engleski

Therapeutic effects of multifunctional iron-chelating agent in a streptozotocin-induced rat model of sporadic Alzheimer's disease

Aim: Rats treated intracerebroventricularly with streptozotocin (STZ-icv) demonstrate cognitive deficits and develop insulin resistant state in the brain. STZ-icv treated ratshave been recently proposed as a non-transgenic model of sporadic Alzheimer’s disease (sAD) and used to test therapeutic potential of various drugs. We aimed to assess the therapeutic potential of a novel multifunctional iron-chelating compound M30 in STZ-icv rat model and possible underlying mechanism of its beneficial effects at the level of expression of the insulin degrading enzyme (IDE) and glycogen synthase kinase 3β(GSK3β) Methods: Adult Male Wistar rats were injected bilaterally icv with STZ (3 mg/kg) or vehicle (controls) and sacrificed one, three, six and nine months after the treatment. Two groups of STZ-icv injected rats were subjected to M30 oral treatment (2 and 10 mg/kg, 3x week) initiated 10 days after the STZ-icv treatment and continued for 11 weeks. Cognitive deficits were measured by Passive Avoidance Test (PA). Protein expression of phospho-GSK3β and IDE in hippocampus (HPC) was measured by SDS-PAGE electrophoresis / immunoblotting.Data were analysed by Kruskal-Wallis, ANOVA and Mann-Whitney U test (p<0.05). Results: STZ-icv rats exhibit significant time-dependent cognitive deficits (60-90%). IDE protein expression was found decreased in HPC in a similar time-dependent manner starting from one month after the STZ-icv administration (-55.88%), persistently up to nine months (-37%). Phospho-GSK3β was found increased after three months (+70%) and decreased after nine months (-45%). M30 (10 mg/kg) treatment improved STZ-icv-induced cognitive deficits and normalized IDE protein expression. Additionally, M30 treatment decreased pGSK3β expression in comparison to the control (-18%) and STZ-icv group (-25%). Conclusion: STZ-icv rat model demonstrates long-term cognitive deficit, decreased hippocampal IDE protein expression and varying pGSK3β expression which tend to correlate mutually, demonstrating similar time-dependent biphasic pattern of changes. Chronic M30 treatment significantly improves cognitive deficits in STZ-icv rat model of sAD which might be related to its effects on IDE, and not on phospho-GSK3β protein expression. Acknowledgement: Supported by UKF, MZOS and DAAD.

iron chelator; streptozotocin; Alzheimer's disease

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