Costantini L C, Chaturvedi P, Armistead D M, McCaffrey P G, Deacon T W, Isacson O
Neuroregeneration Laboratory, Harvard Medical School, McLean Hospital, Belmont, Massachusetts 02178, USA.
Neurobiol Dis. 1998 Aug;5(2):97-106. doi: 10.1006/nbdi.1998.0185.
Protection or regeneration of the dopaminergic (DA) system would be of significant therapeutic value for Parkinson's disease. Immunophilin ligands, such as FK506, can produce neurotrophic effects in vitro and in vivo, but their immunosuppressive effects make them unsuitable for neurological application. This study demonstrates that a novel, nonimmunosuppressive immunophilin ligand (V-10,367) increased the number of neurites extended by tyrosine hydroxylase positive (TH+) DA neurons in embryonic day 14 primary DA neuronal cultures. In contrast, the immunosuppressive immunophilin ligand FK506 increased the length of TH+ neurites. After oral administration in MPTP-treated mice, V-10,367 completely protected against MPTP-induced loss of striatal TH+ axonal density, while FK506 did not. These experiments demonstrate that nonimmunosuppressive immunophilin ligands specifically increase neurite branching in primary DA neuronal culture and possess neurotrophic actions in vivo with potential application to neurodegenerative disease.
多巴胺能（DA）系统的保护或再生对帕金森病具有重大的治疗价值。免疫亲和素配体，如FK506，在体外和体内均可产生神经营养作用，但其免疫抑制作用使其不适用于神经学应用。本研究表明，一种新型的非免疫抑制性免疫亲和素配体（V-10,367）增加了胚胎第14天原代DA神经元培养物中酪氨酸羟化酶阳性（TH+）DA神经元伸出的神经突数量。相比之下，免疫抑制性免疫亲和素配体FK506增加了TH+神经突的长度。在给予MPTP处理的小鼠口服后，V-10,367完全保护其免受MPTP诱导的纹状体TH+轴突密度损失，而FK506则无此作用。这些实验表明，非免疫抑制性免疫亲和素配体在原代DA神经元培养中特异性增加神经突分支，并在体内具有神经营养作用，具有应用于神经退行性疾病的潜力。
