Department of Neuroinflammation, UCL Queen Square Institute of Neurology (Z.Y., Y.X., C.C., K.C., M.S., K.J.S.), University College London, United Kingdom.
Department of Medical Physics and Biomedical Engineering (F.L., I.T.), University College London, United Kingdom.
Stroke. 2024 Jul;55(7):1914-1922. doi: 10.1161/STROKEAHA.124.047154. Epub 2024 Jun 11.
Cerebral small vessel disease is a common cause of vascular cognitive impairment and dementia. There is an urgent need for preventative treatments for vascular cognitive impairment and dementia, and reducing vascular dysfunction may provide a therapeutic route. Here, we investigate whether the chronic administration of nimodipine, a central nervous system-selective dihydropyridine calcium channel blocking agent, protects vascular, metabolic, and cognitive function in an animal model of cerebral small vessel disease, the spontaneously hypertensive stroke-prone rat.
Male spontaneously hypertensive stroke-prone rats were randomly allocated to receive either a placebo (n=24) or nimodipine (n=24) diet between 3 and 6 months of age. Animals were examined daily for any neurological deficits, and vascular function was assessed in terms of neurovascular and neurometabolic coupling at 3 and 6 months of age, and cerebrovascular reactivity at 6 months of age. Cognitive function was evaluated using the novel object recognition test at 6 months of age.
Six untreated control animals were terminated prematurely due to strokes, including one due to seizure, but no treated animals experienced strokes and so had a higher survival (=0.0088). Vascular function was significantly impaired with disease progression, but nimodipine treatment partially preserved neurovascular coupling and neurometabolic coupling, indicated by larger (<0.001) and more prompt responses (<0.01), and less habituation upon repeated stimulation (<0.01). Also, animals treated with nimodipine showed greater cerebrovascular reactivity, indicated by larger dilation of arterioles (=0.015) and an increase in blood flow velocity (=0.001). This protection of vascular and metabolic function achieved by nimodipine treatment was associated with better cognitive function (<0.001) in the treated animals.
Chronic treatment with nimodipine protects from strokes, and vascular and cognitive deficits in spontaneously hypertensive stroke-prone rat. Nimodipine may provide an effective preventive treatment for stroke and cognitive decline in cerebral small vessel disease.
脑小血管疾病是血管性认知障碍和痴呆的常见原因。迫切需要血管性认知障碍和痴呆的预防治疗，而减少血管功能障碍可能提供一种治疗途径。在这里，我们研究了中枢神经系统选择性二氢吡啶钙通道阻滞剂尼莫地平在脑小血管疾病动物模型——自发性高血压卒中易发性大鼠中是否能长期预防血管、代谢和认知功能障碍。
雄性自发性高血压卒中易发性大鼠在 3 至 6 个月大时随机分为接受安慰剂（n=24）或尼莫地平（n=24）饮食的两组。每天检查动物是否有任何神经功能缺损，并在 3 个月和 6 个月时评估神经血管和神经代谢偶联的血管功能，以及在 6 个月时评估脑血管反应性。在 6 个月大时使用新物体识别测试评估认知功能。
由于中风，包括因癫痫发作而提前终止的 1 只，6 只未治疗的对照动物中有 6 只提前死亡，但没有治疗的动物发生中风，因此存活率更高（=0.0088）。随着疾病的进展，血管功能明显受损，但尼莫地平治疗部分保留了神经血管偶联和神经代谢偶联，表现为更大（<0.001）和更迅速的反应（<0.01），以及在重复刺激下更少的习惯化（<0.01）。此外，尼莫地平治疗的动物表现出更大的脑血管反应性，表现为小动脉扩张更大（=0.015）和血流速度增加（=0.001）。尼莫地平治疗对血管和代谢功能的这种保护作用与治疗动物的更好认知功能（<0.001）相关。
慢性尼莫地平治疗可预防自发性高血压卒中易发性大鼠中风以及血管和认知功能障碍。尼莫地平可能为脑小血管疾病中的中风和认知下降提供有效的预防治疗。
