Germani E, Lesma E, Di Giulio A M, Gorio A
Laboratory for Research on Pharmacology of Neurodegenerative Disorders, Pharmacological Laboratories, Department of Medicine, Surgery and Odontoiatry, H.S. Paolo, Milan, Italy.
J Neurosci Res. 1999 Aug 15;57(4):521-8.
Diabetes-induced embryo malformations and growth retardation are correlated with a variety of biochemical changes including oxidative stress. In this study, we show that the morphological alterations are correlated with progressive and selective changes of mRNA expression in specific neurotrophic factors. At embryological stage E-17, diabetes affected both embryo growth and NGF mRNA expression, which was reduced by as much as 90 and 56% in target tissues of sensory system such as tongue and intestine, respectively. The reduction in retina and heart was around 50%. Conversely, the mRNA expression of low-affinity neurotrophin receptor p75 was increased. At birth, BDNF mRNA expression was affected with a significant generalized reduction,while in vibrissae we observed a reduction of BDNF and p75 mRNAs and an increase of NGF. At postnatal day 14, pups from diabetic mothers showed reduced muscle levels of IGF-I, while we observed a partial impairment of substance P axonal transport at postnatal day 28. Treatment of diabetic mothers with silybin, a flavonoid with antioxidant properties, prevented most of the changes in neurotrophic factor expression and substance P axonal transport with no effects on hyperglycemia and embryo growth retardation. These results indicate that oxidative stress may influence neurotrophic factor synthesis in target territories during development. In addition, these data suggest that nervous system abnormalities observed in diabetic embryopathy may also derive by insufficient neurotrophic factor biosynthesis involving sequentially NGF in the embryo and BDNF and IGF-I in the early postnatal days. Insulin treatment of diabetic mothers normalized hyperglycemia and body growth, with consequent regular embryonic and postnatal development.
糖尿病诱导的胚胎畸形和生长迟缓与包括氧化应激在内的多种生化变化相关。在本研究中，我们表明形态学改变与特定神经营养因子中mRNA表达的渐进性和选择性变化相关。在胚胎期E-17，糖尿病影响胚胎生长和NGF mRNA表达，在感觉系统的靶组织如舌和肠中分别降低多达90%和56%。视网膜和心脏中的降低约为50%。相反，低亲和力神经营养因子受体p75的mRNA表达增加。出生时，BDNF mRNA表达受到影响，出现显著的普遍降低，而在触须中我们观察到BDNF和p75 mRNA降低以及NGF增加。在出生后第14天，糖尿病母亲的幼崽肌肉中IGF-I水平降低，而在出生后第28天我们观察到P物质轴突运输部分受损。用具有抗氧化特性的黄酮类化合物水飞蓟宾治疗糖尿病母亲，可预防神经营养因子表达和P物质轴突运输的大部分变化，而对高血糖和胚胎生长迟缓无影响。这些结果表明氧化应激可能在发育过程中影响靶区域的神经营养因子合成。此外，这些数据表明糖尿病胚胎病中观察到的神经系统异常也可能源于神经营养因子生物合成不足，在胚胎期依次涉及NGF，在出生后早期涉及BDNF和IGF-I。对糖尿病母亲进行胰岛素治疗可使高血糖和身体生长正常化，从而使胚胎和出生后发育正常。
