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

Znanstveni rad - Izvorni znanstveni rad

• Autor: Melita Šalković-Petrišić
• Autor: Ana Knezović
• Autor: Jelena Osmanović-Barilar
• Autor: Una Smailović
• Autor: Vladimir Trkulja
• Autor: Peter Riederer
• Autor: Tamar Amit
• Autor: Silvia Mandel
• Autor: Moussa B.H. Youdim
• Autorova ustanova: Sveučilište u Zagrebu; Medicinski fakultet
• Znanstveno / umjetničko područje, polje i grana: BIOMEDICINA I ZDRAVSTVO; Temeljne medicinske znanosti

Sažetak (engleski)

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.

• Ključne riječi (engleski): 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
• Jezik: engleski
• Vrsta publikacije: Znanstveni rad - Izvorni znanstveni rad
• Status objave: Objavljen
• Vrsta recenzije: Recenziran
• Verzija publikacije: Završna verzija rukopisa prihvaćena za objavljivanje (postprint)
• Naslov časopisa: Life Sciences
• Brojčani podaci: vol. 136, str. 108-119
• p-ISSN: 0024-3205
• DOI: https://doi.org/10.1016/j.lfs.2015.06.026
• URN:NBN: urn:nbn:hr:105:013198
• Datum objave publikacije: 2015-09-01
• URL dokumenta: https://doi.org/10.1016/j.lfs.2015.06.026
• Vrsta resursa: Tekst
• Prava pristupa: Otvoreni pristup
• Datum i vrijeme pohrane: 2024-03-28 09:02:31