Simvastatin acutely reduces ischemic brain damage in the immature rat via Akt and CREB activation
Simvastatin acutely reduces ischemic brain damage in the immature rat via Akt and CREB activation
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DOI：
10.1016/j.expneurol.2009.07.026
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发表时间：
2009-11-01
影响因子：
5.3
通讯作者：
Balduini, Walter
中科院分区：
文献类型：
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作者：
Carloni, Silvia;Girelli, Silvia;Balduini, Walter
我们以前已经表明，辛伐他汀（Sim）具有持久的神经保护作用，在新生儿缺氧缺血模型。在此，我们评估了不同剂量和持续时间的Sim治疗的神经保护作用，并进一步探讨其作用机制。对新生大鼠进行右颈动脉闭塞，然后缺氧2.5小时（缺氧缺血，HI）。Sim以10或5 mg/kg的剂量，s.c.从出生后第1天（PN 1）至PN 7，或从PN 4至PN 7以20 mg/kg，或在缺血程序开始前18 h以20 mg/kg单次给药。低剂量治疗或单次给药可有效减少HI诱导的脑损伤及其行为结局。Sim增加神经元细胞中Akt和CREB磷酸化，并且用渥曼青霉素处理完全阻断神经保护和p-Akt。这些数据表明，即使是单次预防性Sim施用也能防止缺氧缺血性脑损伤，并且神经保护部分地通过在神经元细胞中保留Akt和刺激CREB磷酸化来获得。预防性Sim给药启动了已知可增加大脑对有害因素耐受性的生化事件，表明该药物可通过诱导药理学预处理来发挥神经保护作用。(C)2009 Elsevier Inc.所有战斗保留。
We have previously shown that simvastatin (Sim) has long-lasting neuroprotective effects in a neonatal model of hypoxia-ischemia. Herein we evaluated the neuroprotective effect of different doses and duration of Sim treatment and further addressed its mechanism of action. Neonatal rats were subjected to occlusion of the right carotid artery followed by 2.5 h hypoxia (hypoxia-ischemia, HI). Sim was given at the dose of 10 or 5 mg/kg, s.c. from postnatal day 1 (PN1) to PN7, or at 20 mg/kg from PN4 to PN7, or at 20 mg/kg in a single administration 18 h before the onset of the ischemic procedure. Low-dose treatments or a single administration of the drug were effective in reducing HI-induced brain damage and its behavioural outcomes. Sim increased both Akt and CREB phosphorylation in neuronal cells and treatment with wortmannin completely blocked neuroprotection and p-Akt. These data demonstrate that even a single prophylactic Sim administration protects from hypoxic ischemic brain damage and that neuroprotection is in part obtained by preserving Akt and Stimulating CREB phosphorylation in neuronal cells. Prophylactic Sim administration set in motion biochemical events that are known to increase brain tolerance to harmful factors, suggesting that the drug may exert neuroprotection by inducing pharmacological preconditioning. (C) 2009 Elsevier Inc. All Fights reserved.