Hulley P, Schachner M, Lübbert H
Department of Endocrinology and Metabolism, University of Stellenbosch Medical School, Tygerberg, South Africa.
J Neurosci Res. 1998 Jul 15;53(2):129-34. doi: 10.1002/(SICI)1097-4547(19980715)53:2<129::AID-JNR1>3.0.CO;2-9.
Cell adhesion molecules play a central role in neural development and are also critically involved in axonal regeneration and synaptic plasticity in the adult nervous system. We investigated whether the neural cell adhesion molecule L1 was capable of stimulating survival and differentiation in the mid-brain dopaminergic neurons which degenerate in Parkinson's disease. Monoclonal L1 antibodies, known to enhance neurite outgrowth, were substrate-coated or added at the time of plating to medium of cultures containing mid-brain dopaminergic neurons from 14-day-old fetal rats. Tritiated dopamine uptake per well and the number of tyrosine hydroxylase-immunopositive neurons increased in a dose-dependent manner with increasing concentrations of L1 antibody, suggesting that L1 acts directly or indirectly as a growth factor for dopaminergic neurons. A monoclonal L1 antibody not enhancing neurite outgrowth was ineffective. The growth-promoting effects of L1 antibodies on dopaminergic neurons in culture did not appear to be mediated by the cAMP-activated protein kinase A pathway, since combined treatment with a phosphodiesterase inhibitor had only additive effects on the L1-induced increase of dopamine uptake, and in addition, antibodies against L1 failed to protect cultures of dopaminergic neurons against the neurotoxin MPP+, whereas pretreatment with forskolin and phosphodiesterase type-IV inhibitors was strongly protective.
细胞黏附分子在神经发育中起核心作用，并且在成体神经系统的轴突再生和突触可塑性方面也至关重要。我们研究了神经细胞黏附分子L1是否能够刺激中脑多巴胺能神经元的存活和分化，这些神经元在帕金森病中会发生退化。已知能增强神经突生长的单克隆L1抗体，被包被在底物上或在接种时添加到含有14日龄胎鼠中脑多巴胺能神经元的培养物培养基中。每孔的氚标记多巴胺摄取量和酪氨酸羟化酶免疫阳性神经元的数量随着L1抗体浓度的增加呈剂量依赖性增加，这表明L1直接或间接作为多巴胺能神经元的生长因子发挥作用。一种不能增强神经突生长的单克隆L1抗体则没有效果。L1抗体对培养的多巴胺能神经元的促生长作用似乎不是由cAMP激活的蛋白激酶A途径介导的，因为与磷酸二酯酶抑制剂联合处理对L1诱导多巴胺摄取增加只有相加作用，此外，抗L1抗体不能保护多巴胺能神经元培养物免受神经毒素MPP + 的损伤，而用福斯克林和IV型磷酸二酯酶抑制剂预处理则具有很强的保护作用。
