Sanner C A, Cunningham T J, Goldberger M E
Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110.
J Neurosci. 1994 Nov;14(11 Pt 1):6472-80. doi: 10.1523/JNEUROSCI.14-11-06472.1994.
Hemisection of the adult rat spinal cord at T9 transects the ascending ipsilateral axons of Clarke's nucleus (CN) neurons and the descending contralateral axons of red nucleus (RN) neurons. Eight weeks following axotomy, 30% of CN neurons and 22% of RN neurons die. Since both nuclei receive glutamatergic input, we wished to examine the possibility that glutamatergic excitotoxicity contributes to axotomy-induced neuronal death in these nuclei. To test this we studied the effects of administration of the NMDA receptor antagonist MK-801 on cell survival after axotomy. When 1 mg/kg body weight MK-801 is administered subcutaneously every day for 1-8 weeks to hemisected rats, cell death is prevented. Treatment with 0.5 mg/kg body weight MK-801 over the same time periods results in only partial rescue of axotomized neurons. Paradoxically, when 1 mg/kg MK-801 administration is restricted to the first week of an 8 week survival period, cell death in both the RN and CN is greatly exaggerated over the cell loss found in saline-treated animals. Withdrawal of 1 mg/kg MK-801 after 1 week of administration induces the loss of 92% of CN neurons, which is 63% greater than that occurring after axotomy alone. If, however, 1 mg/kg MK-801 is withdrawn after 2 weeks post-axotomy in the RN and 3 weeks postaxotomy in CN, all axotomized neurons survive. This rescue is found at 6 months postsurgery, the longest survival period studied, and therefore appears to be permanent. These results suggest that glutamatergic afferent input contributes significantly to the death of axotomized red nucleus and Clarke's nucleus neurons via NMDA receptors located on these neurons.
在成年大鼠T9水平对脊髓进行半横切，会切断同侧克拉克核（CN）神经元的上行轴突以及对侧红核（RN）神经元的下行轴突。轴突切断术后8周，30%的CN神经元和22%的RN神经元死亡。由于这两个核都接受谷氨酸能输入，我们希望研究谷氨酸能兴奋性毒性是否导致这些核中轴突切断诱导的神经元死亡。为了验证这一点，我们研究了给予NMDA受体拮抗剂MK-801对轴突切断后细胞存活的影响。当每天以1mg/kg体重的剂量对脊髓半横切的大鼠皮下注射MK-801，持续1 - 8周时，可防止细胞死亡。在相同时间段内给予0.5mg/kg体重的MK-801进行治疗，只能部分挽救轴突切断的神经元。矛盾的是，当在8周存活期的第一周仅给予1mg/kg的MK-801时，RN和CN中的细胞死亡比生理盐水处理的动物中发现的细胞损失大大增加。在给药1周后停用1mg/kg的MK-801，会导致92%的CN神经元死亡，这比仅轴突切断后发生的死亡多63%。然而，如果在RN轴突切断后2周和CN轴突切断后3周停用1mg/kg的MK-801，所有轴突切断的神经元都能存活。这种挽救在术后6个月（研究的最长存活期）时仍然存在，因此似乎是永久性的。这些结果表明，谷氨酸能传入输入通过位于这些神经元上的NMDA受体，对轴突切断的红核和克拉克核神经元的死亡有显著贡献。
