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Improving the Reliability and Utility of Streptozotocin-Induced Rat Diabetic Model 时间:2018-09-29 22:30 来源:未知作者:admin 点击: 次 Abstract:The Streptozotocin- (STZ-) induced diabetic model is widely used; however, unexplained acute toxicity has given the model an unreliable reputation. To improve the reliability and utility of this model, we characterize the age dependence of STZ toxicity and introduce novel endpoints to assess diabetic complications and reveal possible mechanisms for diabetic development. Diabetes was induced by STZ injection into male, 6 to 23 weeks old, Sprague-Dawley rats. Their metabolic (glucose, lipids, and hormones), inflammatory (cytokines), histologic and behavioral endpoints were observed for 1.2 years. Analgesic compounds were assessed for efficacy treating neuropathy. Acute mortality, within a week of STZ injection (50–65 mg/kg i.v.), was inversely correlated to animal age. Only 3% of rats, age 6–11 weeks, died in the week following STZ injection, whereas 83% of rats 12 to 17 weeks old and 91% of rats 18 weeks or older died in the same week. Partial model recovery (normalized insulin, glucose and food/water intake) was observed starting at week 36; however, pain scores, kidney enlargement, and cataract formation continued to show progression consistent with the diabetic state. Unique noninvasive observational measurements, such as haircoat quality and diarrhea scores, served as useful endpoints for this model. The increased plasma cytokines (such as TNF-α, IL-4, and IL-6) and inflammatory cell infiltration into the pancreatic islets are strong evidence of inflammation in the STZ-induced diabetic model. Pancreatic tissue staining revealed total islet area reduction and confirmed STZ-specific pancreatic toxicity; however, the β-cell density per area in pancreatic islets and insulin levels statistically increased over time in the diabetic rats, suggesting a mechanism for partial recovery of diabetic symptoms. Voltage-gated sodium channel (NaV1.7 specific, peripherally restricted) blocker, CC4148, inhibited neuropathy without side effects as compared to a nonspecific sodium channel inhibitor, Mexiletine, or GABA analog, Pregabalin, which inhibited neuropathy with side effects.
1. Introduction
Diabetes is generally characterized as type 1, the body not producing enough insulin due to a loss of the insulin-producing β-cells in the pancreas islets, or type 2, where fat, liver, and skeletal muscle cells do not respond to insulin leading to a reduction in their uptake of sugars from the blood stream [1]. Although most patients are type 2 diabetics because hyperglycemia is the principal factor in the etiology and pathogenesis of diabetic complications, both type 1 and type 2 diabetic models are used to study diabetic complications and their potential treatment [1–3]. Type 1 diabetic models are usually easier and cheaper to establish and, therefore, are employed whenever possible. The most common animal model of type 1 diabetes, using STZ intraperitoneal or intravenous (i.p. or i.v.) injection, has been in extensive use since 1963 [1, 2, 4, 5]. STZ is a naturally occurring chemical, a broad-spectrum antibiotic that is particularly toxic to the insulin-producing β-cells of the pancreas. Because of this selective toxicity, it is also used to treat β-cell pancreatic cancers [4, 5]. According to a review, “Despite the large number of publications on the topic, more than 17,000 listings for Streptozotocin on PubMed, investigators inexperienced with a model of STZ-induced diabetes may find it difficult to precisely design new studies. STZ-induced diabetes can be highly variable, and no standard protocol exists for the preparation, dose, or administration of STZ” [6]. Most papers include only the animals where diabetes was successfully induced and provide very little technical details regarding failures during diabetic induction, long-term mortality, and severity of diabetes experienced. However, this information is important for successful diabetic model induction and by improving reproducibility and utility of the model can benefit animal welfare by reducing acute animal mortality and morbidity. Since diabetes in humans is a lifelong chronic disease, long-term observation of this chronic model and its natural recovery should aid the study of diabetes. This report examines the age dependence of acute STZ toxicity and describes the long-term natural course of the model including glucose, HbA1C, lipid, metabolic hormones (such as insulin, glucagon), cytokine levels and clinical conditions, mortality, natural recovery, and multiple diabetic complications resulting from the end-stage of uncontrolled diabetes including the description of novel, stress-free, reproducible behavioral endpoints. The report also includes important information regarding histological changes in β-cells of the pancreatic islets and inflammatory cell infiltration into pancreatic tissue confirming diabetic damage and the involvement of inflammatory mediators in diabetic mechanisms. It is well documented that inflammation mediators and oxidative stress play a big role in the pathogenesis and prevalence of both type 1 and 2 diabetes mellitus [7–12]. Since nerve damage from diabetic hyperglycemia causes pain, several existing and potential pain drugs and Chromocell novel NaV1.7 blocker compound were evaluated as pain treatments in the subject animals.