Diabetic neuropathy: Electrophysiological and morphological study of peripheral nerve degeneration and regeneration in transgenic mice that express IFNβ in β cells

Abstract

Diabetic neuropathy is one of the most frequent complications in diabetes but there are no treatments beyond glucose control, due in part to the lack of an appropriate animal model to assess an effective therapy. This study was undertaken to characterize the degenerative and regenerative responses of peripheral nerves after induced sciatic nerve damage in transgenic rat insulin I promoter / human interferon beta (RIP/IFNbeta) mice made diabetic with a low dose of streptozotocin (STZ) as an animal model of diabetic complications. In vivo, histological and immunohistological studies of cutaneous and sciatic nerves were performed after left sciatic crush. Functional tests, cutaneous innervation, and sciatic nerve evaluation showed pronounced neurological reduction in all groups 2 weeks after crush. All animals showed a gradual recovery but this was markedly slower in diabetic animals in comparison with normoglycemic animals. The delay in regeneration in diabetic RIP/IFNbeta mice resulted in an increase in active Schwann cells and regenerating neurites 8 weeks after surgery. These findings indicate that diabetic-RIP/IFNbeta animals mimic human diabetic neuropathy. Moreover, when these animals are submitted to nerve crush they have substantial deficits in nerve regrowth, similar to that observed in diabetic patients. When wildtype animals were treated with the same dose of STZ, no differences were observed with respect to nontreated animals, indicating that low doses of STZ and the transgene are not implicated in development of the degenerative and regenerative events observed in our study. All these findings indicate that RIP/IFNbeta transgenic mice are a good model for diabetic neuropathy.

Animal Models of Diabetic Neuropathy: Progress Since 1960s

“…Recently, Serafín et al [34] developed a model of diabetic neuropathy in 6-week-old rat insulin I promoter/human interferon-beta (RIP/IFN β ) transgenic ICR mice with a low dose of STZ injection (30 mg/kg BW) for 5 consecutive days. Additionally, in order to induce nerve damage, after 4 weeks of sustained hyperglycemia, the left sciatic nerve was exposed by blunt dissection and crushed at the femur major trochanter level for three times in succession for 30 seconds in anaesthetized animals when intact contralateral nerve was used as a control.…”

Animal Models as Tools to Investigate Antidiabetic and Anti-Inflammatory Plants

“…Accounts of the traditional use of an antidiabetic plant in type 1 or type 2 diabetic patients provide an indication of the type of model (e.g., insulin dependent or noninsulin dependent) that might be suitable for initial investigation of hypoglycemic activity [1, 3, 78, 79, 88]. As it was noted previously, experimentally induced models of insulin-dependent diabetes are often not completely devoid of endogenous insulin.…”

“…However, many of these descriptions are anecdotal accounts of traditional usage, and fewer than half of these plants or plant extracts have received a thorough medical or scientific evaluation of their purported benefits. This paper reviews the preclinical in vivo methods and clinical procedures used to investigate the antidiabetic activity of plants and plant-derived extracts, including a consideration of the ethical issues affecting use of traditional plant treatments for diabetes [1, 2]. …”

Effects of Alpha Lipoic Acid Treatment on Laminin Alteration of the Sciatic Nerve in Streptozotocin Induced Diabetic Rats

“…Some researchers have reported diabetic neuropathy resulted in abnormal deposits of laminin in human and animal models (8), but in contrast Hill et al reported that, in human diabetic neuropathy laminin content in diabetic and control nerves was not significantly different (6). Also Serafin et al (26) assessed laminin in peripheral nerves of STZ-induced diabetic mice, and reported that it did not differ in laminin expression in the diabetic and control nerves. These discrepancies are probably due to differences in experimental methods, in Serafin et al study (26), mice was made diabetic with a low dose of streptozotocin with a short study time period and in Hill et al study (6), duration of diabetes in diabetic patients was different.…”

“…Also Serafin et al (26) assessed laminin in peripheral nerves of STZ-induced diabetic mice, and reported that it did not differ in laminin expression in the diabetic and control nerves. These discrepancies are probably due to differences in experimental methods, in Serafin et al study (26), mice was made diabetic with a low dose of streptozotocin with a short study time period and in Hill et al study (6), duration of diabetes in diabetic patients was different. Diabetes duration and long-term hyperglycemia are the most important reasons for polyneuropathy (22).…”