Glass M, Dragunow M, Faull R L
Departments of Anatomy with Radiology, University of Auckland, Private Bag 92019, Auckland, New Zealand.
Neuroscience. 2000;97(3):505-19. doi: 10.1016/s0306-4522(00)00008-7.
In order to investigate the sequence and pattern of neurodegeneration in Huntington's disease, the distribution and density of cannabinoid CB(1), dopamine D(1) and D(2), adenosine A(2a) and GABA(A) receptor changes were studied in the basal ganglia in early (grade 0), intermediate (grades 1, 2) and advanced (grade 3) neuropathological grades of Huntington's disease. The results showed a sequential pattern of receptor changes in the basal ganglia with increasing neuropathological grades of Huntington's disease. First, the very early stages of the disease (grade 0) were characterized by a major loss of cannabinoid CB(1), dopamine D(2) and adenosine A(2a) receptor binding in the caudate nucleus, putamen and globus pallidus externus and an increase in GABA(A) receptor binding in the globus pallidus externus. Second, intermediate neuropathological grades (grades 1, 2) showed a further marked decrease of CB(1) receptor binding in the caudate nucleus and putamen; this was associated with a loss of D(1) receptors in the caudate nucleus and putamen and a loss of both CB(1) and D(1) receptors in the substantia nigra. Finally, advanced grades of Huntington's disease showed an almost total loss of CB(1) receptors and the further depletion of D(1) receptors in the caudate nucleus, putamen and globus pallidus internus, and an increase in GABA(A) receptor binding in the globus pallidus internus. These findings suggest that there is a sequential but overlapping pattern of neurodegeneration of GABAergic striatal efferent projection neurons in increasing neuropathological grades of Huntington's disease. First, GABA/enkephalin striatopallidal neurons projecting to the globus pallidus externus are affected in the very early grades of the disease. Second, GABA/substance P striatonigral neurons projecting to the substantia nigra are involved at intermediate neuropathological grades. Finally, GABA/substance P striatopallidal neurons projecting to the globus pallidus internus are affected in the late grades of the disease. In addition, the finding that cannabinoid receptors are dramatically reduced in all regions of the basal ganglia in advance of other receptor changes in Huntington's disease suggests a possible role for cannabinoids in the progression of neurodegeneration in Huntington's disease.
为了研究亨廷顿舞蹈病中神经变性的顺序和模式，我们在亨廷顿舞蹈病早期（0级）、中期（1级、2级）和晚期（3级）神经病理学分级的基底神经节中，研究了大麻素CB(1)、多巴胺D(1)和D(2)、腺苷A(2a)和GABA(A)受体的分布及密度变化。结果显示，随着亨廷顿舞蹈病神经病理学分级的增加，基底神经节中受体变化呈现出一种顺序性模式。首先，在疾病的极早期（0级），尾状核、壳核和外侧苍白球中，大麻素CB(1)、多巴胺D(2)和腺苷A(2a)受体结合显著丧失，而外侧苍白球中GABA(A)受体结合增加。其次，中期神经病理学分级（1级、2级）时，尾状核和壳核中CB(1)受体结合进一步显著下降；这与尾状核和壳核中D(1)受体丧失以及黑质中CB(1)和D(1)受体均丧失有关。最后，亨廷顿舞蹈病晚期时，尾状核、壳核和内侧苍白球中CB(1)受体几乎完全丧失，D(1)受体进一步耗竭，内侧苍白球中GABA(A)受体结合增加。这些发现表明，在亨廷顿舞蹈病神经病理学分级增加的过程中，GABA能纹状体传出投射神经元存在一种顺序但重叠的神经变性模式。首先，投射至外侧苍白球的GABA/脑啡肽纹状体苍白球神经元在疾病的极早期受到影响。其次，投射至黑质的GABA/P物质纹状体黑质神经元在中期神经病理学分级时受累。最后，投射至内侧苍白球的GABA/P物质纹状体苍白球神经元在疾病晚期受到影响。此外，在亨廷顿舞蹈病中，大麻素受体在基底神经节所有区域的其他受体变化之前就显著减少，这一发现提示大麻素在亨廷顿舞蹈病神经变性进展中可能发挥作用。
