Aldose Reductase Inhibitor Ameliorates Streptozotocin-induced AD-like Neuropathology

BackgroundAlzheimer’s disease（AD）, the most common type of dementia among old people,is characterized by extracellular-aggregated senile plaque （SP）, intracellularneurofibrillary tangle （NFT） and progressive cognitive disorder. Numerous studieshave shown that patients with diabetes exhibit increased risk of developing AD thannondiabetic individuals, and hyperglycemia may do harm to cognitive function bymultiple ways, one of which is to increase oxidative stress in the brain. However, it isstill unclear whether aldose reductase （AR）, which is activated by hyperglycemia inthe polyol pathway and may play a role in diabetic stress, is involved in ADdevelopment and inhibiting its activity could ameliorateAD-like neuropathology.ObjectiveTo explore the effects of AR inhibitors on streptozotocin-induced AD-likeneuropathology and its underlying mechanism.Materials and methodsTo establish AD-like animal model, a certain number of3-month-old SpragueDawley（SD）rats （300±30g） were treated with streptozotocin （stz） via bilateralintracerebroventricular（icv）injection（3mg/kg）. Recovering from surgery, animalswere administered with AR inhibitors or normal saline （NS） by gavage for threeweeks, once a day. Animals were divided into four groups:（1）control group, whichwere injected with artificial cerebral spinal fluid and gavaged with NS;（2）stz group,which were injected with stz and gavaged with NS;（3） stz+zop group, which wereinjected with stz and gavaged withAR inhibitor zopolresta（tzop,50mg/kg·day）;（4）stz+sob group, which were injected with stz and gavaged with AR inhibitor sorbinil（sob,25mg/kg·day）. Each group consisted of8-10rats. One month after the icvinjection, the phosphorylation status of tau protein and related kinases were detectedvia western blot, oxidative stress markers via assay kits and cognitive function viabehavioral tests.Results1. AR inhibitors ameliorated stz-induced spatial memory dysfunction.While stz-treated rats exhibited severely impaired spatial memory, those alsogavaged with AR inhibitors performed as excellent as normal rats without icv-stzin Morris water maze tests. However, rats in stz group performed quite normalcompared with control group in the learning task, indicating unchanged learningability.2. AR inhibitors reduced stz-induced hyperphosphrylation of tau protein. Compared with control group, tau protein in the rat hippocampus of stz groupwas hyperphosphorylated at threonine205and serine404. Treatment with eitherzopolrestat or sorbinil reduced the phosphorylation of tau protein at the residuesabove.3. AR inhibitors ameliorated stz-induced AD-like neuropathology viamitogen-activated protein kinase （MAPK） signal pathway.The phosphorylation levels of C-Jun N-terminal kinase（JNK）and extracellularregulated protein kinase （Erk1/2）, the major kinases in MAPK signal pathway,were elevated as a result of icv-stz, and this hyperphosphorylation was attenuatedfollowing AR inhibitor gavage. Notably, the phosphorylation level of glycogensynthase kinase-3（GSK-3） at serine9was increased, suggesting a reduction inthe activity of this kinase, which implied GSK-3was not responsible for thehyperphosphorylation of tau protein in icv-stz model.4. Oxidative stress was not involved in stz-induced AD-like pathology.Compared with control group, neither SOD activity nor MDA content in thehippocampus of icv-stz rats displayed significant difference in statistic analysis.Meanwhile, neither of the two AR inhibitors exerted any effect on the abovemarkers for oxidative stress.Conclusion1. AR inhibitors may be used to treat diabetes-related cognitive dysfunction.2. The meliorative effect of AR inhibitors on AD-like neuropathology may be basedon the functions of insulin and MAPK signal pathway.