Mikami Maya, Goubaeva Farida, Song Joseph H, Lee H T, Yang Jay
Department of Anesthesiology, Columbia University P & S, New York, NY 10032, USA.
Eur J Pharmacol. 2008 Jul 28;589(1-3):14-21. doi: 10.1016/j.ejphar.2008.04.045. Epub 2008 Apr 25.
The beta-adrenoceptor blockers exhibit a well-characterized anti-apoptotic property in the heart and kidney while less is known about the effect of this class of drugs on neuronal apoptosis. We studied the effects of three beta-adrenoceptor blockers propranolol (1-(isoproplyamino)-3-(naphthalene-1-yloxy)propan-2-ol), atenolol (2-[4-[2-hydroxy-3-(1-methylethylamino)propoxyl]phenyl]ehanamide), and ICI 118551 (1-[2,3-(dihydro-7-methyl-1H-iden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol), against staurosporine-induced apoptosis in SH-SY5Y human neuroblastoma cells. Staurosporine increased caspase 3-like activity, DNA fragmentation, PARP cleavage, and the number of TUNEL positive cells consistent with the induction of apoptosis. Propranolol and ICI 118551, but not atenolol, demonstrated a concentration-dependent inhibition of caspase 3-like activity. Propranolol and ICI 118551 directly inhibited the enzymatic activity of recombinant caspase 9 while atenolol did not; however, none of the beta-adrenoceptor blockers that were examined directly blocked caspases 2 or 3 activity. In isolated mitochondria, propranolol and ICI 118551 inhibited staurosporine-induced cytochrome c release while atenolol did not. We conclude that propranolol and ICI 118551 protect SH-SY5Y cells against staurosporine-induced apoptosis through a dual action on the mitochondria and on caspase 9 in a cell type and an apoptotic paradigm where the conventional inhibitors of mitochondrial permeability transition such as cyclosporin A and bongkrekic acid demonstrate no protection.
β-肾上腺素能受体阻滞剂在心脏和肾脏中具有明确的抗凋亡特性，而这类药物对神经元凋亡的影响则知之甚少。我们研究了三种β-肾上腺素能受体阻滞剂普萘洛尔（1-(异丙基氨基)-3-(萘-1-基氧基)丙-2-醇）、阿替洛尔（2-[4-[2-羟基-3-(1-甲基乙基氨基)丙氧基]苯基]乙酰胺）和ICI 118551（1-[2,3-(二氢-7-甲基-1H-茚-4-基)氧基]-3-[(1-甲基乙基)氨基]-2-丁醇）对星形孢菌素诱导的SH-SY5Y人神经母细胞瘤细胞凋亡的作用。星形孢菌素增加了半胱天冬酶3样活性、DNA片段化、聚（ADP-核糖）聚合酶裂解以及TUNEL阳性细胞数量，这与凋亡的诱导一致。普萘洛尔和ICI 118551，但不是阿替洛尔，表现出对半胱天冬酶3样活性的浓度依赖性抑制。普萘洛尔和ICI 118551直接抑制重组半胱天冬酶9的酶活性，而阿替洛尔则没有；然而，所检测的β-肾上腺素能受体阻滞剂均未直接阻断半胱天冬酶2或3的活性。在分离的线粒体中，普萘洛尔和ICI 118551抑制星形孢菌素诱导的细胞色素c释放，而阿替洛尔则没有。我们得出结论，普萘洛尔和ICI 118551通过对线粒体和半胱天冬酶9的双重作用，保护SH-SY5Y细胞免受星形孢菌素诱导的凋亡，在这种细胞类型和凋亡模式中，传统的线粒体通透性转换抑制剂如环孢素A和邦克酸没有显示出保护作用。
