Zoli M, Zini I, Grimaldi R, Biagini G, Agnati L F
Institute of Human Physiology, University of Modena, Italy.
Int J Dev Neurosci. 1993 Apr;11(2):175-87. doi: 10.1016/0736-5748(93)90077-q.
Polyamines and ornithine decarboxylase, the polyamine biosynthetic enzyme, have been demonstrated to increase in the early phase of several types of brain lesion. However, their role in the pathogenesis of tissue damage is still debated. In the present paper the effects of treatments with alpha-difluoromethylornithine, a suicide inhibitor of ornithine decarboxylase, have been investigated in a model of transient forebrain ischemia. Three treatment schedules were used: alpha-difluoromethylornithine treatment was either started 3 hr before and repeated 1 hr after the insult, or started at the time of the insult and continued for 3 or 7 days after post-ischemic reperfusion. The rats were sacrificed 4 hr, 7 or 40 days after reperfusion, respectively. The acute experiment demonstrated that alpha-difluoromethylornithine can reduce the increase of glial fibrillary acid protein immunoreactivity, an early marker of astroglial reaction, in ischemic striatum. Subchronic and chronic alpha-difluoromethylornithine treatments induced a worsening of the morphological outcome of the ischemic lesion. In caudate-putamen a trend for an increase of the area of neuronal loss was present after both treatments. In the hippocampal formation, a significant increase in the severity of neuronal lesion was observed in the mildly lesioned CA3 field. In addition, other alterations of lesioned tissue were observed in alpha-difluoromethylornithine-treated animals, including increases of non-neuronal cells at 7 and especially 40 days post-lesion in striatum and CA3 hippocampal field. In conclusion, present data indicate that ornithine decarboxylase activation after ischemic lesion is a crucial factor for survival of mildly lesioned neurons and proper tissue reaction to the ischemic lesion. The experiment on acute alpha-difluoromethylornithine treatment suggests that these effects may be, at least in part, related to putrescine-induced activation of astroglial cells in the early post-lesion period.
多胺以及多胺生物合成酶鸟氨酸脱羧酶已被证实在几种类型的脑损伤早期会增加。然而，它们在组织损伤发病机制中的作用仍存在争议。在本文中，研究了在短暂性前脑缺血模型中使用鸟氨酸脱羧酶的自杀性抑制剂α-二氟甲基鸟氨酸进行治疗的效果。采用了三种治疗方案：α-二氟甲基鸟氨酸治疗要么在损伤前3小时开始并在损伤后1小时重复给药，要么在损伤时开始并在缺血再灌注后持续3天或7天。分别在再灌注后4小时、7天或40天处死大鼠。急性实验表明，α-二氟甲基鸟氨酸可降低缺血纹状体中胶质纤维酸性蛋白免疫反应性的增加，胶质纤维酸性蛋白是星形胶质细胞反应的早期标志物。亚慢性和慢性α-二氟甲基鸟氨酸治疗导致缺血性损伤的形态学结果恶化。在尾状核-壳核，两种治疗后均出现神经元丢失面积增加的趋势。在海马结构中，在轻度损伤的CA3区观察到神经元损伤严重程度显著增加。此外，在α-二氟甲基鸟氨酸治疗的动物中还观察到损伤组织的其他改变，包括纹状体和海马CA3区在损伤后7天尤其是40天时非神经元细胞的增加。总之，目前的数据表明，缺血性损伤后鸟氨酸脱羧酶的激活是轻度损伤神经元存活以及组织对缺血性损伤产生适当反应的关键因素。急性α-二氟甲基鸟氨酸治疗实验表明，这些作用可能至少部分与损伤后早期腐胺诱导的星形胶质细胞激活有关。
