Influence of nerve‐ending activity and of drugs on the rate of paralysis of rat diaphragm preparation by <i>Cl. botulinum</i> type A toxin

Hughes, R.; Whaler, B. C.

doi:10.1113/jphysiol.1962.sp006843

Cited by 154 publications

(80 citation statements)

References 12 publications

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“…The frequency of nerve stimulation markedly affects the rate of action of botulinum toxin (Hughes & Whaler, 1962) and taipoxin (Kamenskaya & Thesleff, 1974). The P-C complex showed no such dependency as increasing the rate of stimulation 40-fold from 0.05 Hz to 2 Hz had no significant effect on the rate of block produced by either 2.3 ,ug/ml or by 15 ,ug/ml P-C complex in 6 experiments.…”

Section: Resultsmentioning

confidence: 90%

The Mode of Action at the Mouse Neuromuscular Junction of the Phospholipase A‐crotapotin Complex Isolated From Venom of the South American Rattlesnake

Hawgood

Smith

1977

British J Pharmacology

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I Phospholipase A2-crotapotin complex (P-C complex) isolated from the venom of Crotalus durissus terrificus induced an irreversible blockade of neuromuscular transmission when twitch tension was measured in the mouse phrenic nerve-hemidiaphragm preparation in vitro at 370C. 2 A similar concentration of the phospholipase A2 (10 jig/ml) alone did not affect neuromuscular transmission and no priming action was detected on later addition of crotapotin. 3 The rate of neuromuscular blockade induced by P-C complex (15,g/ml) was not altered by raising the frequency of nerve stimulation. Lower temperatures markedly increased the time of onset and reduced the rate of blockade (Qlo (27-37°C) of 4.4) whilst replacement of Ca by Sr in the medium prevented this activity. These latter results suggest that enzymatic activity is important iin the neurotoxicity of the complex. 4 A myotoxic action was shown by 30 gg/ml P-C complex and 30 gg/ml phospholipase A2.S P-C complex (150 jg) was injected into the tail vein of mice and the intoxicated hemidiaphragm preparation removed for intracellular recording at 250 C. 6 In fully intoxicated hemidiaphragms, resting membrane potentials were unaltered and endplate potentials (e.p.ps) varied in average amplitude from zero to less than 3 mV. 7 Miniature endplate potential (m.e.p.p.) frequency was lower at fully poisoned endplates than at controls; the frequency rose during a 50 Hz tetanus but was unaffected by either raising external K or the application ofthe Ca-ionophore A23 187. 8 E.p.ps were recorded in partially intoxicated hemidiaphragms with (+)-tubocurarine (0.5-1.0 gg/ml) added to prevent contraction. Evoked release was abnormal as 50 Hz tetanus elicited e.p.ps of very variable amplitude, no facilitation of response was shown to paired stimuli, and tetraethylammonium (0.5 mM) failed to increase e.p.p. amplitudes. 9 M.e.p.ps and e.p.ps were recorded at partially poisoned endplates in low Ca-high Mg solution. A reduction in the quantal content of evoked transmitter release was observed in comparison with controls. 10 M.e.p.ps recorded at partially and at fully intoxicated endplates showed an altered amplitude distribution with a higher proportion of large potentials. 11 It is concluded that P-C complex has a presynaptic site of action and may interfere with depolarization -secretion coupling at the motor nerve terminals.

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Section: Resultsmentioning

confidence: 90%

The Mode of Action at the Mouse Neuromuscular Junction of the Phospholipase A‐crotapotin Complex Isolated From Venom of the South American Rattlesnake

Hawgood

Smith

1977

British J Pharmacology

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“…botulinum toxin in vitro; Burgen et al, 1949). However it is known that the presynaptic blocking effects of botulinum toxin and /3-bungarotoxin are partially dependent upon the frequency of nerve activity (Hughes & Whaler, 1962;Lee & Chang, 1966;Simpson, 1971), and this may be true for Tiger snake toxin. It is also of interest that 83-bungarotoxin, in contrast to Tiger snake toxin, first causes an increase in m.e.p.p.…”

Section: Discussionmentioning

confidence: 99%

Effects of an isolated toxin from Australian Tiger snake (Notechis scutatus scutatus) venom at the mammalian neuromuscular junction

Harris

Karlsson

Thesleff

1973

British J Pharmacology

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Summary The acute effects of a purified toxin from Australian Tiger snake (Notechis scutatus scutatus) venom have been investigated at the mammalian neuromuscular junction. The toxin was injected into the tail vein of mice. Death was due to respiratory paralysis. The resting membrane potential, and action potential of muscle fibres in muscles from in vivo intoxicated animals were normal. The frequency of miniature end plate potentials (m.e.p.p.s) from intoxicated nerve‐muscle preparations was reduced, although m.e.p.p. amplitude was unaltered. Nerve stimulation resulted in end plate potentials (e.p.p.s) of quantal amplitude; only rarely was the e.p.p. large enough to give rise to an action potential. High (20 mm) K+ did not increase m.e.p.p. frequency in intoxicated preparations. The toxin was largely ineffective in vitro. The similarities and differences between this toxin, β‐bungarotoxin and botulinum toxin are discussed.

