Rodriguez-Perez Ana I, Dominguez-Meijide Antonio, Lanciego Jose L, Guerra Maria J, Labandeira-Garcia Jose L
Laboratory of Neuroanatomy and Experimental Neurology, Department of Morphological Sciences, Faculty of Medicine, University of Santiago de Compostela, 15782, Santiago de Compostela, Spain.
Age (Dordr). 2013 Oct;35(5):1675-90. doi: 10.1007/s11357-012-9470-2. Epub 2012 Sep 18.
The possible interaction between brain hypoperfusion related to aging and/or vascular disease, vascular parkinsonism and Parkinson's disease, as well as the possible contribution of aging-related chronic brain hypoperfusion in the development or severity of Parkinson's disease are largely unknown. We used a rat model of chronic cerebral hypoperfusion to study the long-term effects of hypoperfusion on dopaminergic neurons and the possible synergistic effects between chronic hypoperfusion and factors that are deleterious to dopaminergic neurons, such as the dopaminergic neurotoxin 6-hydroxydopamine. Chronic hypoperfusion induced significant loss of dopaminergic neurons and striatal dopaminergic terminals and a reduction in striatal dopamine levels. Furthermore, intrastriatal administration of 6-hydroxydopamine in rats subjected to chronic hypoperfusion induced a significantly greater loss of dopaminergic neurons than in sham-operated control rats. The dopaminergic neuron loss was significantly reduced by oral treatment with angiotensin type 1 receptor antagonist candesartan (3 mg/kg/day). The levels of angiotensin type 2 receptors were lower and the levels of angiotensin type 1 receptors, interleukin-1 β and nicotinamide adenine dinucleotide phosphate oxidase activity were higher in the substantia nigra of rats subjected to chronic hypoperfusion than in control rats; this was significantly reduced by treatment with candesartan. The results suggest that early treatment of vascular disease should be considered in the treatment of aged Parkinson's disease patients and Parkinson's disease patients with cerebrovascular risk factors. The findings also suggest that inhibition of brain renin-angiotensin activity may be useful as a neuroprotective strategy.
与衰老和/或血管疾病相关的脑灌注不足、血管性帕金森综合征和帕金森病之间可能存在的相互作用，以及与衰老相关的慢性脑灌注不足在帕金森病发生或严重程度方面可能产生的影响，目前在很大程度上尚不清楚。我们使用慢性脑灌注不足大鼠模型，研究灌注不足对多巴胺能神经元的长期影响，以及慢性灌注不足与对多巴胺能神经元有害的因素（如多巴胺能神经毒素6-羟基多巴胺）之间可能存在的协同作用。慢性灌注不足导致多巴胺能神经元和纹状体多巴胺能终末显著丢失，以及纹状体多巴胺水平降低。此外，在慢性灌注不足的大鼠纹状体内注射6-羟基多巴胺，所诱导的多巴胺能神经元丢失比假手术对照大鼠显著更严重。口服1型血管紧张素受体拮抗剂坎地沙坦（3毫克/千克/天）可显著减少多巴胺能神经元丢失。与对照大鼠相比，慢性灌注不足大鼠黑质中2型血管紧张素受体水平较低，1型血管紧张素受体、白细胞介素-1β水平及烟酰胺腺嘌呤二核苷酸磷酸氧化酶活性较高；坎地沙坦治疗可使其显著降低。结果表明，在老年帕金森病患者和有脑血管危险因素的帕金森病患者的治疗中，应考虑早期治疗血管疾病。研究结果还表明，抑制脑肾素-血管紧张素活性可能作为一种神经保护策略发挥作用。
