Lercanidipine Rescues Hippocampus Pyramidal Neurons from Mild Ischemia-Induced Delayed Neuronal Death in SHRSP
Lercanidipine Rescues Hippocampus Pyramidal Neurons from Mild Ischemia-Induced Delayed Neuronal Death in SHRSP
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DOI：
10.1007/s10571-011-9649-6
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发表时间：
2011-01
影响因子：
4
通讯作者：
Y. Sakurai‐Yamashita;N. Harada;M. Niwa
中科院分区：
文献类型：
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作者：
Y. Sakurai‐Yamashita;N. Harada;M. Niwa
当双侧颈动脉仅闭塞 10 分钟时，易发生中风的自发性高血压大鼠 (SHRSP) 很容易出现海马锥体细胞缺血和迟发性神经元死亡 (DND)。由于这种闭塞仅引起轻度缺血，因此所产生的 DND 可能是暴露于轻微缺血性损伤的原发性高血压患者痴呆的合适动物模型。本研究旨在比较抗高血压药物乐卡地平、尼卡地平、赖诺普利、缬沙坦和肼屈嗪对 SHRSP 中闭塞诱导的 DND 的影响。药物治疗持续 2 周，即 15 至 17 周龄。 SP 饮食中施用 0.1% 尼卡地平和 0.01 或 0.03% 乐卡地平（分别约为 61.3、5.7 和 18.8 mg/kg/天），其余药物使用微型渗透泵以 10 mg/kg/天施用。这些动物在 16 周龄时接受手术，1 周后通过组织学检查分析 DND。在 15、16 和 17 周龄时测量收缩压。对于长期治疗，钙通道阻滞剂在 8 至 17 周龄时服用。所有抗高血压药物均可显着降低 16 周龄时的收缩压。肼屈嗪和赖诺普利的减少幅度最大；然而，乐卡地平、尼卡地平和缬沙坦可有效地将收缩压降低至中等范围内。仅 0.03% 乐卡地平即可显着抑制 DND。 0.03% 乐卡地平的长期治疗也能保护锥体神经元。这项研究的结果表明，长效、亲脂性钙通道阻滞剂乐卡地平可抑制 SHRSP 中闭塞诱导的 DND，并且乐卡地平可以有效减少原发性高血压患者因轻微缺血性损伤引起的痴呆。
Stroke-prone spontaneously hypertensive rats (SHRSPs) are vulnerable to ischemia and delayed neuronal death (DND) of hippocampus pyramidal cells when bilateral carotid arteries are occluded for only 10 min. Since this occlusion induces just mild ischemia, the resulting DND may be an appropriate animal model for dementia in patient with essential hypertension exposed to small ischemic insults. This study was designed to compare the effects of the antihypertensive drugs lercanidipine, nicardipine, lisinopril, valsartan, and hydralazine on occlusion-induced DND in SHRSPs. Drugs were administered for 2 weeks, from 15 to 17 weeks of age. 0.1% Nicardipine and 0.01 or 0.03% lercanidipine were administered in the SP diet (about 61.3, 5.7, and 18.8 mg/kg/day, respectively), and the remaining drugs were administered at 10 mg/kg/day using the mini-osmotic pump. The animals were operated on at 16 weeks of age, and DND was analyzed by histological examination 1 week later. Systolic blood pressure was measured at 15, 16, and 17 weeks of age. For chronic treatment, Calcium-channel blockers were administered from 8 to 17 weeks of age. All antihypertensive drugs significantly lowered systolic blood pressure at 16 weeks of age. Hydralazine and lisinopril were associated with the greatest reduction; however, lercanidipine, nicardipine, and valsartan effectively reduced systolic blood pressure to within a medium range. DND was significantly inhibited only by 0.03% lercanidipine. Chronic treatment with 0.03% lercanidipine also protected pyramidal neurons. The results of this study demonstrate that the long-acting, lipophilic Calcium-channel blocker lercanidipine inhibits occlusion-induced DND in SHRSPs and that lercanidipine may effectively reduce dementia induced by small ischemic insults in patients with essential hypertension.