Gidday J M, Fitzgibbons J C, Shah A R, Kraujalis M J, Park T S
Department of Neurosurgery, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Pediatr Res. 1995 Sep;38(3):306-11. doi: 10.1203/00006450-199509000-00006.
Because of ontogenic influences on the pathophysiologic mechanisms of brain injury in the perinatal brain, and in particular, the incomplete development of adenosine receptor systems, we investigated the potential for adenosine to provide cerebro-protection in a well established newborn rat model of hypoxia-ischemia. Fifteen litters of postnatal d 7 animals were subjected to unilateral carotid ligation and exposure to hypoxia (8% oxygen) for 3 h. Immediately after hypoxia-ischemia, animals received either the adenosine deaminase inhibitor deoxycoformycin (DCF; 2.5 mg/kg intraperitoneally) or the adenosine uptake inhibitor propentofylline (PPF; 10 mg/kg intraperitoneally); paired littermates received an equivalent volume of normal saline. On postnatal d 14, injury or protection was assessed by differences in hemispheric weights, morphometric determinations of infarct area, and histopathologic analyses. DCF resulted in a 34% (p = 0.02) and 31% (p = 0.03) reduction in hemispheric weight disparities and infarct area, respectively; for PPF, these reductions were 46% (p = 0.03) and 32% (p = 0.04), respectively. Light microscopic examinations of striatum, thalamus, hippocampus, and cortex revealed that both drugs significantly improved histologic scores as well. Measurements in six separate litters indicated that neither drug significantly reduced core body temperature for at least 6 h postadministration. These findings indicate that potentiation of endogenous adenosine levels in the perinatal brain can significantly ameliorate brain injury. Each of these treatment strategies was effective even when administered after the hypoxic-ischemic insult. Thus, further investigations of adenosinergic therapies are warranted in this and other perinatal models of cerebral ischemia to elucidate in detail their potential for clinical application.
由于个体发育对围产期脑损伤病理生理机制的影响，尤其是腺苷受体系统发育不完全，我们在一个成熟的新生大鼠缺氧缺血模型中研究了腺苷提供脑保护的潜力。15窝出生后7天的动物接受单侧颈动脉结扎并暴露于低氧（8%氧气）环境3小时。缺氧缺血后立即给予动物腺苷脱氨酶抑制剂脱氧助间型霉素（DCF；2.5mg/kg腹腔注射）或腺苷摄取抑制剂丙戊茶碱（PPF；10mg/kg腹腔注射）；配对的同窝出生动物接受等量生理盐水。在出生后第14天，通过半球重量差异、梗死面积的形态学测定和组织病理学分析来评估损伤或保护情况。DCF分别使半球重量差异和梗死面积减少了34%（p = 0.02）和31%（p = 0.03）；对于PPF，这些减少分别为46%（p = 0.03）和32%（p = 0.04）。对纹状体、丘脑、海马和皮质的光镜检查显示，两种药物也显著改善了组织学评分。在六个独立窝中的测量表明，两种药物在给药后至少6小时内均未显著降低核心体温。这些发现表明，增强围产期脑内源性腺苷水平可显著改善脑损伤。即使在缺氧缺血性损伤后给药，这些治疗策略中的每一种都是有效的。因此，在这个和其他围产期脑缺血模型中，有必要进一步研究腺苷能疗法，以详细阐明其临床应用潜力。
