Elsevier

Biochemical Pharmacology

Volume 35, Issue 18, 15 September 1986, Pages 3115-3121
Biochemical Pharmacology

Elevated choline levels in brain: A non-cholinergic component of organophosphate toxicity

https://doi.org/10.1016/0006-2952(86)90395-3Get rights and content

Abstract

The role of cholinergic and non-cholinergic mechanisms in mediating organophosphate cholinesterase (ChE) inhibitor-induced elevations in choline levels in brain was investigated. The nerve agents soman and sarin, when administered to rats at doses greater than the ic50 for acetylChE inhibition, significantly increased the levels of choline and acetylcholine in both the striatum and hippocampus. The elevation in choline levels was evident 1 hr after injection with a maximal increase at 2 hr. Levels of choline returned to control by 4 hr. In contrast, the administration of diisopropyl phosphorofluoridate at doses greater than the ic50 for acetylChE inhibition increased the levels of acetylcholine, but did not alter the concentration of choline during the first 3 hr. Between 4 and 24 hr after injection, however, a significant decrease in choline levels was apparent. This effect persisted for 48 hr. When rats were pretreated with the anticonvulsant diazepam, the sarin- and soman-induced increases in choline levels were attenuated significantly. Results indicate that the organophosphates differentially alter the levels of choline in brain and suggest that the effect of soman and sarin to elevate choline levels is not a reflection of excessive cholinergic activity, but rather may be a consequence of the excitotoxic actions of these compounds.

References (35)

  • M. Kakihana et al.

    Jap. J. Pharmac.

    (1984)
  • V. Doležal et al.

    Biochem. biophys. Res. Commun.

    (1984)
  • O. Mayer et al.

    Biochem. Pharmac.

    (1971)
  • J.J. O'Neill

    Fund. appl. Toxic.

    (1981)
  • R. Jović et al.

    Biochem. Pharmac.

    (1971)
  • D.E. Schmidt et al.

    Analyt. Biochem.

    (1975)
  • G.L. Ellman et al.

    Biochem. Pharmac.

    (1961)
  • H. Ladinsky et al.

    Biochem. Pharmac.

    (1974)
  • J.A. Lipp

    Electroenceph. clin. Neurophysiol.

    (1972)
  • P.M. Lundy et al.

    Neuropharmacology

    (1983)
  • G. Lundgren et al.

    Biochem. Pharmac.

    (1977)
  • N.G. Bazán

    Biochim. biophys. Acta

    (1970)
  • R.W. Russell et al.

    Neuropharmacology

    (1981)
  • P.E. Potter et al.

    Eur. J. Pharmac.

    (1984)
  • P. Desnuelle et al.

    Biochim. biophys. Acta

    (1960)
  • J.H. Brown et al.

    Toxicon

    (1966)
  • T-M. Shih

    Psychopharmacology

    (1982)
  • Cited by (46)

    • Molecular interactions of chemical warfare agents with biological systems

      2022, Sensing of Deadly Toxic Chemical Warfare Agents, Nerve Agent Simulants, and their Toxicological Aspects
    • Crossroads in the evaluation of paraoxonase 1 for protection against nerve agent and organophosphate toxicity

      2012, Toxicology Letters
      Citation Excerpt :

      An efficient therapeutic strategy to combat against accidental or intentional exposure to organophosphate (OP) or chemical warfare nerve agent (CWNA) is of high demand both in civilian and military sectors. The rapid dangerous toxic effects of OP or CWNA exposure is primarily due to the irreversible inhibition of the abundant cholinergic enzyme, acetylcholinesterase (AChE) which is present in both central and peripheral nervous systems (Aldridge and Davison, 1953; Bajgar, 2004; Flynn and Wecker, 1986). The irreversible inhibition of AChE, which catabolizes the major neurotransmitter acetylcholine (ACh), can lead to the accumulation of ACh in the nervous system resulting in cholinergic crisis (Aldridge and Davison, 1953; Flynn and Wecker, 1986).

    • In vitro efficacy of paraoxonase 1 from multiple sources against various organophosphates

      2011, Toxicology in Vitro
      Citation Excerpt :

      The primary mode of action of various organophosphates (OPs) and chemical warfare nerve agents (CWNAs) is irreversible inhibition of the enzyme acetylcholinesterase (AChE) both in central and peripheral nervous systems (Aldridge and Davison, 1953; Shih et al., 2005). Accumulation of acetylcholine (ACh) leads to hypercholinergy, seizure, neuropathology and neurobehavioral deficits (Bajgar, 2004; Flynn and Wecker, 1986). The current treatment for OPs and CWNAs consist of a regimen of atropine, a muscarinic ACh receptor antagonist to counteract accumulation of ACh, 2-pralidoxime to reactivate OP-inhibited AChE, and benzodiazepines to treat seizures (Kadriu et al., 2009; Koplovitz and Stewart, 1994; Shih et al., 2007; Worek et al., 1996).

    • Recombinant paraoxonase 1 protects against sarin and soman toxicity following microinstillation inhalation exposure in guinea pigs

      2011, Toxicology Letters
      Citation Excerpt :

      It can hydrolyze large amounts of OPs and CWNAs compared to the stoichiometric bioscavenger human butyrylcholinesterase (BChE), which acts in a 1:1 ratio, and would thus require smaller doses and would reduce the cost of treatment (Doctor et al., 1991; Doctor and Saxena, 2005; Lenz et al., 2005; Lenz et al., 2007; Rochu et al., 2007). The mechanism of action of OPs and CWNAs has been well described as the irreversible inhibition of acetylcholinesterase (AChE) in the central and peripheral nervous system leading to abnormal accumulation of acetylcholine resulting in overstimulation of cholinergic transmission (Aldridge and Davison, 1953; Bajgar, 2004; Flynn and Wecker, 1986). An effective countermeasure strategy for OP and CWNA toxicity has been centered on the development of catalytic bioscavenger enzymes as pretreatments which can rapidly hydrolyze large amounts of OPs and CWNAs in the blood before they reach their targets.

    • Protective efficacy of catalytic bioscavenger, paraoxonase 1 against sarin and soman exposure in guinea pigs

      2011, Biochemical Pharmacology
      Citation Excerpt :

      Chemical warfare nerve agents (CWNAs) and organophosphate (OP) pesticides exert their biological effects mainly by the irreversible inhibition of acetylcholinesterase (AChE), an enzyme involved in the catabolism of neurotransmitter acetylcholine (ACh) [1–3].

    View all citing articles on Scopus
    View full text