7
作者：
Basavarajappa BS;Shivakumar M;Joshi V;Subbanna S
通讯作者：
Subbanna S