Iron chelators are pluripotent neuronal anti-apoptotic agents which have been shown to slow clinical progression in Alzheimer's Disease and enhanced metabolic recovery in cerebral ischemia models. The precise mechanism(s) by which these agents exert their salutary effects remains unclear. In preliminary studies, we have found that structurally distinct iron chelators, deferoxamine mesylate, and mimosine prevent apoptosis induced by glutathione-depletion and oxidative stress in embryonic cortical neurons. We correlated the protective effects of iron chelators with their ability to increase protein expression and enzyme activity of two glycolytic enzymes, lactate dehydrogenase (LDH) and aldolase. The increase in glycolytic enzyme activity induced by iron chelators could be abrogated by actinomycin-D, an mRNA synthase inhibitor, suggesting that the induction is partly transcriptional. consistent with these findings, we demonstrated that iron chelators enhance DNA-binding of two transcription factor complexes, hypoxia- inducible factor-1 (HIF-1) and ATF-1/CREB, in cortical cultures as well as in H19-7 neuronal cell line. Finally, we have shown that message levels for LDH and erythropoietin, genes whose expression is known to be regulated by HIF-1, were elevated in cortical cultures. in response to iron chelator treatment. These preliminary results suggests the following overall hypothesis: iron chelators exert their pluripotent neuroprotective effects, in part by activating a signal transduction pathway that leads to increased expression of genes (e.g., glycolytic enzymes, the growth factor, erythropoietin, or the antioxidant, heme oxygenase) known to compensate for hypoxic or oxidative stress. We propose to test this hypothesis by: 1) determining whether iron chelators enhance heterodimeric HIV-1 (HIF-1 alpha + HIF-1 beta) and/or ATF-1/CREB DNA binding by decreasing peroxide levels; 2) determining the HIF-1 regulated genes induced by iron chelators in embryonic cortical neurons; 3) determining whether enforced expression of HIF-1alpha, HIF- 1beta, ATF-1, or CREB is sufficient for protection from oxidative stress-induced apoptosis; and 4) determining whether HIF-1 is necessary for protection from oxidative stress-induced apoptosis by iron chelators. These studies will define whether HIF-1 is a viable molecular target for therapy of neurological diseases that have been associated with oxidative stress and apoptosis including stroke, Alzheimer's Disease, Parkinson's Disease, and Fredrich's Ataxia. Furthermore, these studies also promise to further define mechanisms of protection by small molecule iron chelators.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS039170-01
Application #
2911176
Study Section
Special Emphasis Panel (ZRG1-MDCN-2 (01))
Program Officer
Spinella, Giovanna M
Project Start
1999-07-15
Project End
2003-06-30
Budget Start
1999-07-15
Budget End
2000-06-30
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02215
Alim, Ishraq; Haskew-Layton, Renee E; Aleyasin, Hossein et al. (2014) Spatial, temporal, and quantitative manipulation of intracellular hydrogen peroxide in cultured cells. Methods Enzymol 547:251-73
Haskew-Layton, Renée E; Payappilly, Jimmy B; Smirnova, Natalya A et al. (2010) Controlled enzymatic production of astrocytic hydrogen peroxide protects neurons from oxidative stress via an Nrf2-independent pathway. Proc Natl Acad Sci U S A 107:17385-90
Ratan, Rajiv R; Noble, Mark (2009) Novel multi-modal strategies to promote brain and spinal cord injury recovery. Stroke 40:S130-2
Sleiman, Sama F; Basso, Manuela; Mahishi, Lata et al. (2009) Putting the 'HAT' back on survival signalling: the promises and challenges of HDAC inhibition in the treatment of neurological conditions. Expert Opin Investig Drugs 18:573-84
Siddiq, Ambreena; Aminova, Leila R; Troy, Carol M et al. (2009) Selective inhibition of hypoxia-inducible factor (HIF) prolyl-hydroxylase 1 mediates neuroprotection against normoxic oxidative death via HIF- and CREB-independent pathways. J Neurosci 29:8828-38
Aminova, Leila R; Chavez, Juan C; Lee, Junghee et al. (2005) Prosurvival and prodeath effects of hypoxia-inducible factor-1alpha stabilization in a murine hippocampal cell line. J Biol Chem 280:3996-4003
Siddiq, Ambreena; Ayoub, Issam A; Chavez, Juan C et al. (2005) Hypoxia-inducible factor prolyl 4-hydroxylase inhibition. A target for neuroprotection in the central nervous system. J Biol Chem 280:41732-43
Lee, Junghee; Kim, Chun-Hyung; Simon, David K et al. (2005) Mitochondrial cyclic AMP response element-binding protein (CREB) mediates mitochondrial gene expression and neuronal survival. J Biol Chem 280:40398-401
Ryu, Hoon; Lee, Junghee; Olofsson, Beatrix A et al. (2003) Histone deacetylase inhibitors prevent oxidative neuronal death independent of expanded polyglutamine repeats via an Sp1-dependent pathway. Proc Natl Acad Sci U S A 100:4281-6
Ryu, Hoon; Lee, Junghee; Zaman, Khalequz et al. (2003) Sp1 and Sp3 are oxidative stress-inducible, antideath transcription factors in cortical neurons. J Neurosci 23:3597-606

Showing the most recent 10 out of 13 publications