Implanted fibroblasts genetically engineered to produce brain-derived neurotrophic factor prevent 1-methyl-4-phenylpyridinium toxicity to dopaminergic neurons in the rat.

The trophism of brain-derived neurotrophic factor (BDNF) for dopaminergic cells in culture has led to significant interest in the role of BDNF in the etiology and potential treatment of Parkinson disease. Previous in vivo investigation of BDNF delivery to axotomized substantia nigra dopaminergic neurons in the adult rat has shown no protective effect. In this study, we produced nigral degeneration by infusing 1-methyl-4-phenylpyridinium (MPP+), a mitochondrial complex I inhibitor and the active metabolite of 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP), into the rat striatum. The subsequent loss of nigral neurons was presumably due to mitochondrial toxicity after MPP+ uptake and retrograde transport to the substantia nigra. We engineered immortalized rat fibroblasts to secrete human BDNF and implanted these cells near the substantia nigra 7 days before striatal MPP+ infusion. We found that BDNF-secreting fibroblasts markedly increased nigral dopaminergic neuronal survival when compared to control fibroblast implants. The observation that BDNF prevents MPTP-induced dopaminergic neuronal degeneration in the adult brain has significance for the treatment of neurodegenerative disorders, which may involve mitochondrial dysfunction, such as Parkinson disease. IMAGES:

脑源性神经营养因子（brain-derived neurotrophic factor, BDNF）对体外培养的多巴胺能细胞的营养作用，使得学界对BDNF在帕金森病（Parkinson disease）的病因学及潜在治疗中的作用产生了浓厚兴趣。此前针对成年大鼠轴突切断的黑质多巴胺能神经元的体内BDNF递送研究，未显示出保护效果。本研究通过向大鼠纹状体灌注1-甲基-4-苯基吡啶鎓（1-methyl-4-phenylpyridinium, MPP+）——一种线粒体复合物I抑制剂，同时也是1-甲基-4-苯基-1,2,3,6-四氢吡啶（1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, MPTP）的活性代谢物——来诱导黑质变性。MPP+被摄取并逆向转运至黑质后，所引发的黑质神经元丢失推测源于其线粒体毒性。我们将永生化大鼠成纤维细胞工程化改造，使其分泌人源BDNF，并在纹状体MPP+灌注前7天将这些细胞移植至黑质附近。结果发现，与对照成纤维细胞移植组相比，分泌BDNF的成纤维细胞显著提高了黑质多巴胺能神经元的存活率。本研究观察到BDNF可在成年大脑中阻断MPTP诱导的多巴胺能神经元变性，这对于治疗涉及线粒体功能障碍的神经退行性疾病（如帕金森病）具有重要意义。IMAGES: