Matsukawa Noriyuki, Yasuhara Takao, Hara Koichi, Xu Lin, Maki Mina, Yu Guolong, Kaneko Yuji, Ojika Kosei, Hess David C, Borlongan Cesar V
Department of Neurology, Medical College of Georgia, Augusta, GA 30912, USA.
BMC Neurosci. 2009 Oct 6;10:126. doi: 10.1186/1471-2202-10-126.
Minocycline, a second-generation tetracycline with anti-inflammatory and anti-apoptotic properties, has been shown to promote therapeutic benefits in experimental stroke. However, equally compelling evidence demonstrates that the drug exerts variable and even detrimental effects in many neurological disease models. Assessment of the mechanism underlying minocycline neuroprotection should clarify the drug's clinical value in acute stroke setting.
Here, we demonstrate that minocycline attenuates both in vitro (oxygen glucose deprivation) and in vivo (middle cerebral artery occlusion) experimentally induced ischemic deficits by direct inhibition of apoptotic-like neuronal cell death involving the anti-apoptotic Bcl-2/cytochrome c pathway. Such anti-apoptotic effect of minocycline is seen in neurons, but not apparent in astrocytes. Our data further indicate that the neuroprotection is dose-dependent, in that only low dose minocycline inhibits neuronal cell death cascades at the acute stroke phase, whereas the high dose exacerbates the ischemic injury.
The present study advises our community to proceed with caution to use the minimally invasive intravenous delivery of low dose minocycline in order to afford neuroprotection that is safe for stroke.
米诺环素是一种具有抗炎和抗凋亡特性的第二代四环素，已被证明在实验性中风中具有治疗益处。然而，同样有说服力的证据表明，该药物在许多神经疾病模型中会产生可变甚至有害的影响。评估米诺环素神经保护作用的机制应能阐明该药物在急性中风情况下的临床价值。
在此，我们证明米诺环素通过直接抑制涉及抗凋亡Bcl-2/细胞色素c途径的凋亡样神经元细胞死亡，减轻了体外（氧糖剥夺）和体内（大脑中动脉闭塞）实验诱导的缺血性缺陷。米诺环素的这种抗凋亡作用在神经元中可见，但在星形胶质细胞中不明显。我们的数据进一步表明，神经保护作用是剂量依赖性的，即只有低剂量的米诺环素在急性中风阶段抑制神经元细胞死亡级联反应，而高剂量则会加重缺血性损伤。
本研究建议我们的研究群体谨慎进行低剂量米诺环素的微创静脉给药，以便为中风提供安全的神经保护。
