Volpe B T, Wildmann J, Altar C A
Department of Neurology and Neuroscience, Cornell University Medical College, White Plains, NY, USA.
Neuroscience. 1998 Apr;83(3):741-8. doi: 10.1016/s0306-4522(97)00424-7.
GABAergic neurons in the rat substantia nigra die after inhibitory inputs to the nigra have been killed, and glutamatergic inputs disinhibited, by striatal-pallidal injections of ibotenic acid. This delayed transneuronal injury model imitates the neuron loss observed in Huntington's disease, and may also imitate neuron loss distant from the primary injury in stroke and Parkinson's disease. Because the neurotrophins brain-derived neurotrophic factor and neurotrophin-3 can prevent excitotoxic killing of cultured GABA neurons, we tested whether either factor could protect nigral neurons from transneuronal degeneration. A continuous, three week supranigral infusion of brain-derived neurotrophic factor completely prevented the loss of nigral neurons caused by the ibotenic acid-induced destruction of the caudate-putamen and globus pallidus, and brain-derived neurotrophic factor increased nigral neuron size by 25%. These effects were specific to the TrkB tyrosine kinase receptor that mediates brain-derived neurotrophic factor actions, since supranigral infusions of saline or the TrkC preferring neurotrophin-3, did not prevent nigral neuron loss or induce a hypertrophic response. Neither trophic factor influenced the ibotenic acid destruction of striatal or pallidal neurons. These results demonstrate that exogenously supplied brain-derived neurotrophic factor can prevent delayed, transneuronal loss, and implicate decreased excitatory amino acid transmission or diminished nigral neuron susceptibility to glutamate inputs in the protective effect of brain-derived neurotrophic factor.
通过向纹状体-苍白球注射鹅膏蕈氨酸来杀死黑质的抑制性输入，并解除谷氨酸能输入的抑制后，大鼠黑质中的γ-氨基丁酸能神经元会死亡。这种延迟性跨神经元损伤模型模仿了在亨廷顿舞蹈病中观察到的神经元丢失，也可能模仿了中风和帕金森病中远离原发性损伤部位的神经元丢失。由于神经营养因子脑源性神经营养因子和神经营养因子-3可以防止培养的γ-氨基丁酸能神经元发生兴奋性毒性杀伤，因此我们测试了这两种因子是否能保护黑质神经元免受跨神经元变性的影响。持续三周向黑质上方输注脑源性神经营养因子可完全防止因鹅膏蕈氨酸诱导的尾状核-壳核和苍白球破坏而导致的黑质神经元丢失，并且脑源性神经营养因子使黑质神经元大小增加了25%。这些作用对介导脑源性神经营养因子作用的TrkB酪氨酸激酶受体具有特异性，因为向黑质上方输注生理盐水或偏爱TrkC的神经营养因子-3并不能防止黑质神经元丢失或诱导肥大反应。两种营养因子均未影响鹅膏蕈氨酸对纹状体或苍白球神经元的破坏。这些结果表明，外源性提供的脑源性神经营养因子可以防止延迟性跨神经元丢失，并提示脑源性神经营养因子的保护作用与兴奋性氨基酸传递减少或黑质神经元对谷氨酸输入的敏感性降低有关。
