Seki Masaaki, Tanaka Takayuki, Nawa Hiroyuki, Usui Tomoaki, Fukuchi Takeo, Ikeda Kazuhito, Abe Haruki, Takei Nobuyuki
Department of Molecular Neurobiology, Brain Research Institute, Niigata University, 1-757 Asahimachi, Niigata, Niigata 951-8585, Japan.
Diabetes. 2004 Sep;53(9):2412-9. doi: 10.2337/diabetes.53.9.2412.
Although neurotrophins have been assessed as candidate therapeutic agents for neural complications of diabetes, their involvement in diabetic retinopathy has not been fully characterized. We found that the protein and mRNA levels of brain-derived neurotrophic factor (BDNF) in streptozotocin-induced diabetic rat retinas were reduced to 49% (P < 0.005) and 74% (P < 0.05), respectively, of those of normal control animals. In addition, dopaminergic amacrine cells appeared to be degenerating in the diabetic rat retinas, as revealed by tyrosine hydroxylase (TH) immunoreactivity. Overall TH protein levels in the retina were decreased to one-half that of controls (P < 0.01), reflecting reductions in the density of dopaminergic amacrine cells and the intensity of TH immunoreactivity within them. To confirm the neuropathological implications of BDNF reduction, we administered BDNF protein into the vitreous cavities of diabetic rats. Intraocular administration of BDNF rescued dopaminergic amacrine cells from neurodegeneration and counteracted the downregulation of TH expression, demonstrating its therapeutic potential. These findings suggest that the early retinal neuropathy of diabetes involves the reduced expression of BDNF and can be ameliorated by an exogenous supply of this neurotrophin.
尽管神经营养因子已被评估为糖尿病神经并发症的候选治疗药物，但其在糖尿病视网膜病变中的作用尚未完全明确。我们发现，链脲佐菌素诱导的糖尿病大鼠视网膜中脑源性神经营养因子（BDNF）的蛋白质和mRNA水平分别降至正常对照动物的49%（P < 0.005）和74%（P < 0.05）。此外，酪氨酸羟化酶（TH）免疫反应显示，糖尿病大鼠视网膜中的多巴胺能无长突细胞似乎正在退化。视网膜中总的TH蛋白水平降至对照组的一半（P < 0.01），这反映出多巴胺能无长突细胞密度的降低以及其中TH免疫反应强度的降低。为了证实BDNF减少的神经病理学意义，我们将BDNF蛋白注入糖尿病大鼠的玻璃体腔。眼内注射BDNF可使多巴胺能无长突细胞免于神经退变，并抵消TH表达的下调，证明了其治疗潜力。这些发现表明，糖尿病早期视网膜神经病变涉及BDNF表达的降低，并且外源性补充这种神经营养因子可以改善这种病变。
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