PMID- 20043814
OWN - NLM
STAT- MEDLINE
DCOM- 20110224
LR  - 20191027
IS  - 1875-5828 (Electronic)
IS  - 1567-2050 (Linking)
VI  - 7
IP  - 4
DP  - 2010 Jun
TI  - Up-regulation of hypoxia-inducible factor (HIF)-1alpha and HIF-target genes in 
      cortical neurons by the novel multifunctional iron chelator anti-Alzheimer drug, 
      M30.
PG  - 300-6
AB  - 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, Abeta. Here, we show that M30 activates the 
      hypoxia-inducible factor (HIF)-1alpha signaling pathway, thus promoting 
      HIF-1alpha mRNA and protein expression levels, as well as increasing 
      transcription of HIF-1alpha-dependent genes, including vascular endothelial 
      growth factor, erythropoietin, enolase-1, p21 and tyrosine hydroxylase in rat 
      primary cortical cells. In addition, M30 also 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- 3beta (GSK-3beta) 
      signaling pathway revealed that M30 enhanced the levels of phospho-AKT (Ser473) 
      and phospho- GSK-3beta (Ser9) and attenuated Tau phosphorylation. M30 was also 
      shown to protect cultured cortical neurons against Abeta(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.
FAU - Avramovich-Tirosh, Y
AU  - Avramovich-Tirosh Y
AD  - Eve Topf Centers of Excellence for Neurodegenerative Diseases Research and 
      Department of Pharmacology, Rappaport Family Research Institute, Technion-Faculty 
      of Medicine, Haifa, 31096, Israel.
FAU - Bar-Am, O
AU  - Bar-Am O
FAU - Amit, T
AU  - Amit T
FAU - Youdim, M B H
AU  - Youdim MB
FAU - Weinreb, O
AU  - Weinreb O
LA  - eng
PT  - Journal Article
PL  - United Arab Emirates
TA  - Curr Alzheimer Res
JT  - Current Alzheimer research
JID - 101208441
RN  - 0 (5-(N-methyl-N-propargylaminomethyl)-8-hydroxyquinoline)
RN  - 0 (Chelating Agents)
RN  - 0 (Hif1a protein, rat)
RN  - 0 (Hydroxyquinolines)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Neuroprotective Agents)
SB  - IM
MH  - Alzheimer Disease/*drug therapy/metabolism/pathology
MH  - Animals
MH  - Cells, Cultured
MH  - Cerebral Cortex/drug effects/metabolism/pathology
MH  - Chelating Agents/*pharmacology/therapeutic use
MH  - Drug Delivery Systems
MH  - Hydroxyquinolines/*pharmacology/therapeutic use
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/agonists/*biosynthesis/metabolism
MH  - Neurons/drug effects/*metabolism/*pathology
MH  - Neuroprotective Agents/*pharmacology/therapeutic use
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Up-Regulation/*drug effects
EDAT- 2010/01/02 06:00
MHDA- 2011/02/25 06:00
CRDT- 2010/01/02 06:00
PHST- 2009/06/09 00:00 [received]
PHST- 2009/11/05 00:00 [accepted]
PHST- 2010/01/02 06:00 [entrez]
PHST- 2010/01/02 06:00 [pubmed]
PHST- 2011/02/25 06:00 [medline]
AID - CAR -54 [pii]
AID - 10.2174/156720510791162403 [doi]
PST - ppublish
SO  - Curr Alzheimer Res. 2010 Jun;7(4):300-6. doi: 10.2174/156720510791162403.