engleski

Neuroprotective-neurorestorative potential of the novel multi-target, iron-chelator, M-30 in non-transgenic rat model of sporadic Alzheimer's disease

Objectives: The novel multi-target, neuroprotective-neurorestorative iron chelator, M-30 has demonstrated iron chelating potency, radical scavenging and neurorescue activities in several models of neurodegenerative diseases including transgenic mice model of Alzheimer’s disease (AD). Considering the involvement of iron accumulation and brain insulin dysfunction in the pathophysiology of sporadic AD (sAD), we have investigated the pharmacological potential of M30 in a recently cognitively characterized, non-transgenic streptozotocin-intracerebroventricularly treated (STZ-icv) rat model of AD, which develops insulin resistant brain state. Methods: Two groups of STZ-icv (3 mg/kg) injected adult male Wistar rats were subjected to 11 week-long M30 treatment (2 and 10 mg/kg, per os, 3x week) initiated 10 days after the STZ-icv injection. Cognitive deficits were measured by Morris Water Maze Swimming Test (MWM) and Passive Avoidance Test (PA). Insulin receptor (IR) and insulin degrading enzyme (IDE) protein expression was measured in hippocampus (HPC) by Western blot analysis. Data were analysed by Kruscal-Wallis ANOVA test (p<0.05). Results: STZ-icv injected rats exhibit significant dose (0, 3-3 mg/kg)- and time (≥9 months)-dependent cognitive deficits in MWM and PA test (40-90%). M30 (10/mg/kg) decreased the number of mistakes (M) and increased the time spent in targeted quadrant (T) in MWM test in STZ-icv treated rats measured 2 (M), 4 (M, T), 8 (M, T) and 12 (M) weeks after the STZ-icv treatment, and normalized the latency time in PA test to the control values 12 weeks after STZ-icv treatment (P<0.05). Both M30 doses significantly increased IDE values (20-35%) in STZ-icv rats (P<0.05) while IR levels remained unchanged in all groups at time point of 12 weeks. Conclusion: Long-term, M-30 post-damage treatment significantly improves cognitive deficits and normalizes decreased hippocampal IDE levels in non-transgenic, STZ-icv rat model of sAD. Supported by MZOS (108-1080003-0020), DAAD and UKF

streptozotocin; Alzheimer’s disease; iron-chelator M30

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