Changes in peptidyl-prolyl cis/trans isomerase activity and FK506 binding protein expression following neuroprotection by FK506 in the ischemic rat brain
Changes in peptidyl-prolyl cis/trans isomerase activity and FK506 binding protein expression following neuroprotection by FK506 in the ischemic rat brain
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DOI：
10.1016/s0306-4522(03)00404-4
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发表时间：
2003-01-01
期刊：
影响因子：
3.3
通讯作者：
Herdegen, T
中科院分区：
文献类型：
--
作者：
Brecht, S;Schwarze, K;Herdegen, T
FK506 是一种免疫抑制剂，在脑缺血后也具有神经保护作用。 FK506 与细胞内蛋白 (FKBP) 结合，这些蛋白具有广泛的功能，但共同具有肽基-脯氨酰顺/反异构酶活性。短暂局灶性缺血后，我们分析了 FKBP12、52 和 65 的表达以及总 FKBP 酶活性。此外，我们还研究了FK506对神经元信号转导和梗塞区域灌注变化的影响。雄性大鼠短暂大脑中动脉闭塞90分钟后，通过Western blot分析FK506处理和对照动物中FKBP12、52和65的表达，并测定肽基-脯氨酰顺/反异构酶活性。磁共振成像用于测量组织灌注、血管源性水肿的发展和梗死面积。为了研究神经元应激信号级联反应，通过免疫组织化学分析激活转录因子2（ATF-2）、Fas-配体（Fas-L）和c-Jun的表达和磷酸化。FK506使脑梗塞体积减少53%并减轻细胞毒性水肿。 FK506 剂量依赖性地增加和阻断梗塞区域中的总 FKBP 酶活性。脑缺血选择性上调FKBP表达。 FK506处理不影响表达模式。 FK506 处理后，梗死周围区域神经元中的 c-Jun 磷酸化和 Fas-L 表达降低，而 ATF-2 表达得以保留。 FK506 可减少大脑缺血性损伤。首次表明，FK506 的神经保护作用还包括抑制体内 FKBP 的脑肽基脯氨酰顺/反异构酶活性，而缺血后 FKBP12、52 和 65 的表达水平略有变化，并且 FK506 治疗不会抑制表达模式。然而，FKBP 酶活性的变化导致梗塞周围区域应激细胞体反应的抑制，如通过抑制 c-Jun 磷酸化和 Fas-L 表达所观察到的。 (C) 2003 国际广播组织。由爱思唯尔有限公司出版。保留所有权利。
FK506 is an immunosuppressant also showing neuroprotection following cerebral ischemia. FK506 binds to intracellular proteins (FKBP) which have a wide range of functions but have in common the peptidyl-prolyl cis/trans isomerase activity. Following transient focal ischemia, we have analyzed the expression of FKBP12, 52 and 65 and the total FKBP enzyme activity. Furthermore, we have investigated the effect of FK506 on signal transduction in neurons and perfusion changes in the infarct area.After 90 min of transient middle cerebral artery occlusion in male rats the expression of FKBP12, 52 and 65 was analyzed by Western blot in FK506-treated and control animals and the peptidyl-prolyl cis/trans isomerase activity was determined. Magnetic resonance imaging was used to measure tissue perfusion, development of vasogenic edema and infarct size. To investigate the neuronal stress signal cascade, activating transcription factor 2 (ATF-2), Fas-ligand (Fas-L) and c-Jun expression and phosphorylation were analyzed by immunohistochemistry.FK506 decreased the cerebral infarct volume by 53% and reduced the cytotoxic edema. The total FKBP enzymatic activity in the infarct area was increased and blocked dose dependently by FK506. FKBP expression was selectively upregulated by cerebral ischemia. FK506 treatment does not influence the expression patterns. c-Jun phosphorylation in neurons of the per-infarct area and Fas-L expression was reduced by FK506 treatment whereas ATF-2 expression was preserved. Cerebral ischemic damage to the brain was reduced by FK506. It was shown for the first time that neuroprotection by FK506 also included the suppression of the cerebral peptidylprolyl cis/trans isomerase activity of FKBP in vivo whereas the expression levels of FKBP12, 52 and 65 following ischemia changed slightly and FK506 treatment does not suppress the expression patterns. However, changes of FKBP enzymatic activity result in suppression of the stress cell body response in the peri-infarct area as observed by suppression of c-Jun phosphorylation and Fas-L expression. (C) 2003 IBRO. Published by Elsevier Ltd. All rights reserved.