Maekawa Tatsuya, Tadaki Hironobu, Sasase Tomohiko, Motohashi Yu, Miyajima Katsuhiro, Ohta Takeshi, Kume Shinichi
Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka, Japan; Laboratory of Animal Physiology and Functional Anatomy, Graduate School of Agriculture, Kyoto University, Kitashirakawa Oiwake-cho, Sakyo-ku, Kyoto, Japan.
Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka, Japan.
J Pharmacol Toxicol Methods. 2017 Nov-Dec;88(Pt 2):160-166. doi: 10.1016/j.vascn.2017.09.257. Epub 2017 Sep 29.
To establish an animal model for diabetic peripheral neuropathy (DPN) at an earlier stage, we performed functional and pathophysiological evaluations in Spontaneously Diabetic Torii (SDT) fatty rats before 16weeks of age.
Male SDT fatty rats were treated with vehicle or phlorizin (100 to 150mg/kg/day) from 5 to 16weeks. Sprague-Dawley (SD) rats were used as age-matched controls. Body weights and biochemical parameters were measured over time. During the treatment period, the sensory and motor nerve conduction velocity (SNCV and MNCV) of the sciatic nerve, blood pressure, pupil size, and electrocardiograms were measured. At 16weeks, the rats were sacrificed and sural nerves and intraepidermal nerves were sampled for histological studies, electron microscopic analysis and assessments of nerve fiber density.
Functional abnormalities, such as delays of SNCV, increase of blood pressure, reduced pupillary reactivity, and decrease of the coefficient of variance of R-R intervals were observed in SDT fatty rats. Histopathologically, decreased intraepidermal nerve fiber density, mitochondrial abnormalities of small myelinated fibers, and vacuolation and mitochondrial swelling of unmyelinated fibers were found in SDT fatty rats. These changes were prevented by well-controlled blood glucose with phlorizin treatment.
Male SDT fatty rats can help future work on DPN in diabetes with obesity, since this rat exhibited functional and pathological abnormalities in somatic and autonomic nerve from an early stage of diabetes.
为了在更早阶段建立糖尿病周围神经病变（DPN）的动物模型，我们在16周龄之前对自发性糖尿病Torii（SDT）肥胖大鼠进行了功能和病理生理学评估。
雄性SDT肥胖大鼠在5至16周期间接受载体或根皮苷（100至150mg/kg/天）治疗。将Sprague-Dawley（SD）大鼠用作年龄匹配的对照。随时间测量体重和生化参数。在治疗期间，测量坐骨神经的感觉和运动神经传导速度（SNCV和MNCV）、血压、瞳孔大小和心电图。在16周时，处死大鼠并采集腓肠神经和表皮内神经用于组织学研究、电子显微镜分析和神经纤维密度评估。
在SDT肥胖大鼠中观察到功能异常，如SNCV延迟、血压升高、瞳孔反应性降低以及R-R间期变异系数降低。组织病理学上，SDT肥胖大鼠的表皮内神经纤维密度降低、小髓鞘纤维线粒体异常以及无髓鞘纤维空泡化和线粒体肿胀。根皮苷治疗通过良好控制血糖预防了这些变化。
雄性SDT肥胖大鼠有助于未来对伴有肥胖的糖尿病患者的DPN研究，因为这种大鼠从糖尿病早期就表现出躯体和自主神经的功能和病理异常。
