Grieb Paweł
Department of Experimental Pharmacology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Str. Pawinskiego 5, 02-106, Warsaw, Poland.
Mol Neurobiol. 2016 Apr;53(3):1741-1752. doi: 10.1007/s12035-015-9132-3. Epub 2015 Mar 7.
Streptozotocin (STZ), a glucosamine-nitrosourea compound derived from soil bacteria and originally developed as an anticancer agent, in 1963 has been found to induce diabetes in experimental animals. Since then, systemic application of STZ became the most frequently studied experimental model of insulin-dependent (type 1) diabetes. The compound is selectively toxic toward insulin-producing pancreatic beta cells, which is explained as the result of its cellular uptake by the low-affinity glucose transporter 2 (GLUT2) protein located in their cell membranes. STZ cytotoxicity is mainly due to DNA alkylation which results in cellular necrosis. Besides pancreatic beta cells, STZ applied systemically damages also other organs expressing GLUT2, such as kidney and liver, whereas brain is not affected directly because blood-brain barrier lacks this transporter protein. However, single or double intracerebroventricular (icv) STZ injection(s) chronically decrease cerebral glucose uptake and produce multiple other effects that resemble molecular, pathological, and behavioral features of Alzheimer's disease (AD). Taking into consideration that glucose hypometabolism is an early and persistent sign of AD and that Alzheimer's brains present features of impaired insulin signaling, icv STZ injections are exploited by some investigators as a non-transgenic model of this disease and used for preclinical testing of pharmacological therapies for AD. While it has been assumed that icv STZ produces cerebral glucose hypometabolism and other effects directly through desensitizing brain insulin receptors, the evidence for such mechanism is poor. On the other hand, early data on insulin immunoreactivity showed intense insulin expression in the rodent brain, and the possibility of local production of insulin in the mammalian brain has never been conclusively excluded. Also, there are GLUT2-expressing cells in the brain, in particular in the circumventricular organs and hypothalamus; some of these cells may be involved in glucose sensing. Thus, icv STZ may damage brain glucose insulin producing cells and/or brain glucose sensors. Mechanistic explanation of the mode of action of icv STZ, which is currently lacking, would provide a valuable contribution to the field of animal models of Alzheimer's disease.
链脲佐菌素（STZ）是一种从土壤细菌中提取的氨基葡萄糖亚硝基脲化合物，最初作为抗癌药物开发，1963年发现它可在实验动物中诱发糖尿病。从那时起，STZ的全身应用成为胰岛素依赖型（1型）糖尿病研究最频繁的实验模型。该化合物对产生胰岛素的胰腺β细胞具有选择性毒性，这被解释为其通过位于细胞膜上的低亲和力葡萄糖转运蛋白2（GLUT2）被细胞摄取的结果。STZ的细胞毒性主要是由于DNA烷基化，导致细胞坏死。除了胰腺β细胞外，全身应用的STZ还会损害其他表达GLUT2的器官，如肾脏和肝脏，而大脑不受直接影响，因为血脑屏障缺乏这种转运蛋白。然而，单次或双次脑室内（icv）注射STZ会长期降低脑葡萄糖摄取，并产生多种其他类似于阿尔茨海默病（AD）分子、病理和行为特征的效应。考虑到葡萄糖代谢减退是AD的早期和持续症状，且阿尔茨海默病患者的大脑存在胰岛素信号受损的特征，一些研究人员将icv注射STZ作为该疾病的非转基因模型，并用于AD药物治疗的临床前测试。虽然人们一直认为icv注射STZ直接通过使脑胰岛素受体脱敏而产生脑葡萄糖代谢减退和其他效应，但这种机制的证据并不充分。另一方面，关于胰岛素免疫反应性的早期数据显示啮齿动物大脑中胰岛素表达强烈，哺乳动物大脑中胰岛素局部产生的可能性从未被确凿排除。此外，大脑中存在表达GLUT2的细胞，特别是在室周器官和下丘脑；其中一些细胞可能参与葡萄糖传感。因此，icv注射STZ可能会损害脑葡萄糖胰岛素产生细胞和/或脑葡萄糖传感器。目前缺乏对icv注射STZ作用方式的机制解释，这将为阿尔茨海默病动物模型领域做出有价值的贡献。
