Liu X H, Eun B L, Silverstein F S, Barks J D
Department of Pediatrics, University of Michigan, Ann Arbor, USA.
Pediatr Res. 1996 Dec;40(6):797-803. doi: 10.1203/00006450-199612000-00004.
Platelet-activating factor (PAF) is overproduced in ischemic brain. Although postischemic PAF antagonist administration protects the mature brain in some models, little is known about the effects of PAF antagonists in the immature brain. We hypothesized that the PAF antagonist BN 52021 would attenuate perinatal cerebral hypoxic-ischemic injury. To elicit focal hypoxic-ischemic brain injury, 7-d-old (P7) rats (n = 111) underwent right carotid ligation, followed by 2.5-3.25 h of hypoxia (fractional concentration of inspired O2 = 0.08). BN 52021 neuroprotection was evaluated in three groups of experiments: 1) 25 mg/kg/dose, 0 and 2 h posthypoxia; 2), 25 mg/kg/dose immediately before and 1 h after hypoxia; and 3) posthypoxia-ischemia treatment with BN 52021 12.5, 25, or 50 mg/kg/dose in 2 doses 0 and 2 h after hypoxia. All experiments included concurrent vehicle-injected controls. To quantitate severity of injury, bilateral regional cross-sectional areas (groups 1 and 2) or hemisphere weights (group 3) were evaluated on P12. Both pre- and posthypoxic treatment with BN 52021 (25 mg/kg/dose, two serial doses) decreased the incidence of cerebral infarction from 90% to about 30% (p < 0.02, Fisher's exact test). Measurement of cross-sectional areas confirmed neuroprotection and indicated some benefit of pre- over posthypoxic-ischemic treatment in hippocampus and cortex. Over the dose range tested, the neuroprotective effect of BN 52021 administration was not dose-dependent. In contrast, BN 52021 did not attenuate N-methyl-D-aspartate-induced hippocampal excitotoxic injury in P7 rats. Either prophylactic or "rescue" administration of PAF antagonists decreases the incidence and severity of brain injury associated with an episode of perinatal cerebral hypoxia-ischemia.
血小板活化因子（PAF）在缺血性脑中产生过多。尽管在某些模型中，缺血后给予PAF拮抗剂可保护成熟脑，但关于PAF拮抗剂对未成熟脑的影响知之甚少。我们假设PAF拮抗剂BN 52021可减轻围产期脑缺氧缺血性损伤。为引发局灶性缺氧缺血性脑损伤，7日龄（P7）大鼠（n = 111）行右颈动脉结扎，随后进行2.5 - 3.25小时的缺氧（吸入氧气分数浓度= 0.08）。在三组实验中评估BN 52021的神经保护作用：1）25 mg/kg/剂量，缺氧后0小时和2小时；2）缺氧前即刻和缺氧后1小时给予25 mg/kg/剂量；3）缺氧后缺血时用12.5、25或50 mg/kg/剂量的BN 52021在缺氧后0小时和2小时分2次给药。所有实验均包括同时注射载体的对照组。为定量损伤严重程度，在P12时评估双侧区域横截面积（第1组和第2组）或半球重量（第3组）。缺氧前和缺氧后用BN 52021（25 mg/kg/剂量，连续2剂）治疗均将脑梗死发生率从90%降至约30%（p < 0.02，Fisher精确检验）。横截面积测量证实了神经保护作用，并表明缺氧前治疗比缺氧后缺血治疗在海马体和皮质中有一定益处。在所测试的剂量范围内，给予BN 52021的神经保护作用不依赖剂量。相反，BN 52021并未减轻P7大鼠中N - 甲基 - D - 天冬氨酸诱导的海马体兴奋性毒性损伤。预防性或“挽救性”给予PAF拮抗剂均可降低与围产期脑缺氧缺血发作相关的脑损伤的发生率和严重程度。
