Cyanide-induced neurotoxicity is accompanied by destabilization of neuronal Ca+ homeostasis, triggering an uncontrolled, sustained rise in cytosolic free Ca2+ which in turn activates several neurotoxic pathways. This study will characterize the Ca2+ dependent signal cascades activated by cyanide and determine the mechanism of the subsequent neuronal dysfunction and injury in two neuronal models, the PC12 cell and primary cultured cerebellar granule cells. This will include studying the effect of cyanide on the nitric oxide signal cascade, protein kinase C activation and translocation, and calmodulin/calmodulin-dependent protein kinase II. Cyanide's action on each Ca2+ dependent system will be correlated with alterations in neuronal biochemistry and injury. The mechanism underlying cyanide-induced excitotoxicity will also be studied. Direct interaction of cyanide with the NMDA receptor redox modulatory site will be related to the excitotoxic response. Additionally, the role oxidative stress (hydroperoxide generation), inositol (1,4,5) triphosphate cascade and potassium channels play in the cyanide-induced excitotoxic response will be addressed. Finally, the contribution of genomic activation to the neurotoxicity will be determined. This includes correlation of cyanide stimulated proto-oncogene (c-fos) expression with the cytotoxic response. Nerve growth factor differentiated PC12 cells will be used to study cyanide-induced apoptotic death and the influence of impaired Ca2+ regulation and sustained activation of intracellular signal transduction on the apoptotic process. The long-term goal of this project is to develop an in-depth understanding of the mechanism of toxicity of a xenobiotic in the CNS by relating sustained activation of Ca2+ dependent cascades to neuronal cytotoxic responses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES004140-12
Application #
2430306
Study Section
Toxicology Subcommittee 2 (TOX)
Project Start
1986-06-01
Project End
1999-01-31
Budget Start
1997-06-01
Budget End
1999-01-31
Support Year
12
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Purdue University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
072051394
City
West Lafayette
State
IN
Country
United States
Zip Code
47907
Leavesley, Heather B; Li, Li; Mukhopadhyay, Soma et al. (2010) Nitrite-mediated antagonism of cyanide inhibition of cytochrome c oxidase in dopamine neurons. Toxicol Sci 115:569-76
Zhang, Lu; Li, Li; Liu, Han et al. (2009) BNIP3 mediates cell death by different pathways following localization to endoplasmic reticulum and mitochondrion. FASEB J 23:3405-14
Zhang, X; Li, L; Zhang, L et al. (2009) Cyanide-induced death of dopaminergic cells is mediated by uncoupling protein-2 up-regulation and reduced Bcl-2 expression. Toxicol Appl Pharmacol 238:11-9
Leavesley, Heather B; Li, Li; Prabhakaran, Krishnan et al. (2008) Interaction of cyanide and nitric oxide with cytochrome c oxidase: implications for acute cyanide toxicity. Toxicol Sci 101:101-11
Li, L; Prabhakaran, K; Zhang, X et al. (2008) 1Alpha,25-dihydroxyvitamin D3 attenuates cyanide-induced neurotoxicity by inhibiting uncoupling protein-2 up-regulation. J Neurosci Res 86:1397-408
Prabhakaran, K; Li, L; Zhang, L et al. (2007) Upregulation of BNIP3 and translocation to mitochondria mediates cyanide-induced apoptosis in cortical cells. Neuroscience 150:159-67
Zhang, X; Li, L; Prabhakaran, K et al. (2007) Uncoupling protein-2 up-regulation and enhanced cyanide toxicity are mediated by PPARalpha activation and oxidative stress. Toxicol Appl Pharmacol 223:10-9
Zhang, L; Li, L; Liu, H et al. (2007) HIF-1alpha activation by a redox-sensitive pathway mediates cyanide-induced BNIP3 upregulation and mitochondrial-dependent cell death. Free Radic Biol Med 43:117-27
Li, Li; Prabhakaran, Krishnan; Zhang, Xun et al. (2006) PPARalpha-mediated upregulation of uncoupling protein-2 switches cyanide-induced apoptosis to necrosis in primary cortical cells. Toxicol Sci 93:136-45
Prabhakaran, K; Li, L; Borowitz, J L et al. (2006) Inducible nitric oxide synthase up-regulation and mitochondrial glutathione depletion mediate cyanide-induced necrosis in mesencephalic cells. J Neurosci Res 84:1003-11

Showing the most recent 10 out of 65 publications