Gabryel Bozena, Chalimoniuk Malgorzata, Stolecka Anna, Waniek Katarzyna, Langfort Jozef, Malecki Andrzej
Department of Pharmacology, Medical University of Silesia, Poland.
J Pharmacol Sci. 2006 Sep;102(1):77-87.
In the present study, we investigated whether the protective effect of FK506 and cyclosporin A (CsA) against in vitro ischemic injury of astrocytes might be mediated through attenuation of cytosolic isoform of phospholipase A(2) (cPLA(2)) expression and activity as well as inhibition of arachidonic acid (AA) release. On the 21st day in vitro, cultures of rat astrocytes were subjected to ischemia-simulating conditions (combined oxygen glucose deprivation) for 8 h and exposed to FK506 (10 - 1,000 nM) and CsA (0.25 - 10 microM). Obtained data suggest the cross-talk between the action of 0.25 - 10 microM CsA as well as 1 microM FK506 on calcineurin (CaN) and cPLA(2) in anti-apoptotic signal transduction pathways. Moreover, we have shown that immunosuppressants at these concentrations protected glial cells against ischemia-induced apoptosis through the increase of cell viability, mitochondrial function restoration, and attenuation of oxidative stress. Finally, in our study, low concentrations of FK506 (10 and 100 nM) exerted limited effects on the assessed parameters. Our findings document a key role either for CaN or cPLA(2) expression attenuation and AA release inhibition in the antiapoptotic effect of FK506 and CsA in ischemic astrocytes.
在本研究中，我们调查了FK506和环孢素A（CsA）对星形胶质细胞体外缺血性损伤的保护作用是否可能通过减弱胞质型磷脂酶A2（cPLA2）的表达和活性以及抑制花生四烯酸（AA）释放来介导。在体外培养的第21天，将大鼠星形胶质细胞培养物置于模拟缺血条件（联合氧葡萄糖剥夺）下8小时，并分别用FK506（10 - 1000 nM）和CsA（0.25 - 10 μM）处理。所得数据表明，在抗凋亡信号转导途径中，0.25 - 10 μM的CsA以及1 μM的FK506对钙调神经磷酸酶（CaN）和cPLA2的作用之间存在相互作用。此外，我们已经表明，这些浓度的免疫抑制剂通过提高细胞活力、恢复线粒体功能和减轻氧化应激来保护神经胶质细胞免受缺血诱导的凋亡。最后，在我们的研究中，低浓度的FK506（10和100 nM）对所评估的参数产生的影响有限。我们的研究结果证明，CaN或cPLA2表达减弱以及AA释放抑制在FK506和CsA对缺血星形胶质细胞的抗凋亡作用中起关键作用。