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“…However, the clostridial toxins botulinum neurotoxin A and tetanus neurotoxin both share sites of action with LEV, entering vesicles by binding to SV2 within the vesicle lumen (Dong et al 2006;Yeh et al 2010). Botulinum neurotoxin A seems to exhibit a latency before effect, which is shortened when neurotransmitter release is stimulated (Hughes and Whaler 1962). Similarly, staining for tetanus neurotoxin demonstrates that its activity-dependent entry into nerve terminals resembles LEV (Yeh et al 2010).…”

Section: Synaptic Activity Modulates the Efficacy Of Levmentioning

confidence: 99%

A new mechanism for antiepileptic drug action: vesicular entry may mediate the effects of levetiracetam

Meehan¹,

Yang²,

McAdams³

et al. 2011

Journal of Neurophysiology

114

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A new mechanism for antiepileptic drug action: vesicular entry may mediate the effects of levetiracetam. J Neurophysiol 106: 1227-1239, 2011. First published June 8, 2011 doi:10.1152/jn.00279.2011 is one of the most commonly prescribed antiepileptic drugs, but its mechanism of action is uncertain. Based on prior information that LEV binds to the vesicular protein synaptic vesicle protein 2A and reduces presynaptic neurotransmitter release, we wanted to more rigorously characterize its effect on transmitter release and explain the requirement for a prolonged incubation period for its full effect to manifest. During whole cell patch recordings from rat hippocampal pyramidal neurons in vitro, we found that LEV decreased synaptic currents in a frequency-dependent manner and reduced the readily releasable pool of vesicles. When we manipulated spontaneous activity and stimulation paradigms, we found that synaptic activity during LEV incubation alters the time at which LEV's effect appears, as well as its magnitude. We believe that synaptic activity and concomitant vesicular release allow LEV to enter recycling vesicles to reach its binding site, synaptic vesicle protein 2A. In support of this hypothesis, a vesicular "load-unload" protocol using hypertonic sucrose in the presence of LEV quickly induced LEV's effect. The effect rapidly disappeared after unloading in the absence of LEV. These findings are compatible with LEV acting at an intravesicular binding site to modulate the release of transmitter and with its most marked effect on rapidly discharging neurons. Our results identify a unique neurobiological explanation for LEV's highly selective antiepileptic effect and suggest that synaptic vesicle proteins might be appropriate targets for the development of other neuroactive drugs.epilepsy; synaptic vesicle protein 2A; synaptic vesicle release; hippocampal slice LEVETIRACETAM (LEV) IS AN antiepileptic drug (AED) with a unique mode of action and efficacy against focal and generalized seizures. The exact mechanism by which this drug reduces seizures is still under investigation. LEV does not inhibit voltage-gated Na ϩ channels (Zona et al. 2001), nor does it modulate GABA receptors (Margineanu and Klitgaard 2003), two common AED mechanisms. It is established that LEV binds to a presynaptic protein, synaptic vesicle protein 2A (SV2A), located in the membrane of synaptic vesicles (Lynch et al. 2004). The precise function of SV2A is also unknown, but studies of cultured neurons from SV2A knockout mice show a reduced postsynaptic response, due to a lower initial vesicle release probability (Custer et al. 2006) and a decrease in the total amount of neurotransmitter release during a stimulus train compared with controls (Chang and Sudhof 2009).Because SV2A plays a modulatory, but not essential, role in neurotransmission, it is unclear how a ligand binding to SV2A might alter neurotransmitter release.The cellular mechanism of action of LEV remains paradoxical. While it seems to do nothing to normal synaptic transmission, i...

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Influence of nerve‐ending activity and of drugs on the rate of paralysis of rat diaphragm preparation by Cl. botulinum type A toxin

Cited by 154 publications

References 12 publications

The Mode of Action at the Mouse Neuromuscular Junction of the Phospholipase A‐crotapotin Complex Isolated From Venom of the South American Rattlesnake

The Mode of Action at the Mouse Neuromuscular Junction of the Phospholipase A‐crotapotin Complex Isolated From Venom of the South American Rattlesnake

Effects of an isolated toxin from Australian Tiger snake (Notechis scutatus scutatus) venom at the mammalian neuromuscular junction

A new mechanism for antiepileptic drug action: vesicular entry may mediate the effects of levetiracetam

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