Modification of cholinergically induced convulsive activity and cyclic GMP levels in the CNS

Lundy, Paul M.; Shaw, Roger

doi:10.1016/0028-3908(83)90260-5

Cited by 47 publications

(18 citation statements)

References 37 publications

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“…At these doses, brain cholinesterase was inhibited 65-90% by GB or DFP (VanMeter et al, 1978). An estimate of cholinesterase inhibition greater than 60% for the onset of seizures is consistent with that estimated as the threshold for GD-induced behavioral convulsions, 60-70% in mouse (Lundy and Frew, 1984) and 90% in rats (Lundy & Shaw, 1983). Earlier investigators had estimated greater levels of ChE depression at convulsive doses ; the differences may be attributable to -differences in methodological sensitivity.…”

Section: Effects Of Gd and Other Anticholinesterases On Eeg Activitysupporting

confidence: 75%

Neurobiology of Acetylcholine

Dun¹,

Perlman²,

Karczmar³

1987

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Section: Effects Of Gd and Other Anticholinesterases On Eeg Activitysupporting

confidence: 75%

Neurobiology of Acetylcholine

Dun¹,

Perlman²,

Karczmar³

1987

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“…Oxime effects at the central nervous system level, following cerebral AChE reactivation, have been intensely and controversially discussed (Bajgar, 2004;Lundy and Shaw, 1983;Lundy et al, 2006). Oximes, in first instance, due to their polar quaternary ammonium-based chemical structure, are far from fulfilling the minimum conditions requested for BBB penetration at an efficient concentration level.…”

Section: Discussionmentioning

confidence: 99%

“…It exhibits beneficial effects in soman intoxication, but no correlations with the cerebral AChE reactivation and the anticonvulsant effect have been reported (Lundy and Shih, 1983;Lundy and Shaw, 1983;van Helden et al, 1994van Helden et al, , 1996.…”

Section: Ache Reactivation In Various Cerebral Areasmentioning

confidence: 95%

Pharmacokinetics and pharmacodynamics of some oximes and associated therapeutic consequences: a critical review

Voicu

Bajgar

Medvedovici

et al. 2010

J of Applied Toxicology

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Undoubtedly, the use of oximes represents real progress in counteracting intoxications with organophosphates (OP), through potentiating antidotal effects of atropine. The penetration extent of these compounds through the blood-brain barrier (BBB) to significantly reactivate phosphorylated or phosphonylated acetylcholinesterase (AChE) in the brain still remains a debatable issue. Penetration of biological barriers by oximes was investigated mainly through determination of several quantitative parameters characterizing digestive absorption and BBB penetration. A weak penetration of biological barriers could be concluded from the available experimental data. The functional parameters/therapeutic effects following the penetration of oximes through BBB, more precisely the antagonism of OP-induced seizures and hypothermia, prevention of brain damage and respiratory center protection, leading to the final end-point, the survival of intoxicated organisms, are of high interest. It seems obvious that oximes are weakly penetrating the BBB, with minimal brain AChE reactivation (<5%) in important functional areas, such as the ponto-medullar. The cerebral protection achieved through administration of oximes is only partial, without major impact on the antagonism of OP-induced seizures, hypothermia and respiratory center inhibition. The antidotal effects probably result from synergic effects of other PD properties, different from the brain AChE reactivation process. Oxime structures especially designed for enhanced BBB penetration, through potentiating the hydrophobic characteristics, more often produce neurotoxic effects. Certainly, obtaining oximes with broad action spectrum (active against all OP types) would make a sense, but certainly, such a target is not achievable only through the increase in their penetrability in the brain.

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“…Moreover, it is known that the blood-brain barrier becomes more permeable during organophosphate-induced convulsive activity (Ashani and Catravas 1981), but whether this happens to an equal extent in both sexes has not been determined. The low levels of HI-6 in brain found in the present study suggest the contribution by HI-6 to protection against soman poisoning, through its central activity is limited (Lundy and Shaw 1983). In addition, it is of interest to note that soman-induced convulsions failed to result in additional concentrations of [14C] HI-6 in the brains of either sex, as might be predicted if the blood-brain barrier became more permeable.…”

Section: Discussionmentioning

confidence: 85%

Distribution of the bispyridinium oxime [14C] HI-6 in male and female rats

Lundy¹,

Hand²,

Broxup³

et al. 1990

Arch Toxicol

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Female rats poisoned with multiple LD50s of soman or tabun have been shown previously to respond to the protective effects of HI-6 more positively than male rats. This present study was designed first to determine the distribution pattern and concentration of [14C] HI-6 in rats, and secondly, to determine the possibility that HI-6 might be located in high concentrations in critical tissues in the female as opposed to the male. To these ends, [14C] HI-6 was administered to groups of male and female rats and its radiolabelled distribution determined by whole body autoradiography and/or by measurement of its actual concentration, by scintillation spectrometry. The experiments were repeated in the presence of 2 x LD50 soman and supporting therapy with atropine. In both sexes, HI-6 levels were highest in the kidney, followed in order by cartilage greater than plasma greater than liver greater than heart greater than or equal to lung greater than or equal to diaphragm greater than brain and spinal cord. The relative distribution in the two sexes was confirmed by both methods and was not significantly altered in the presence of soman and atropine. The lack of a measurable difference in tissue distribution of [14C] HI-6 derived radioactivity between males and females suggested that the hormone-dependent difference in the protective effects previously observed was not due to selective accumulation of [14C] HI-6 in organs believed to be important in its therapeutic activity, such as brain or diaphragm.

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Modification of cholinergically induced convulsive activity and cyclic GMP levels in the CNS

Cited by 47 publications

References 37 publications

Neurobiology of Acetylcholine

Neurobiology of Acetylcholine

Pharmacokinetics and pharmacodynamics of some oximes and associated therapeutic consequences: a critical review

Distribution of the bispyridinium oxime [14C] HI-6 in male and female rats

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