Calcium channel blocking as a therapeutic strategy for Alzheimer's disease: the case for isradipine.
Calcium channel blocking as a therapeutic strategy for Alzheimer's disease: the case for isradipine.
复制标题
DOI：
10.1016/j.bbadis.2011.08.013
复制
发表时间：
2011-12
期刊：
影响因子：
--
通讯作者：
Quinn JF
中科院分区：
文献类型：
--
作者：
Anekonda TS;Quinn JF
阿尔茨海默病是老年人中最具破坏性的神经退行性疾病，但治疗选择严重有限。通过干预β淀粉样蛋白产生位点来改变阿尔茨海默病病理的药物开发努力在很大程度上是无效的或没有定论的。最大的挑战是确定和定义下游机制，可靠地预测临床症状。β -淀粉样蛋白的积累通过位于海马和皮层神经元体树突和轴突上的质膜l型钙通道导致细胞内钙的失调。矛盾的是，l型钙通道亚型Cav1.2也促进突触可塑性和空间记忆。细胞内钙的增加可调节淀粉样蛋白前体蛋白的加工，并影响多种下游途径，包括高磷酸化tau蛋白的增加和自噬的抑制。isradipine是美国联邦药物管理局批准的二氢吡啶钙通道阻滞剂，可选择性结合海马Cav1.2。我们的研究表明，isradipine在体外通过抑制钙流入细胞质和抑制Cav1.2表达来减轻β淀粉样蛋白低聚物的毒性。我们之前的研究表明，对阿尔茨海默病的三重转基因动物模型给予伊拉西平是耐受性良好的。我们的研究结果进一步表明，isradipine具有生物可利用性，降低了tau负担，并改善了大脑的自噬功能。更好地了解钙通道阻滞剂的脑药代动力学对于在未来任何阿尔茨海默病的临床试验中设计合适药物剂量的新实验至关重要。这篇综述强调了Cav1.2通道过表达、过度磷酸化tau的积累和自噬抑制在阿尔茨海默病中的重要性，以及伊斯拉地平对这一途径的调节。
Alzheimer’s disease is the most devastating neurodegenerative disorder in the elderly, yet treatment options are severely limited. The drug development effort to modify Alzheimer’s disease pathology by intervention at beta amyloid production sites has been largely ineffective or inconclusive. The greatest challenge has been to identify and define downstream mechanisms reliably predictive of clinical symptoms. Beta amyloid accumulation leads to dysregulation of intracellular calcium by plasma membrane L-type calcium channels located on neuronal somatodendrites and axons in the hippocampus and cortex. Paradoxically, L-type calcium channel subtype Cav1.2 also promotes synaptic plasticity and spatial memory. Increased intracellular calcium modulates amyloid precursor protein processing and affects multiple downstream pathways including increased hyperphosphorylated tau and suppression of autophagyIsradipine is a Federal Drug Administration-approved dihydropyridine calcium channel blocker that binds selectively to Cav1.2 in the hippocampus. Our studies have shown that isradipine in vitro attenuates beta amyloid oligomer toxicity by suppressing calcium influx into cytoplasm and by suppressing Cav1.2 expression. We have previously shown that administration of isradipine to triple transgenic animal model for Alzheimer’s disease was well-tolerated. Our results further suggest that isradipine became bioavailable, lowered tau burden, and improved autophagy function in the brain. A better understanding of brain pharmacokinetics of calcium channel blockers will be critical for designing new experiments with appropriate drug doses in any future clinical trials for Alzheimer’s disease. This review highlights the importance of Cav1.2 channel overexpression, the accumulation of hyperphosphorylated tau and suppression of autophagy in Alzheimer’s disease and modulation of this pathway by isradipine.
登录
查看更多内容
影响因子：
4.3
作者：
ARISPE, N;POLLARD, HB;ROJAS, E
通讯作者：
ROJAS, E
影响因子：
82.9
作者：
Alonso, AD;GrundkeIqbal, I;Iqbal, K
通讯作者：
Iqbal, K
影响因子：
8.6
作者：
Chan, C. Savio;Gertler, Tracy S.;Surmeier, D. James
通讯作者：
Surmeier, D. James
DOI：
10.1083/jcb.201002108
发表时间：
2010-08-23
期刊：
The Journal of cell biology
影响因子：
--
作者：
Cherra SJ 3rd;Kulich SM;Uechi G;Balasubramani M;Mountzouris J;Day BW;Chu CT
通讯作者：
Chu CT
DOI：
10.1073/pnas.87.10.3861
发表时间：
1990-05-01
影响因子：
11.1
作者：
CATALDO, AM;NIXON, RA
通讯作者：
NIXON, RA