Hilton G D, Nuñez J L, McCarthy M M
Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Neuroscience. 2003;116(2):383-91. doi: 10.1016/s0306-4522(02)00716-9.
Premature and full-term human infants are at considerable risk of excitotoxic-mediated brain damage due to hypoxia-ischemia, infection or other trauma. Glutamate receptor activation is a major source of excitoxicity in the adult and developing brain, and the hippocampus is particularly vulnerable to damage. The seven-day-old rat is a widely used model of pediatric brain damage, in large part due to the relative insensitivity of the brain to exogenous glutamate treatment prior to this age. We have reexamined the possible role of glutamate in pediatric brain damage in the newborn rat using kainic acid treatment and attending to the sex of the animal as well as the effects of pretreatment with the gonadal steroid estradiol. Consistent with previous studies, we found no evidence of damage 7 days posttreatment in the CA1 region of the hippocampus in males or females. There was also little to no damage in the CA2/3 or dentate gyrus of males. In females, however, kainic-acid treatment induced substantial damage in the dentate gyrus and moderate damage in CA2/3, as assessed by neuron number and regional volume. Pretreatment with estradiol was protective against kainic acid-induced damage in females but was permissive for damage in the dentate gyrus of males. Estradiol treatment in the absence of kainic acid treatment was also neuroprotective in females in that it increased neuron number and volume throughout the hippocampal formation, suggesting that the basis of the sex difference observed in hippocampal volume was hormonally mediated. There was no effect of exogenous estradiol given to males in the absence of kainic acid. We conclude that the newborn female rat brain, but not the male, is sensitive to glutamate-mediated toxicity and that gonadal steroids play a complex role in both naturally occurring sex differences in hippocampal volume and response to injury.
早产和足月出生的人类婴儿，由于缺氧缺血、感染或其他创伤，面临着兴奋性毒性介导的脑损伤的重大风险。谷氨酸受体激活是成体和发育中大脑兴奋性毒性的主要来源，海马体尤其容易受到损伤。七日龄大鼠是广泛使用的小儿脑损伤模型，很大程度上是因为在此年龄之前大脑对外源性谷氨酸处理相对不敏感。我们使用 kainic 酸处理并关注动物的性别以及性腺类固醇雌二醇预处理的影响，重新审视了谷氨酸在新生大鼠小儿脑损伤中的可能作用。与先前的研究一致，我们发现在处理后 7 天，雄性和雌性大鼠海马体 CA1 区域均没有损伤的证据。雄性大鼠的 CA2/3 或齿状回也几乎没有损伤。然而，通过神经元数量和区域体积评估，kainic 酸处理在雌性大鼠中诱导了齿状回的实质性损伤和 CA2/3 的中度损伤。雌二醇预处理对雌性大鼠 kainic 酸诱导的损伤具有保护作用，但对雄性大鼠齿状回的损伤具有促进作用。在没有 kainic 酸处理的情况下，雌二醇处理对雌性大鼠也具有神经保护作用，因为它增加了整个海马结构中的神经元数量和体积，这表明观察到的海马体体积性别差异的基础是由激素介导的。在没有 kainic 酸的情况下，给雄性大鼠注射外源性雌二醇没有效果。我们得出结论，新生雌性大鼠的大脑对谷氨酸介导的毒性敏感，而雄性则不然，并且性腺类固醇在海马体体积的自然性别差异和对损伤的反应中都起着复杂的作用。
