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

Šalković-Petrišić, Melita and Knezović, Ana and Osmanović-Barilar, Jelena and Smailović, Una and Trkulja, Vladimir and Riederer, Peter and Amit, Tamar and Mandel, Silvia and Youdim, Moussa B.H. (2015) Multi-target iron-chelators improve memory loss in a rat model of sporadic Alzheimer's disease. Life Sciences, 136. pp. 108-119. ISSN 0024-3205

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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.

Item Type: Article
MeSH: Alzheimer Disease/chemically induced ; Alzheimer Disease/drug therapy ; Alzheimer Disease/psychology ; Animals ; Disease Models, Animal ; Drug Evaluation, Preclinical ; Hydroxyquinolines/pharmacology ; Hydroxyquinolines/therapeutic use ; Iron Chelating Agents/pharmacology ; Iron Chelating Agents/therapeutic use ; Male ; Memory Disorders/drug therapy ; Memory, Long-Term/drug effects ; Neuroprotective Agents/pharmacology ; Neuroprotective Agents/therapeutic use ; Piperazines/pharmacology ; Piperazines/therapeutic use ; Rats, Wistar ; Streptozocin
Departments: Hrvatski institut za istraživanje mozga
Katedra za farmakologiju
Depositing User: Martina Žužak
Status: Published
Šalković-Petrišić, MelitaUNSPECIFIED
Osmanović-Barilar, JelenaUNSPECIFIED
Trkulja, VladimirUNSPECIFIED
Riederer, PeterUNSPECIFIED
Youdim, Moussa B.H.UNSPECIFIED
Date: 1 September 2015
Date Deposited: 25 Jan 2018 12:25
Last Modified: 24 Jul 2020 09:07
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