Lastres-Becker I, Cebeira M, de Ceballos M L, Zeng B Y, Jenner P, Ramos J A, Fernández-Ruiz J J
Department of Biochemistry and Molecular Biology, Faculty of Medicine, Complutense University, 28040 Madrid, Spain.
Eur J Neurosci. 2001 Dec;14(11):1827-32. doi: 10.1046/j.0953-816x.2001.01812.x.
Recent evidence obtained in rat models of Parkinson's disease showed that the density of cannabinoid CB1 receptors and their endogenous ligands increase in basal ganglia. However, no data exists from post-mortem brain of humans affected by Parkinson's disease or from primate models of the disorder. In the present study, we examined CB1 receptor binding and the magnitude of the stimulation by WIN55,212-2, a specific CB1 receptor agonist, of [35S]GTPgammaS binding to membrane fractions from the basal ganglia of patients affected by Parkinson's disease. In Parkinson's disease, WIN55,212-2-stimulated [35S]GTPgammaS binding in the caudate nucleus, putamen, lateral globus pallidus and substantia nigra was increased, thus indicating a more effective activation of GTP-binding protein-coupled signalling mechanisms via CB1 receptors. This was accompanied by an increase in CB1 receptor binding in the caudate nucleus and the putamen, although no changes were observed in the lateral globus pallidus and the substantia nigra. Because Parkinson's disease patients had been chronically treated with l-DOPA, brains were studied from normal common marmosets and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated animals with and without chronic L-DOPA treatment. MPTP-lesioned marmosets had increased CB1 receptor binding in the caudate nucleus and the putamen compared to control marmosets, as well as increased stimulation of [35S]GTPgammaS binding by WIN55,212-2. However, following l-DOPA treatment these parameters returned towards control values. The results indicate that a nigro-striatal lesion is associated with an increase in CB1 receptors in the basal ganglia in humans and nonhuman primates and that this increase could be reversed by chronic l-DOPA therapy. The data suggest that CB1 receptor blockade might be useful as an adjuvant for the treatment of parkinsonian motor symptoms.
帕金森病大鼠模型的最新证据表明，基底神经节中大麻素CB1受体及其内源性配体的密度增加。然而，尚无来自帕金森病患者尸检脑或该疾病灵长类动物模型的数据。在本研究中，我们检测了帕金森病患者基底神经节膜部分中CB1受体结合情况以及特异性CB1受体激动剂WIN55,212-2对[35S]GTPγS结合的刺激程度。在帕金森病中，WIN55,212-2刺激的尾状核、壳核、外侧苍白球和黑质中的[35S]GTPγS结合增加，这表明通过CB1受体对GTP结合蛋白偶联信号机制的激活更有效。这伴随着尾状核和壳核中CB1受体结合增加，尽管外侧苍白球和黑质中未观察到变化。由于帕金森病患者长期接受左旋多巴治疗，因此对正常普通狨猴以及接受和未接受长期左旋多巴治疗的1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）处理的动物的脑进行了研究。与对照狨猴相比，MPTP损伤的狨猴尾状核和壳核中CB1受体结合增加，WIN55,212-2对[35S]GTPγS结合的刺激也增加。然而，左旋多巴治疗后这些参数恢复到对照值。结果表明，黑质纹状体损伤与人类和非人类灵长类动物基底神经节中CB1受体增加有关，并且这种增加可通过长期左旋多巴治疗逆转。数据表明，CB1受体阻断可能作为帕金森病运动症状治疗的辅助手段有用。
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