Kearns C M, Cass W A, Smoot K, Kryscio R, Gash D M
Department of Anatomy and Neurobiology, University of Kentucky Medical Center, Lexington, Kentucky 40536, USA.
J Neurosci. 1997 Sep 15;17(18):7111-8. doi: 10.1523/JNEUROSCI.17-18-07111.1997.
Glial cell line-derived neurotrophic factor (GDNF) injected intranigrally protects midbrain dopamine neurons against 6-hydroxydopamine (6-OHDA) toxicity. The timing between GDNF administration and exposure to 6-OHDA is critical in achieving optimal protection. When injected 6 hr before an intranigral injection of 6-OHDA, GDNF provides complete protection as measured by the number of surviving neurons in the substantia nigra of adult rats. The surviving neuronal population decreases by approximately 50% with 12 and 24 hr separating GDNF and 6-OHDA administrations. In controls with 6-OHDA lesions, there is <10% survival of nigral dopamine neurons. No significant increase in survival is seen with either concurrent injections of GDNF and 6-OHDA or 1 hr GDNF pretreatment. Based on HPLC measurements, striatal and midbrain dopamine levels are at least twofold higher on the lesioned side in animals receiving GDNF 6 hr before a 6-OHDA lesion compared with vehicle recipients. Protein synthesis is necessary for GDNF-induced neuroprotective effects because cycloheximide pretreatment that inhibits protein synthesis also blocks neuroprotection.
经黑质内注射的胶质细胞源性神经营养因子（GDNF）可保护中脑多巴胺能神经元免受6-羟基多巴胺（6-OHDA）毒性的影响。给予GDNF与暴露于6-OHDA之间的时间间隔对于实现最佳保护至关重要。当在黑质内注射6-OHDA前6小时注射GDNF时，以成年大鼠黑质中存活神经元数量衡量，GDNF可提供完全保护。若GDNF与6-OHDA给药间隔12小时和24小时，存活的神经元数量会减少约50%。在6-OHDA损伤的对照组中，黑质多巴胺能神经元的存活率低于10%。同时注射GDNF和6-OHDA或GDNF预处理1小时，均未见存活率显著增加。基于高效液相色谱测量，与接受赋形剂的动物相比，在6-OHDA损伤前6小时接受GDNF的动物，其损伤侧纹状体和中脑多巴胺水平至少高出两倍。蛋白质合成对于GDNF诱导的神经保护作用是必需的，因为抑制蛋白质合成的环己酰亚胺预处理也会阻断神经保护作用。
