Greco Rosaria, Amantea Diana, Blandini Fabio, Nappi Giuseppe, Bagetta Giacinto, Corasaniti M Tiziana, Tassorelli Cristina
IRCCS C. Mondino Institute of Neurology Foundation, 27100 Pavia, Italy.
Int Rev Neurobiol. 2007;82:423-35. doi: 10.1016/S0074-7742(07)82024-1.
Transient focal ischemia caused by middle cerebral artery occlusion (MCAo) produces apoptotic cell death in the penumbra area. Bcl-2 is a protooncogene that plays a major antiapoptotic role, at the cellular level, by counteracting the activation of apoptosis effectors, that is, caspases. It has been suggested that nitroglycerin (NTG), a nitric oxide donor, reduces ischemia/reperfusion-induced brain damage via the inhibition of caspase activity and NMDA receptor. In this chapter, we evaluated the protective effects of NTG against cerebral damage caused by transient (2h) MCAo (tMCAo) focusing our interest on the potential effects on Bcl-2 expression. Male Wistar rats were administered intraperitoneally (i.p.) with NTG (10mg/kg) or vehicle (PEG, 1ml/kg) 20min before the induction of MCAo by intraluminal silicon-coated filament (0.37-mm diameter). Cerebral infarct volume was measured 22h after reperfusion, while cortical Bcl-2 expression was evaluated at the end of 2-h MCAo (without reperfusion) and at 5h of reperfusion. The results show significant reduction of the infarct volume in rats preinjected with NTG, as compared to the vehicle group. After 2h of occlusion, no significant difference was seen in Bcl-2 expression in the ipsilateral and contralateral cortex of either experimental groups (NTG and vehicle). However, 5h after reperfusion, a significant increase of Bcl-2 expression was detected in the damaged cortex of control rats, probably reflecting a compensatory response aiming at counteracting the cell death process; this increase was absent in the NTG-treated rats. These data, while confirming the neuroprotective effect of NTG in an in vivo ischemia/reperfusion model, seem to suggest that the drug may act by downsizing the complex chain of events underlying apoptosis activation and consequent activation of antiapoptotic responses.
大脑中动脉闭塞（MCAo）引起的短暂性局灶性缺血会在半暗带区域导致凋亡性细胞死亡。Bcl-2是一种原癌基因，在细胞水平上，它通过对抗凋亡效应器（即半胱天冬酶）的激活发挥主要的抗凋亡作用。有人提出，一氧化氮供体硝酸甘油（NTG）通过抑制半胱天冬酶活性和NMDA受体来减少缺血/再灌注诱导的脑损伤。在本章中，我们评估了NTG对短暂性（2小时）MCAo（tMCAo）所致脑损伤的保护作用，重点关注其对Bcl-2表达的潜在影响。在通过腔内硅涂层细丝（直径0.37毫米）诱导MCAo前20分钟，雄性Wistar大鼠腹腔注射（i.p.）NTG（10毫克/千克）或溶剂（聚乙二醇，1毫升/千克）。再灌注22小时后测量脑梗死体积，而在2小时MCAo结束时（无再灌注）和再灌注5小时时评估皮质Bcl-2表达。结果显示，与溶剂组相比，预先注射NTG的大鼠梗死体积显著减小。闭塞2小时后，两个实验组（NTG组和溶剂组）同侧和对侧皮质的Bcl-2表达均无显著差异。然而，再灌注5小时后，在对照大鼠受损皮质中检测到Bcl-2表达显著增加，这可能反映了旨在对抗细胞死亡过程的代偿反应；在NTG处理的大鼠中未出现这种增加。这些数据在证实NTG在体内缺血/再灌注模型中的神经保护作用的同时，似乎表明该药物可能通过缩减凋亡激活及随后抗凋亡反应激活所涉及的复杂事件链来发挥作用。
