Spraggins Y R, Seidler F J, Slotkin T A
Department of Pharmacology, Duke University Medical Center, Durham, N.C. 27710.
Biol Neonate. 1994;66(5):254-66. doi: 10.1159/000244115.
The immature brain is resistant to cell damage from hypoxia, such as that experienced during parturition. Because cocaine causes cerebral ischemia, we examined whether cocaine interferes with this resistance. On postnatal days 1, 4 or 8, neonatal rats were given an acute injection of saline or cocaine (30 mg/kg s.c.) and were then exposed to 7% O2 for 2 h. At the end of the exposure period, activity of ornithine decarboxylase (ODC), an enzymatic marker for activation of cell damage/repair, was assessed in different brain regions. Across all ages and regions, cocaine by itself suppressed ODC, reflecting reduced cell metabolism in the face of ischemia; the protein synthetic rate, assessed with [3H]leucine incorporation, was largely preserved during the drug insult. On postnatal day 1, hypoxia alone also led to a reduction in forebrain ODC as part of the protective metabolic response, with preservation of protein synthesis despite restricted oxygen availability. However, when cocaine and hypoxia were combined, ODC was induced and protein synthesis fell, indicating the onset of cell damage. By 4 days of age, brain maturation produced a change in the metabolic response to hypoxia alone, characterized by ODC induction; when cocaine was present, the response to hypoxia was exacerbated. At 8 days of age, neonatal brain again showed ODC induction with hypoxia, but in this case, cocaine pretreatment reduced the effect on ODC. Measurements of the patterns of protein synthesis during and after hypoxia indicated that cocaine pretreatment was enhancing the cell damage component of the response (increased protein synthesis during hypoxia) and reducing the cell repair component (decreased ability to induce ODC). In contrast to the interaction of acute cocaine with hypoxia, chronic prenatal treatment with cocaine did not elicit exacerbation of the cell damage markers during a subsequent exposure to postnatal hypoxia; worsening of hypoxic cell injury thus occurs only when cocaine is present concurrently with the hypoxia, as would be expected from direct ischemic actions of cocaine. Enhanced sensitivity to hypoxia-induced brain cell damage could be an important contributing factor to the net effects of cocaine on brain development in light of the acute ischemia associated with 'crack' cocaine smoking, hypoxia/ischemia from cigarette smoking, or hypoxia during parturition.
未成熟的大脑对缺氧引起的细胞损伤具有抵抗力，比如分娩过程中经历的缺氧。由于可卡因会导致脑缺血，我们研究了可卡因是否会干扰这种抵抗力。在出生后第1、4或8天，给新生大鼠急性注射生理盐水或可卡因（30毫克/千克，皮下注射），然后使其暴露于7%氧气环境中2小时。在暴露期结束时，在不同脑区评估鸟氨酸脱羧酶（ODC）的活性，ODC是细胞损伤/修复激活的一种酶标志物。在所有年龄段和脑区中，可卡因本身会抑制ODC，这反映出在缺血情况下细胞代谢降低；用[3H]亮氨酸掺入法评估的蛋白质合成速率在药物损伤期间基本保持。在出生后第1天，单独缺氧也会导致前脑ODC降低，这是保护性代谢反应的一部分，尽管氧气供应受限，但蛋白质合成仍得以维持。然而，当可卡因和缺氧同时存在时，ODC被诱导且蛋白质合成下降，表明细胞损伤开始。到4日龄时，大脑成熟使单独缺氧时的代谢反应发生变化，其特征是ODC被诱导；当存在可卡因时，对缺氧的反应会加剧。在8日龄时，新生大脑在缺氧时再次出现ODC诱导，但在这种情况下，可卡因预处理降低了对ODC的影响。对缺氧期间及之后蛋白质合成模式的测量表明，可卡因预处理增强了反应中的细胞损伤成分（缺氧期间蛋白质合成增加）并降低了细胞修复成分（诱导ODC的能力下降）。与急性可卡因与缺氧的相互作用不同，孕期长期用可卡因治疗在随后的出生后缺氧暴露期间并未引发细胞损伤标志物的加剧；因此，只有当可卡因与缺氧同时存在时，缺氧性细胞损伤才会恶化，这正如可卡因的直接缺血作用所预期的那样。鉴于与吸食“快克”可卡因相关的急性缺血、吸烟导致的缺氧/缺血或分娩期间的缺氧，对缺氧诱导的脑细胞损伤的敏感性增强可能是可卡因对大脑发育产生净效应的一个重要促成因素。
