Roliram Improved Cognitive Impairment And Neuroinflammation In Diabetic Encephalopathy

Part one Objective To observe changes of cognitive function and the expression oftumor necrosis factor α(TNF-α)， interleukin10(IL-10)in hippocampus of diabeticencephalopathy(DE)rats，assess the role of inflammation in the possible pathogenesis ofDE. Methods30male SD rats were randomly divided into control group and diabetesmellitus group. After4weeks of feeding high fat diet，diabetes mellitus group according to30mg/kg intraperitoneally injected with streptozotocin(STZ) to establish type2diabetesmellitus(T2DM) rat model. Body weight，fasting blood glucose，fasting serum insulin wereobserved before streptozocin injection and the end of experiment. At the end of theexperiment， cognition were evaluated according to Morris water maze test. Theconcentration of beta-amyloid(Aβ) in hippocampus of diabetic rats were detected throughenzyme linked immunosorbent assay，the expression of TNF-α，IL-10were detected bywestern blotting. The expression of Aβ， TNF-α， IL-10were observed throughimmunohistochemistry. Results Compared to control group，fasting blood glucose，fasting serum insulin were higher，and body weight was less in diabetic rats (all P＜0.001).Time spent in the target quadrant in diabetes mellitus group was shorter than controlgroup(P＜0.01). The frequency of crossing original platform site was less than controlgroup(P＜0.01). Compared with control group the expression of Aβ，TNF-α werehigher(both P＜0.01)，and IL-10were lower(P＜0.01)in diabetes mellitus group. Thepositive expression of Aβ，TNF-α were obviously and IL-10were less obviously observedin diabetes mellitus group according to immunohistochemistry. Conclusions T2DMcould induced DE, DE rats showed spatial learning and memory were impaired，Aβdeposited more in hippocampus，inflammation aggravated and decline in cognition ispossibly related to inflammatory cytokines expressing out of balance.Part two Objective To observe whether rolipram the inhibitor of phosphodiesterase 4(PDE4) could improve cognitive decline and reduce inflammatory cytokins inhippocampus of DE rats. Methods45male SD rats were randomly divided intocontrol group， diabetes mellitus group and rolipram group. Diabetes mellitus group androlipram group were fed with high-fat diet and a low-dose of STZ(30mg/kg，i.p.) treated tocreate T2DM model. Body weight，fasting blood glucose，fasting serum insulin wereobserved before streptozocin injection and the end of experiment. After STZ injected2months， rats in rolipram group were treated for23days (0.5mg/kg).2-week treatmentlater Morris water maze was performed to evaluate spatial learning and memory in rats.The expression of Aβ1-40and Aβ1-42in hippocampus were detected through enzymelinked immunosorbent assay，meanwhile TNF-α，IL-10， cyclic AMP response elementbinding protein (CREB) and phospho-CREB (pCREB) were quantified by westernblotting. Results Compared to control group，fasting blood glucose，fasting seruminsulin were higher，and body weight was less in diabetic rats (all P＜0.001). There was nosignificant change between rolipram treated and untreated diabetic rats (P＞0.05). Inhidden platform test， the escape latency in diabetes mellitus group was prolong，timespent in target quadrant was shorter and frequency of crossing the original platform sitewas less compared with control group and rolipram group. Expression of Aβ1-40andAβ1-42in rats’ hippocampus were increased in diabetes group and rolipram groupcompared with control group(all P＜0.01)， the changes were no significant betweenrolipram group and diabetes mellitus group(both P＞0.05). Expression of TNF-α in rats’hippocampus was increased in diabetes mellitus group and decreased in rolipram group (allP＜0.01)；IL-10，CREB and pCREB were less in diabetes mellitus group and higher inrolipram group(all P＜0.01). Conclusion cognition decline in DE rats could beimproved by rolipram，an inhibition of PDE4，which increased expression of CREB andphosphorylation of CREB as well as restored imbalance of inflammatory cytokines in rats’hippocampus.