Sala M, Leone M P, Lampugnani P, Matturri L, Gori E
Institute of Pharmacology, Faculty of Mathematical, Physical and Natural Sciences, University of Milan, Italy.
Eur J Pharmacol. 1997 Jun 11;328(2-3):143-52. doi: 10.1016/s0014-2999(97)83040-3.
The effectiveness of defibrotide, a single-stranded polydeoxyribonucleotide compound, in preventing damage caused by cerebral ischemia was studied. Global ischemia was induced in anesthetized gerbils by bilateral carotid artery occlusion for 10 min. Defibrotide (100 mg/kg) or saline was injected, i.v., immediately after reperfusion. The following parameters were evaluated simultaneously: (1) electroencephalographic (EEG) spectral power, recorded before, during and after the ischemic period; (2) body temperature, monitored with a rectal thermistor probe after reperfusion for 120 min; (3) spontaneous motility, evaluated through a photocell system and quantified in terms of total distance travelled in 30 min, 1 h after recirculation and at periods over 15 days; (4) mnemonic functions assessed by passive avoidance test from 3 to 15 days after ischemia; (5) histological examination, 7 days after reperfusion, counting CA1 hippocampal neuronal cells. The ischemia-induced complete flattening of spectral power was significantly reversed (P < 0.01) by post-ischemic treatment with defibrotide between 30 and 90 min after ischemia. A complete recovery of total EEG spectral power was seen in the defibrotide group at 6 h and the saline ischemic group at 1 day. Seven days after bilateral carotid occlusion, there was a significant decrease in spectral power (-70% +/- 6) together with a loss of the number of CA1 cells in the saline ischemic group (-64%). Treatment with defibrotide significantly protected against the decrease in spectral power (-30% +/- 7) and cell loss (-9%). Finally, the number of animals found to be protected against the ischemia-induced flattening was significantly larger for defibrotide-treated gerbils than for saline-treated animals throughout the experiment except for the third day. Body temperature was significantly decreased only at 30 min after reperfusion in both ischemic and sham-operated groups. Defibrotide reduced ischemia-induced hypermotility but only 6 h after the insult. The ischemia-induced impairment of memory was partially reversed within 3 days in the defibrotide-treated animals and fully reversed within 7 days in the defibrotide group and 15 days in the saline group. Our results demonstrate that defibrotide, even when administered after the post-ischemic period, possesses anti-ischemic properties. The mechanism by which defibrotide protects the ischemic reperfused brain is still largely unknown. However, a neuroprotection via adenosine A1 and A2 subtype receptor interaction can be put forward.
研究了单链多脱氧核糖核苷酸化合物去纤苷预防脑缺血所致损伤的有效性。通过双侧颈动脉闭塞10分钟在麻醉的沙鼠中诱导全脑缺血。再灌注后立即静脉注射去纤苷（100mg/kg）或生理盐水。同时评估以下参数：（1）缺血期前后及期间记录的脑电图（EEG）频谱功率；（2）再灌注后120分钟用直肠热敏电阻探头监测体温；（3）通过光电管系统评估自发活动，并根据再循环后30分钟、1小时及15天以上期间的总行进距离进行量化；（4）缺血后3至15天通过被动回避试验评估记忆功能；（5）再灌注7天后进行组织学检查，计数海马CA1神经元细胞。缺血诱导的频谱功率完全平坦化在缺血后30至90分钟通过缺血后用去纤苷治疗得到显著逆转（P<0.01）。去纤苷组在6小时时脑电图总频谱功率完全恢复，生理盐水缺血组在1天时恢复。双侧颈动脉闭塞7天后，生理盐水缺血组的频谱功率显著降低（-70%±6），同时CA1细胞数量减少（-64%）。去纤苷治疗显著预防了频谱功率降低（-30%±7）和细胞丢失（-9%）。最后，在整个实验中，除第三天外，去纤苷治疗的沙鼠中被发现对缺血诱导的平坦化有保护作用的动物数量显著多于生理盐水治疗的动物。缺血组和假手术组仅在再灌注后30分钟体温显著降低。去纤苷减少了缺血诱导的活动亢进，但仅在损伤后6小时。缺血诱导的记忆障碍在去纤苷治疗的动物中在3天内部分逆转，在去纤苷组中7天内完全逆转，在生理盐水组中15天内完全逆转。我们的结果表明，去纤苷即使在缺血期后给药也具有抗缺血特性。去纤苷保护缺血再灌注脑的机制仍 largely 未知。然而，可以提出通过腺苷A1和A2亚型受体相互作用的神经保护作用。
