Donadoni M L, Gavezzotti R, Borella F, Di Giulio A M, Gorio A
Department of Pharmacology, Chemotherapy and Medical Toxicology, University of Milano, Italy.
J Pharmacol Exp Ther. 1995 Jul;274(1):570-6.
The extranuclear endogenous mono-ADP-ribosylation of proteins in cellular fractions from retinas of control and diabetic rats was studied. At least six proteins were ADP-ribosylated in the crude extract, membrane and cytosolic fractions from control preparations, whereas in diabetic rats the number of labeled proteins and the extent of labeling were highly reduced. Treatment of diabetic animals with silybin, a flavonoid with ADP-ribosyltransferase inhibitory activity, did not affect hyperglycemia, but prevented the alterations of the extent of ADP-ribosylation of the 38 K cytosolic, 39 K, 40 K membrane and 39 K, 41 K and 42 K crude extract proteins. These data suggest a hyperactivity of extranuclear endogenous protein mono-ADP-ribosylation in the diabetic rat retina, and that treatment with silybin inhibits such enzyme activity, thus improving the extent of ADP-ribosylation. Sciatic nerve axonal transport of substance P was reduced markedly in diabetic rats, and inhibition of mono-ADP-ribosylation with silybin prevented such a loss in spite of high blood glucose levels. These results suggest that the abnormal endogenous ADP-ribosylation of proteins might play a role in the onset of diabetic peripheral neuropathy and its inhibition may represent a novel pharmacological approach to the treatment of diabetes complications.
对正常大鼠和糖尿病大鼠视网膜细胞组分中蛋白质的核外内源性单 ADP 核糖基化进行了研究。在正常制剂的粗提物、膜和胞质组分中，至少有六种蛋白质发生了 ADP 核糖基化，而在糖尿病大鼠中，标记蛋白质的数量和标记程度显著降低。用具有 ADP 核糖基转移酶抑制活性的黄酮类化合物水飞蓟宾治疗糖尿病动物，并未影响高血糖，但可防止 38K 胞质、39K、40K 膜以及 39K、41K 和 42K 粗提物蛋白质的 ADP 核糖基化程度改变。这些数据表明糖尿病大鼠视网膜中核外内源性蛋白质单 ADP 核糖基化活性增强，而水飞蓟宾治疗可抑制这种酶活性，从而改善 ADP 核糖基化程度。糖尿病大鼠中 P 物质的坐骨神经轴突运输显著减少，尽管血糖水平较高，但水飞蓟宾抑制单 ADP 核糖基化可防止这种减少。这些结果表明，蛋白质异常的内源性 ADP 核糖基化可能在糖尿病周围神经病变的发病中起作用，抑制这种作用可能代表一种治疗糖尿病并发症的新药理学方法。
