Study On The Screening Of A Novel Aldose Reductase Inhibitor And The Effect Of Type 2 Diabetic Neuropathy

Diabetes is regarded as the one of three stubborn diseases by WHO.Normally it is classified into Type 1(Diabetes Mellitus,T1DM)and Type 2(Diabetes Mellitus,T2DM).Patients usually suffer from diabetic complications(DCC)with development of T2DM,and diabetic nephropathy(DN)is the most common one that is the one of main reasons causing death.Pathogenesis of diabetic complications is complex,Now,the main ideas about drugs in the development of diabetic complications,were based on the regulation of metabolic mechanisms targeting key metabolic processes,in which,aldose reductase inhibitors(ARI)is the hotspot and the main directions in drug research of prevention and treatment for DN.By the systematic study on basis classification,structural features and structure-activity relationship,we establish theoretical model of aldose reductase inhibitors.Based on thisl,several structural of Aldose reductase inhibitors were screened,synthesized,characterized and evaluated.We found that the activity of compound "1-acetyl-5-phenyl-lH-pyrrol-3-yl acetate(APPA)" was highest,and the mechanism of the compound against aldose reductase was non-competitive.Subsequently,we found that APPA,not only to inhibitory AR,but also inhibitory advanced glycation end products(AGE)and scavenging free radicals,with which the pathogenesis of diabetic complications and DN is closely related,therefore,APPA,as a anti-DN lead Compound,was further studied.In vitro,We choose the damage model of rat glomerular mesangial cells(HBZY-1)induced by high glucose,and further studied the action of APPA on renal mesangial cells(HBZY-1)and the possible mechanism of APPA for DN.Results:Compared with high glucose group(HG),low,medium and high-dose group of APPA had different increased the proportion of cells in G1 phase.Content of Collagen ??Laminin and relative express of TGF-?1 are low,and there are significant differences in low,medium and high three-dose group of APPA compared with the high glucose group.Conclusion:APPA has protective effect on the damage model of rat renal mesangial cells induced by high glucose..In vivo,we made early type 2 diabetes mellitus(T2DM)nephropathy model using Wistar male rats by "triple Law"methods(unilateral nephrectomy ?high-sugar high-fat diet + STZ intraperitoneally)to study the APPA for prevention and treatment of early DN rats and to explore the possible mechanism.Methods:60 male rats fed adaptability for one week.Except for normal control group 6,the remaining rats were unilateral nephrectomy,high-sugar high-fat diet for four weeks,then thrice injected STZ,each 35mg.Four weeks later,the remaining rats were randomly divided into five groups,DN pathological control group;low,medium and high dose(40,80,160 mg.kg-1)of treatment group of APPA;positive control group(epalrestat,EPS,dose 100mg.kg-1),course of eight weeks.Results:Compared with DN group,low,medium and high dose of APPA can significantly improve symptoms of polydipsia and polyuria,reduce blood glucose and urinary microalbumin(mAlb),increased T-AOC,CAT activity and GSH levels in DN rats.Compared with DN group,low dose of APPA can significantly reduce level of Collagen IV,and low,medium and high dose of APPA can reduce express of TGF-?1,and renal tissue morphology in rats was improved.Conclusion:APPA has certain therapeutic effects on early DN rats.In conclusion,our study demonstrated for the first time that APPA,as one of 5-phenylpyrrole derivatives,is a novel Aldose Reductase Inhibitor which was designed,synthesized and screened,and has therapeutic effects to early 2 diabetic nephropathy.This paper provides a novel candidate drugs for the treatment of DN,and a new idea for exploring novel anti-diabetic complication drug.