engleski

Therapeutic potential of novel multifunctional iron chelator on cognitive deficits and insulin degrading enzyme expression in the rat model of sporadic Alzheimer's disease

Background There is a need in modern pharmacology for the representative animal model which should accurately mimic sporadic Alzheimer’s disease (sAD), the prevailing type of dementia in humans, and thus could be suitable for novel drug testing. Rats treated intracerebroventricularly with a betacytotoxic agent streptozotocin (STZ-icv), have been recently proposed as a non-transgenic sAD model which demonstrates AD-like pathology features at cognitive, neurochemical and structural level. In addition to the cognitive deficits, pathological accumulation of amyloid β (Aβ) peptide is one of the neuropathological hallmarks of sAD, and growing body of evidence suggests the involvement of insulin degrading enzyme (IDE), responsible for Aβ degradation, in sAD pathophysiology. We have explored the time course of cognitive deficits and hippocampal (HPC) IDE expression in the STZ-icv rat model of sAD, and therapeutic potential of novel multifunctional iron-chelating drug M30 to improve these deficits. Materials and methods Adult Male Wistar rats were injected bilaterally icv with STZ (0.3, 1 and 3 mg/kg) or vehicle (controls) and sacrificed one week, one-, three-, six- and nine months after the treatment. Two groups of STZ-icv (3 mg/kg) injected rats were additionally subjected to 11-week long M30 oral treatment (2 and 10 mg/kg, 3x week) initiated 10 days after the STZ-icv treatment. Cognitive deficits were measured by Morris Water Maze Swimming Test (MWM) and Passive Avoidance Test (PA). IDE protein expression in HPC was measured by SDS-PAGE electrophoresis / immunoblotting. Data were analysed by Kruskal-Wallis and Mann-Whitney U test (p<0.05). Results STZ-icv rats exhibit significant dose- and time-dependent cognitive deficits in PA test (40-90%), while IDE protein expression was found decreased not earlier than one month after the STZ-icv administration (-55, 88%), persisting decreased untill six months (-26%). Treatment with high M30 dose improved STZ-icv induced cognitive deficits observed as decreased number of mistakes in MWM test (-60%) and increased latency time in PA test (+300%). Treatment with both M30 doses significantly increased IDE protein expression in comparison with the STZ-icv treatment alone (low dose +19%, high dose +37%). Conclusion STZ-icv rat model demonstrates long-term cognitive deficit and decreased hippocampal IDE protein expression which tend to correlate mutually. Chronic M30 treatment, initiated after the development of cognitive deficits, significantly improves cognitive deficit as well as decreased IDE protein expression in the STZ-icv rat model of sAD, suggesting that multifunctional iron-chelating drugs might have a therapeutic potential in sAD treatment. Acknowledgements Supported by UKF, MZOS and DAAD.

iron-chelator M30; cognition; streptozotocin; Alzheimer's disease

nije evidentirano