| Objective:The streptozotocin (STZ)-induced animal may be an appropriate model for theinvestigation of AD and related dementia. Therefore, this study was designed to investigatethe beneficial effect of telmisartan, a dual ARB/partial PPAR-γ agonist, onintracerebroventricular (ICV) STZ-induced cognitive impairment in rats.Method:Adult male Wistar rats were ICV injected with STZ (3mg/kg, on day1and3)(n=30).An artificial cerebrospinal fluid was given to the control group (n=10) instead of STZ.Learning and memory performance were assessed using the "Morris water maze test".After confirmation of acquisition impairment with these tests, the STZ treated group wasdivided into three subgroups: Model group (STZ alone; n=10); telmisartan group(STZ+telmisartan; n=10) and GW9662group (STZ+telmisartan+GW9662; n=10). The rats inthe telmisartan group were administered intragastrically with telmisartan(13.3mg. kg-1.d-1)and the rats in the GW9662group were treated with not only telmisartan but also GW9662(10mg. kg-1.d-1) starting from the24th day after STZ injection. The Morris water mazetest was reapplied on the8weeks after telmisartan and GW9662intervention. All of therats were sacrificed on next day. Then we quantitated the insulin receptor (IR), insulin-likegrowth factor-1(IGF-1) receptor and PPARγ by Western blots and RT PCR analysis.Result1）Cognitive tasksThe mice in model group exhibited longer escape latency and less across platform index than control or telmisartan group(all P<0.01). However, this difference did notexist between GW9662group and STZ group (P>0.05).2）other biological indexsOur results suggested that no difference of systolic blood pressure, blood glucose andinsulin level could be found in all groups (P>0.05). In parallel with the cognitive tests,serum IGF-1levels were increased in model groups compared to the control group. Incontrast, telmisartan treatment alone significantly decreased serum IGF-1levels (P <0.001). There was no significant difference in serum IGF-1levels between GW9662groupand model group(P>0.05)3）Western blot analysis:The protein content of insulin receptor (IR), insulin-like growth factor-1receptor(IGF-1R)and PPARγ in hippocampus were found significantly decreased in model group ascompared with control group（P<0.01）. In contrast, telmisartan treatment significantlyincreased these protein contents (P <0.001). No changes of the protein content could bedetected between GW9662group and model group (NS).4）RT-PCR analysis:The expression of IR, IGF-1R and PPARγ mRNA in hippocampus were founddecreased in model group as compared to control（P<0.01）. Whereas telmisartan groupwas found to have a significantly increased in all mRNA expression than model group（P<0.01）. In addition, there is no significant difference between GW9662group andmodel group（NS）.Conclusion:1) A rat model of cognitive dysfunction, which had longer escape latency and lessacross platform index, was established by ICV injected with STZ.2) These results clearly indicated that telmisartan treatment was effective in reducingthe cognitive impairment caused by STZ in rats. The basis might be that it could decreased the insulin resistance in brain, partly because of the up-regulation of PPAR-γ inhippocampus. |
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