Abstract

Cyanide-induced neurotoxicity is accompanied by a marked rise in cytosolic free calcium which activates a series of biochemical events culminating in the signs, symptoms and lesions of cyanide poisoning. This study will determine the underlying mechanism of the cyanide-induced rise in cytosolic calcium and investigate the intraneuronal reactions triggered by the elevated calcium. Proposed experiments will correlate the rise in cytosolic calcium with membrane potentials and intracellular ions (H+ and Cl-) by employing new fluorometric probes and a neurosecretory cell line (PC12 cells). Additionally, the relationship of glutamate excitotoxic neurotransmitter system to cyanide neurotoxicity will be studied in PC12 cells and mouse brain slices. The importance of the entry of cyanide anion through chloride channels will also be evaluated in isolated cells. Finally the contribution of cyanide-induced lipid peroxidation to perturbation of cell membranes will be determined in biochemical and morphological studies. The proposed work will give a more clear understanding of the mechanism of toxicity of a xenobiotic in the CNS and will correlate the biochemical defects, the structural alterations and the functional changes which characterize cyanide intoxication.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES004140-07
Application #
3252115
Study Section
Toxicology Subcommittee 2 (TOX)
Project Start
1986-06-15
Project End
1994-05-31
Budget Start
1992-06-01
Budget End
1993-05-31
Support Year
7
Fiscal Year
1992
Total Cost
Indirect Cost

  Institution

Name
Purdue University
Department
Type
Schools of Pharmacy
DUNS #
072051394
City
West Lafayette
State
IN
Country
United States
Zip Code
47907

  Publications

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
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
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

Showing the most recent 10 out of 65 publications