期刊
CURRENT ALZHEIMER RESEARCH
卷 7, 期 4, 页码 300-306出版社
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/156720510791162403
关键词
Alzheimer's disease; neuroprotection; iron chelation; amyloidogenic A beta peptide; hypoxia-inducible factor-1 alpha
资金
- Alzheimer's Drug Discovery Foundation (ADDF)
- Alzheimer's Association (Chicago, USA)
- Technion-Research and Development (Haifa, Israel)
Based on a multimodal drug design paradigm, we have synthesized a multifunctional non-toxic, brain permeable iron chelator, M30, possessing the neuroprotective propargylamine moiety of the anti-Parkinsonian drug, rasagiline (Azilect) and antioxidant-iron chelator moiety of an 8-hydroxyquinoline derivative of our iron chelator, VK28. M30 was recently found to confer potential neuroprotective effects in vitro and in various preclinical neurodegenerative models and regulate the levels and processing of the Alzheimer's amyloid precursor protein and its toxic amyloidogenic derivative, A. Here, we show that M30 activates the hypoxia-inducible factor (HIF)-1 alpha signaling pathway, thus promoting HIF-1 alpha mRNA and protein expression levels, as well as increasing transcription of HIF-1 alpha-dependent genes, including vascular endothelial growth factor, erythropoietin, enolase-1, p21 and tyrosine hydroxylase in rat primary cortical cells. In addition, M30 increased the expression levels of the transcripts of brain derived neurotrophic factor (BDNF) and growth-associated protein-43 (GAP-43). Regarding aspects of relevance to Alzheimer's disease (AD), western blotting analysis of glycogen synthase kinase-3 beta (GSK-3 beta) signaling pathway revealed that M30 enhanced the levels of phospho-AKT (Ser473) and phospho-GSK-3 beta (Ser9) and attenuated Tau phosphorylation. M30 was also shown to protect cultured cortical neurons against A beta(25-35) toxicity. All these multimodal pharmacological activities of M30 might be beneficial for its potent efficacy in the prevention and treatment of neurodegenerative conditions, such as Parkinson's disease and AD in which oxidative stress and iron-mediated toxicity are involved.
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