Abstract

Neurotoxicity after cyanide exposure is generally believed to result from inhibition of cytochrome oxidase and subsequent histotoxic anoxia. However, the relationship between histotoxic anoxia and the symptoms produced by cyanide is poorly defined. Our preliminary studies indicate cyanide elevates neuronal cytosolic free calcium and this parallels the appearance of many of the symptoms of cyanide toxicity. We hypothesize that cyanide produces a rapid rise in neuronal cytosolic free calcium which activates a series of biochemical events culminating in the characteristic signs, symptoms and lesions of cyanide poisoning. Proposed experiments are designed to determine the source of the increased cytosolic calcium and to correlate changes in calcium homeostasis with the energy status of a cyanide-induced accumulation of intracellular calcium to release of neurotransmitters in cyanide intoxicated mice and in the PC12 cell line. Finally, the role of calcium in lipid peroxidation will be examined as an explanation for cyanide-induced neuronal lesions. The proposed studies represents a new approach to the investigation of cyanide toxicity and will yield important information on the biochemical mechanism(s) of cyanide induced neurotoxicity.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES004140-02
Application #
3252111
Study Section
Toxicology Study Section (TOX)
Project Start
1986-06-15
Project End
1989-05-31
Budget Start
1987-06-01
Budget End
1988-05-31
Support Year
2
Fiscal Year
1987
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