engleski

Multi-target iron-chelators improve memory loss in a rat model of sporadic Alzheimer's disease

AIM: Novel effective treatment is urgently needed for sporadic Alzheimer's disease (sAD). M30 ([5-(N-methyl-N-propargylaminomethyl)-8- hydroxyquinoline]) and HLA-20 (5-{; ; ; 4- propargylpiperazin-1-ylmethyl}; ; ; -8- hydroxyquinoline) are brain permeable, iron chelating compounds with antioxidant activity, showing also neuroprotective activity in animal models of neurodegeneration.Weaimed to explore their therapeutic potential in non-transgenic (non-Tg) rat model of sAD developed by intracerebroventricular administration of streptozotocin (STZ-icv). MAIN METHODS: Therapeutic effects of chronic oral M30 (2 and 10 mg/kg) and HLA20 (5 and 10 mg/kg) treatment on cognitive impairment in STZ-icv rat model were explored by Morris Water Maze (MWM) and Passive Avoidance (PA) tests in neuropreventive and neurorescue paradigms. Data were analysed by Kruskal–Wallis and Mann–Whitney U test (p b 0.05). KEY FINDINGS: Five-day oral pre- treatment with M30 and HLA20 dose-dependently prevented development of spatial memory impairment (MWM probe trial-time +116%/M30 ; +60%/HLA20) in STZ-icv rat model (p b 0.05). Eleven-week oral treatment with M30 (3×/week), initiated 8 days after STZ-icv administration dosedependently ameliorated already developed cognitive deficits in MWM test (reduced number of mistakes 3 months after the STZ-icv treatment — 59% ; p b 0.05) and fully restored them in PA test (+314% ; p b 0.05). Chronic M30 treatment fully restored (−47%/PHF1 ; −65%/AT8 ; p b 0.05) STZ-induced hyperphosphorylation of tau protein and normalized decreased expression of insulin degrading enzyme (+37% ; p b 0.05) in hippocampus. SIGNIFICANCE: The results provide first evidence of therapeutic potential of M30 and HLA20 in STZ- icv rat model of sAD with underlying molecular mechanism, further supporting the important role of multi-target ironchelators in sAD treatment.

Alzheimer's disease ; HLA20 compound ; Insulin degrading enzyme ; M30 compound ; Memory ; Streptozotocin ; Tau protein

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