title: Multi-target iron-chelators improve memory loss in a rat model of sporadic Alzheimer's disease.
abstract: OBJECTIVE
  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).
  
  
  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).
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmacology and Croatian Institute for Brain Research, University of Zagreb School of Medicine, Salata 11, HR 10 000 Zagreb, Croatia. Electronic address: melitas@mef.hr.
authors.forename: Melita
authors.initials: M
authors.lastname: Salkovic-Petrisic
authors.affiliation: Department of Pharmacology and Croatian Institute for Brain Research, University of Zagreb School of Medicine, Salata 11, HR 10 000 Zagreb, Croatia.
authors.forename: Ana
authors.initials: A
authors.lastname: Knezovic
authors.affiliation: Department of Pharmacology and Croatian Institute for Brain Research, University of Zagreb School of Medicine, Salata 11, HR 10 000 Zagreb, Croatia.
authors.forename: Jelena
authors.initials: J
authors.lastname: Osmanovic-Barilar
authors.affiliation: Department of Pharmacology and Croatian Institute for Brain Research, University of Zagreb School of Medicine, Salata 11, HR 10 000 Zagreb, Croatia.
authors.forename: Una
authors.initials: U
authors.lastname: Smailovic
authors.affiliation: Department of Pharmacology and Croatian Institute for Brain Research, University of Zagreb School of Medicine, Salata 11, HR 10 000 Zagreb, Croatia.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Trkulja
authors.affiliation: University Hospital Wuerzburg, Center of Mental Health, Department of Clinical Neurochemistry, Clinic and Policlinic of Psychiatry, Psychosomatic and Psychotherapy, University of Wuerzburg, Fuechsleinstr. 15, 97080 Wuerzburg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Riederer
authors.affiliation: Eve Topf Center for Neurodegenerative Diseases Research and Department of Molecular Pharmacology, Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: Tamar
authors.initials: T
authors.lastname: Amit
authors.affiliation: Bruce Ruth Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel.
authors.forename: Silvia
authors.initials: S
authors.lastname: Mandel
authors.affiliation: Eve Topf Center for Neurodegenerative Diseases Research and Department of Molecular Pharmacology, Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: Moussa B H
authors.initials: MB
authors.lastname: Youdim
mesh_terms: D000544:Alzheimer Disease / Q000139:chemically induced / Q000188:drug therapy* / Q000523:psychology; D000818:Animals; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006912:Hydroxyquinolines / Q000494:pharmacology* / Q000627:therapeutic use; D007502:Iron Chelating Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy*; D057567:Memory, Long-Term / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D017208:Rats, Wistar; D013311:Streptozocin
chemical_list: D006912:Hydroxyquinolines; D007502:Iron Chelating Agents; D018696:Neuroprotective Agents; D010879:Piperazines; C505060:5-((4-prop-2-ynylpiperazin-1-yl)methyl)quinolin-8-ol; D013311:Streptozocin
keywords: Alzheimer's disease; HLA20 compound; Insulin degrading enzyme; M30 compound; Memory; Streptozotocin; Tau protein