Seizures induced by fluoroacetic acid and fluorocitric acid may involve chelation of divalent cations in the spinal cord

Hornfeldt, Carl S.; Larson, Alice A.

doi:10.1016/0014-2999(90)90170-b

Cited by 45 publications

(25 citation statements)

References 20 publications

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“…At longer postdrug intervals and higher doses, neurons are indirectly affected by the rising levels of excitatory amino acids due to inhibition of glial excitatory amino acid transport. Indeed, refl ective of this indirect effect on neurons, seizures have also been reported in response to gliatoxic doses of this compound [79] .…”

Section: Why Is This Important?mentioning

confidence: 97%

Central Proinflammatory Cytokines and Pain Enhancement

2005

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Enhanced pain is a component of the ‘sickness response’ which is an evolutionarily adaptive constellation of responses that enhance the survival of the host. Proinflammatory cytokines mediate these sickness behaviors, and whether proinflammatory cytokines are involved in exaggerated pain has become an intriguing question. Studies suggest that spinal cord glial cells (astrocytes and microglia) are activated in conditions that lead to enhanced pain. Not only is glial activation associated with enhanced pain, but it is also integral to the induction and maintenance of these pain states. Proinflammatory cytokines can be released by activated astrocytes and microglia within the central nervous system. This review will discuss the role of proinflammatory cytokines in experimental models of prolonged pain states. Administration of exogenous proinflammatory cytokines facilitates pain, and agents that antagonize proinflammatory cytokine actions have been shown to block and/or reverse enhanced pain. These findings suggest that blocking the synthesis and/or release of proinflammatory cytokines may be viable strategies for the treatment of pathological pain. Gene therapy to augment the endogenous anti-inflammatory cytokine, interleukin-10, is one of the more promising therapies currently under study.

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Section: Why Is This Important?mentioning

confidence: 97%

Central Proinflammatory Cytokines and Pain Enhancement

2005

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“…Glutamate, lactate, EDTA and EGTA produced convulsions similar to FA. These compounds are structurally unrelated to FA, but have one common feature with it: the ability to chelate calcium ions, as judged from the fact that their neurotoxicity is considerably reduced by coadministration of calcium (Hornfeldt and Larson, 1990). Along with increased citrate level, activation of anaerobic neuronal glucose metabolism and accumulation of lactic acid in the cerebrospinal fluid may also be responsible for a coma with convulsions (Stewart et al, 1970).…”

Section: Pathogenesis: Action Of Fa On the Cells Of Nervous Systemmentioning

confidence: 99%

Toxicology of fluoroacetate: a review, with possible directions for therapy research

2006

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Fluoroacetate (FA; CH2FCOOR) is highly toxic towards humans and other mammals through inhibition of the enzyme aconitase in the tricarboxylic acid cycle, caused by 'lethal synthesis' of an isomer of fluorocitrate (FC). FA is found in a range of plant species and their ingestion can cause the death of ruminant animals. Some fluorinated compounds -- used as anticancer agents, narcotic analgesics, pesticides or industrial chemicals -- metabolize to FA as intermediate products. The chemical characteristics of FA and the clinical signs of intoxication warrant the re-evaluation of the toxic danger of FA and renewed efforts in the search for effective therapeutic means. Antidotal therapy for FA intoxication has been aimed at preventing fluorocitrate synthesis and aconitase blockade in mitochondria, and at providing citrate outflow from this organelle. Despite a greatly improved understanding of the biochemical mechanism of FA toxicity, ethanol, if taken immediately after the poisoning, has been the most acceptable antidote for the past six decades. This review deals with the clinical signs and physiological and biochemical mechanisms of FA intoxication to provide an explanation of why, even after decades of investigation, has no effective therapy to FA intoxication been elaborated. An apparent lack of integrated toxicological studies is viewed as a limiter of progress in this regard. Two principal ways of developing effective therapies for FA intoxication are considered. Firstly, competitive inhibition of FA interaction with CoA and of FC interaction with aconitase. Secondly, channeling the alternative metabolic pathways by orienting the fate of citrate via cytosolic aconitase, and by maintaining the flux of reducing equivalents into the TCA cycle via glutamate dehydrogenase.

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“…Since glia readily export citrate to the extracellular fluid (Sonnewald et al, 1991), its concentration in the extracellular fluid may increase several fold. Citrate is a chelator of calcium with a kDa of ϳ10 -5 (Hornfeldt and Larson, 1990). A reduction of the calcium concentration in the extracellular fluid is known to increase neuronal excitability (Campbell and Hille, 1976;Davies and Petersen, 1989).…”

Section: Mechanism Of Toxicitymentioning

confidence: 99%

Use of fluorocitrate and fluoroacetate in the study of brain metabolism

Fonnum

Johnsen

Hassel

1997

Glia

227

136

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Fluoroacetate and its toxic metabolite fluorocitrate cause inhibition of aconitase. In brain tissue, both substances are preferentially taken up by glial cells and leads to inhibition of the glial TCA cycle. It is important to realise, however, that the glia‐specificity of these compounds depends both on the dosage and on the model used. The glia‐inhibitory effect of fluorocitrate as obtained by intracerebral microinjection in vivo is reversible within 24 h. A substantial inhibition of the glial TCA cycle by systemic administration of fluoroacetate requires a lethal dose. Inhibition of the glial aconitase leads to accumulation of citrate and to a reduction in the formation of glutamine. Whereas the former is likely to be responsible for the main toxic effect of these compounds possibly by chelation of free calcium ions, it is the latter that has received most attention in the study of glial‐neuronal interactions, since glutamine is an important precursor for transmitter glutamate and GABA. GLIA 21: 106–113, 1997. © 1997 Wiley‐Liss, Inc.

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Seizures induced by fluoroacetic acid and fluorocitric acid may involve chelation of divalent cations in the spinal cord

Cited by 45 publications

References 20 publications

Central Proinflammatory Cytokines and Pain Enhancement

Central Proinflammatory Cytokines and Pain Enhancement

Toxicology of fluoroacetate: a review, with possible directions for therapy research

Use of fluorocitrate and fluoroacetate in the study of brain metabolism

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