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

LIFE SCIENCES

卷:136

Article

Salkovic-Petrisic, Melita^1,2  Knezovic, Ana^1,2  Osmanovic-Barilar, Jelena^1,2  Smailovic, Una^1,2  Trkulja, Vladimir^1,2  Riederer, Peter³  Amit, Tamar^4,5  Mandel, Silvia⁶  Youdim, Moussa B. H.^4,5 

[1] Univ Zagreb, Sch Med, Dept Pharmacol, Salata 11, HR-10000 Zagreb, Croatia

[2] Univ Zagreb, Sch Med, Croatian Inst Brain Res, HR-10000 Zagreb, Croatia

[3] Univ Wurzburg, Univ Hosp Wuerzburg, Ctr Mental Hlth, Dept Clin Neurochem,Clin & Policlin Psychiat Psyc, D-97080 Wurzburg, Germany

[4] Technion Israel Inst Technol, Fac Med, Eve Topf Ctr Neurodegenerat Dis Res, Haifa, Israel

[5] Technion Israel Inst Technol, Fac Med, Dept Mol Pharmacol, Haifa, Israel

[6] Technion Israel Inst Technol, Bruce Ruth Rappaport Fac Med, IL-31096 Haifa, Israel

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

DOI  :  10.1016/j.lfs.2015.06.026

来源: Elsevier

【 摘 要 】

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. We aimed 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 < 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 < 0.05). Eleven-week oral treatment with M30 (3x/week), initiated 8 days after STZ-icv administration dose-dependently ameliorated already developed cognitive deficits in MWM test (reduced number of mistakes 3 months after the STZ-icv treatment - 59%; p < 0.05) and fully restored them in PA test (+ 314%; p < 0.05). Chronic M30 treatment fully restored (-47%/PHF1; -65%/AT8; p < 0.05) STZ-induced hyperphosphorylation of tau protein and normalized decreased expression of insulin degrading enzyme (+ 37%; p < 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 iron-chelators in sAD treatment. (C) 2015 Elsevier Inc. All rights reserved.

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