Benkovic Stanley Anthony, O'Callaghan James Patrick, Miller Diane Bemis
Toxicology and Molecular Biology Branch, Centers for Disease Control and Prevention-National Institute for Occupational, Safety and Health, Mailstop 3014, 1095 Willowdale Road, Morgantown, WV 26505, USA.
Brain Res. 2006 Jan 27;1070(1):215-31. doi: 10.1016/j.brainres.2005.11.065. Epub 2006 Jan 5.
We evaluated regional neuropathological changes in adult and aged male mice treated systemically with kainic acid (KA) in a strain reported to be resistant to excitotoxic neuronal damage, C57BL/6. KA was administered in a single intraperitoneal injection. Adult animals were dosed with 35 mg/kg KA, while aged animals received a dose of 20 mg/kg in order to prevent excessive mortality. At time-points ranging from 12 h to 7 days post-treatment, animals were sacrificed and prepared for histological evaluation utilizing the cupric-silver neurodegeneration stain, immunohistochemistry for GFAP and IgG, and lectin staining. In animals of both ages, KA produced argyrophilia in neurons throughout cortex, hippocampus, thalamus, and amygdala. Semi-quantitative analysis of neuropathology revealed a similar magnitude of damage in animals of both ages, even though aged animals received less toxicant. Additional animals were evaluated for KA-induced reactive gliosis, assayed by an ELISA for GFAP, which revealed a 2-fold elevation in protein levels in adult mice, and a 2.5-fold elevation in aged animals. Histochemical evaluation of GFAP and lectin staining revealed activation of astrocytes and microglia in regions with corresponding argyrophilia. IgG immunostaining revealed a KA-induced breach of the blood-brain barrier in animals of both ages. Our data indicate widespread neurotoxicity following kainic acid treatment in C57BL/6J mice, and reveal increased sensitivity to this excitotoxicant in aged animals.
我们评估了在一种据报道对兴奋性毒性神经元损伤具有抗性的品系C57BL/6成年和老年雄性小鼠中，经全身注射海藻酸（KA）后的区域神经病理学变化。KA通过单次腹腔注射给药。成年动物给予35mg/kg的KA，而老年动物接受20mg/kg的剂量以防止过高的死亡率。在治疗后12小时至7天的时间点，处死动物并利用铜银神经变性染色、GFAP和IgG免疫组织化学以及凝集素染色进行组织学评估。在两个年龄段的动物中，KA均在整个皮质、海马体、丘脑和杏仁核的神经元中产生嗜银性。神经病理学的半定量分析显示，尽管老年动物接受的毒物较少，但两个年龄段动物的损伤程度相似。通过ELISA检测GFAP对另外的动物进行KA诱导的反应性胶质增生评估，结果显示成年小鼠的蛋白水平升高了2倍，老年动物升高了2.5倍。GFAP和凝集素染色的组织化学评估显示，在具有相应嗜银性的区域星形胶质细胞和小胶质细胞被激活。IgG免疫染色显示，两个年龄段的动物均存在KA诱导的血脑屏障破坏。我们的数据表明，C57BL/6J小鼠经海藻酸处理后存在广泛的神经毒性，并揭示老年动物对这种兴奋性毒物的敏感性增加。
