Chlortetracycline and demeclocycline inhibit calpains and protect mouse neurons against glutamate toxicity and cerebral ischemia
Chlortetracycline and demeclocycline inhibit calpains and protect mouse neurons against glutamate toxicity and cerebral ischemia
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DOI：
10.1074/jbc.m503113200
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发表时间：
2005-10-07
影响因子：
4.8
通讯作者：
Preston, E
中科院分区：
文献类型：
--
作者：
Jiang, SX;Lertvorachon, J;Preston, E
二甲胺四环素是脑缺血动物模型中一种有效的神经保护四环素。我们检测了氯四环素（CTC）和去环素（DMC）的保护作用，发现这两种四环素对体外谷氨酸诱导的神经元死亡和体内脑缺血也有有效的神经保护作用。然而，与米诺环素相比，CTC和DMC似乎通过一种独特的机制赋予神经保护作用。CTC和DMC不是抑制小胶质细胞激活和半胱天冬酶，而是抑制钙蛋白酶活性。此外，CTC和DMC仅弱拮抗n -甲基- d -天冬氨酸（NMDA）受体活性，分别导致16%和14%的NMDA诱导的全细胞电流抑制和部分阻断NMDA诱导的Ca2+内流，这通常被认为是神经元死亡的主要触发因素。体外和体内实验表明，这两种化合物选择性地抑制了谷氨酸治疗和脑缺血后激活的钙蛋白酶I和钙蛋白酶II的活性。相比之下，二甲胺四环素没有明显抑制钙蛋白酶活性。综上所述，这些结果表明，CTC和DMC通过抑制细胞内Ca2+的升高和钙蛋白酶的抑制来提供神经保护。
Minocycline is a potent neuroprotective tetracycline in animal models of cerebral ischemia. We examined the protective properties of chlortetracycline (CTC) and demeclocycline (DMC) and showed that these two tetracyclines were also potent neuroprotective against glutamate-induced neuronal death in vitro and cerebral ischemia in vivo. However, CTC and DMC appeared to confer neuroprotection through a unique mechanism compared with minocycline. Rather than inhibiting microglial activation and caspase, CTC and DMC suppressed calpain activities. In addition, CTC and DMC only weakly antagonized N-methyl-D-aspartate ( NMDA) receptor activities causing 16 and 14%, respectively, inhibition of NMDA-induced whole cell currents and partially blocked NMDA-induced Ca2+ influx, commonly regarded as the major trigger of neuronal death. In vitro and in vivo experiments demonstrated that the two compounds selectively inhibited the activities of calpain I and II activated following glutamate treatment and cerebral ischemia. In contrast, minocycline did not significantly inhibit calpain activity. Taken together, these results suggested that CTC and DMC provide neuroprotection through suppression of a rise in intracellular Ca2+ and inhibition of calpains.