Binding of some organophosphorus compounds at adenosine receptors in guinea pig brain membranes

Lau, Wai‐Man; Freeman, Shirley E.; Szilágyi, M.

doi:10.1016/0304-3940(88)90282-0

Cited by 13 publications

(6 citation statements)

References 15 publications

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“…The action of this protection was attributed to cholinergic mechanisms wherein the adenosine A1 receptor agonists binding to A1 adenosine receptor caused inhibition of ACh release, and reduced ACh levels in rat brains were reported in this study (Van Helden et al, 1998). However, the organophosphorus anti-cholinesterase compounds sarin, tabun (O-ethyl dimethylamidophosphorylcyanide) and soman have previously been shown to interact directly with brain A1 adenosine receptors, which could subsequently affect the ion permeability of synaptic membranes and cause toxicity (Lau et al, 1988). Therefore, A1 agonists may competitively alter the action of these agents at adenosine receptor sites.…”

Section: Adenosine Receptor Agonistsmentioning

confidence: 65%

“…AntiAChE nerve agents such as soman can, to varying degrees, inhibit serine protease and bind to adenosine receptors (Lau et al, 1988). The situation is complicated further because anti-AChE compounds, which include nerve agents, also have variable NMDA antagonist activity that does not correlate with the degree of antiAChE activity (Johnson and Michaelis, 1992;Tang and Cassel, 1998).…”

Section: Multiple Drug/agent Actions and Mtmcsmentioning

confidence: 98%

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Putative role of proteolysis and inﬂammatory response in the toxicity of nerve and blister chemical warfare agents: implications for multi‐threat medical countermeasures

Cowan¹,

Broomfield²,

Lenz³

et al. 2003

J of Applied Toxicology

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Despite the contrasts in chemistry and toxicity, for blister and nerve chemical warfare agents there may be some analogous proteolytic and inflammatory mediators and pathological pathways that can be pharmacological targets for a single-drug multi-threat medical countermeasure. The dermal-epidermal separation caused by proteases and bullous diseases compared with that observed following exposure to the blister agent sulfur mustard (2,2'-dichlorodiethyl sulfide) has fostered the hypothesis that sulfur mustard vesication involves proteolysis and inflammation. In conjunction with the paramount toxicological event of cholinergic crisis that causes acute toxicity and precipitates neuronal degeneration, both anaphylactoid reactions and pathological proteolytic activity have been reported in nerve-agent-intoxicated animals. Two classes of drugs already have demonstrated multi-threat activity for both nerve and blister agents. Serine protease inhibitors can prolong the survival of animals intoxicated with the nerve agent soman and can also protect against vesication caused by the blister agent sulfur mustard. Poly (ADP-ribose) polymerase (PARP) inhibitors can reduce both soman-induced neuronal degeneration and sulfur-mustard-induced epidermal necrosis. Protease and PARP inhibitors, like many of the other countermeasures for blister and nerve agents, have potent primary or secondary anti-inflammatory pharmacology. Accordingly, we hypothesize that drugs with anti-inflammatory actions against either nerve or blister agent might also display multi-threat efficacy for the inflammatory pathogenesis of both classes of chemical warfare agent.

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Section: Adenosine Receptor Agonistsmentioning

confidence: 65%

Section: Multiple Drug/agent Actions and Mtmcsmentioning

confidence: 98%

Putative role of proteolysis and inﬂammatory response in the toxicity of nerve and blister chemical warfare agents: implications for multi‐threat medical countermeasures

Cowan¹,

Broomfield²,

Lenz³

et al. 2003

J of Applied Toxicology

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“…Such changes could be indirectly triggered by: (i) excessive activation followed by desensitization of nicotinic and muscarinic receptors during the time AChE activity is inhibited by soman, (ii) activation or inactivation of second messenger mechanisms secondary to direct interactions of soman with specific neurotransmitter receptors (Lau et al, 1988; Silveira et al, 1990), and/or (iii) direct activation by soman of intracellular pathways that control gene expression (Osterreicher et al, 2007). …”

Section: Discussionmentioning

confidence: 99%

Galantamine counteracts development of learning impairment in guinea pigs exposed to the organophosphorus poison soman: Clinical significance

et al. 2011

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Galantamine, a drug used to treat Alzheimer’s disease, protects guinea pigs against the acute toxicity and lethality of organophosphorus (OP) compounds, including soman. Here, we tested the hypothesis that a single exposure of guinea pigs to 1xLD50 soman triggers cognitive impairments that can be counteracted by galantamine. Thus, animals were injected intramuscularly with saline (0.5 ml/kg) or galantamine (8 mg/kg) and 30 min later injected subcutaneously with soman (26.3 µg/kg) or saline. Cognitive performance was analyzed in the Morris water maze (MWM) four days or three months after the soman challenge. Fifty percent of the saline-injected animals that were challenged with soman survived with mild-to-moderate signs of acute toxicity that subsided within a few hours. These animals showed no learning impairment and no memory retention deficit, when training in the MWM started four days post-soman challenge. In contrast, animals presented significant learning impairment when testing started three months post-challenge. Though the magnitude of the impairment correlated with the severity of the acute toxicity, animals that presented no or only mild signs of toxicity were also learning impaired. All guinea pigs that were treated with galantamine survived the soman challenge with no signs of acute toxicity and learned the MWM task as control animals, regardless of when testing began. Galantamine also prevented memory extinction in both saline-and soman-challenged animals. In conclusion, learning impairment develops months after a single exposure to 1xLD50 soman, and galantamine prevents both the acute toxicity and the delayed cognitive deficits triggered by this OP poison.

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“…Acute cholinergic abnormality develops within a few minutes to several hours after exposure, and affects peripheral muscarinic and nicotinic receptors, as well as the central nervous system, through the inhibition of serine-containing esterases, of which AChE is clinically the most important (Lotti et al, 1986). There are few that interact directly with muscarinic receptors (Silveira et al, 1990), and pathways other than cholinergic ones can be affected (Fosbraey et al, 1990;Lau et al, 1988). There are few that interact directly with muscarinic receptors (Silveira et al, 1990), and pathways other than cholinergic ones can be affected (Fosbraey et al, 1990;Lau et al, 1988).…”

Section: Acute Cholinergic Toxicitymentioning

confidence: 99%

Neurotoxicity of Organophosphates and Carbamates

Gill

Flora²,

Pachauri

et al. 2011

Anticholinesterase Pesticides

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Binding of some organophosphorus compounds at adenosine receptors in guinea pig brain membranes

Cited by 13 publications

References 15 publications

Putative role of proteolysis and inﬂammatory response in the toxicity of nerve and blister chemical warfare agents: implications for multi‐threat medical countermeasures

Putative role of proteolysis and inﬂammatory response in the toxicity of nerve and blister chemical warfare agents: implications for multi‐threat medical countermeasures

Galantamine counteracts development of learning impairment in guinea pigs exposed to the organophosphorus poison soman: Clinical significance

Neurotoxicity of Organophosphates and Carbamates

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