Dibenzylamine - a novel blocker of the voltage-dependent K + current in myocardial mouse cells

Doepner, Bettina; Koopmann, R.; Knopp, Andreas; Hirche, Hans-Jürgen; Benndorf, Klaus

doi:10.1007/s002100100406

Cited by 4 publications

(3 citation statements)

References 20 publications

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“…DBA mediates effects thought previously to be attributable to DL-BHB blockade of cardiac K ϩ channels and anticonvulsive actions of ketone bodies (Doepner et al, 1997(Doepner et al, , 2001Rho et al, 2002;Donevan et al, 2003). Investigations using DL-BHB must take this parameter into account.…”

Section: Discussionmentioning

confidence: 99%

Depolarizing Actions of GABA in Immature Neurons Depend Neither on Ketone Bodies Nor on Pyruvate

Tyzio¹,

Allène²,

Nardou³

et al. 2011

J. Neurosci.

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Section: Discussionmentioning

confidence: 99%

Depolarizing Actions of GABA in Immature Neurons Depend Neither on Ketone Bodies Nor on Pyruvate

Tyzio¹,

Allène²,

Nardou³

et al. 2011

J. Neurosci.

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“…This possibility, however, has yet to be confirmed. Doepner et al (23) recently demonstrated that DBA blocked voltage‐dependent K + currents in mouse cardiac myocytes, specifically inhibiting the slow component of the recovery from inactivation.…”

Section: Discussionmentioning

confidence: 99%

Voltage‐Dependent Block of N‐Methyl‐d‐Aspartate Receptors by the Novel Anticonvulsant Dibenzylamine, a Bioactive Constituent of l‐(+)‐β‐Hydroxybutyrate

et al. 2003

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Summary:Purpose: Previously we demonstrated that L-(+)-β-hydroxybutyrate (L-BHB), acetoacetate (ACA), acetone, and dibenzylamine (DBA) were anticonvulsant in an audiogenic seizure-susceptible model, and that DBA was a bioactive contaminant identified in commercial lots of L-BHB. In the present study, we asked whether these effects could be mediated by ionotropic glutamate or γ -aminobutyric acid A (GABA A ) receptors.Methods: We studied the effects of both stereoisomers of BHB (as well as the racemate), ACA, and DBA on N-methyl-Daspartate (NMDA), α-amino-3-hydroxy-5methyl-4-isoxazoleproprionic acid (AMPA), and GABA A receptors in cultured rodent neocortical neurons by using whole-cell voltage-clamp recording techniques.Results: Only L-BHB and DBA exerted a concentration-and voltage-dependent block of NMDA-evoked currents, whereas none of the tested substrates affected AMPA-or GABA-activated currents. The kinetics of whole-cell block by L-BHB and DBA were similar, providing additional evidence that DBA is responsible for the anticonvulsant activity of L-BHB.

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“…Interestingly, earlier studies had shown the presence of a contaminant dibenzylamine in some BHB sources that act on various channels that appears to mediate the actions thought to be mediated by BHB (Doepner et al., 1997, 2001; Rho et al., 2002; Donevan et al., 2003) raising strong concern as to the reliability of conclusions derived from BHB experiments. We discovered that one of the BHB sources used in the laboratory (Acros Organics) indeed contained this contaminant and showed that this efficiently altered DF GABA and corresponding brain patterns as viewed with our imaging techniques.…”

Section: The Developmental Gaba Actions Shift Is Not Conditioned By Amentioning

confidence: 99%

Excitatory action of GABA on immature neurons is not due to absence of ketone bodies metabolites or other energy substrates

2011

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SUMMARYBrain slices incubated with glucose have provided most of our knowledge on cellular, synaptic, and network driven mechanisms. It has been recently suggested that c-aminobutyric acid (GABA) excites neonatal neurons in conventional glucose-perfused slices but not when ketone bodies metabolites, pyruvate, and/or lactate are added, suggesting that the excitatory actions of GABA are due to energy deprivation when glucose is the sole energy source. In this article, we review the vast number of studies that show that slices are not energy deprived in glucose-containing medium, and that addition of other energy substrates at physiologic concentrations does not alter the excitatory actions of GABA on neonatal neurons. In contrast, lactate, like other weak acids, can produce an intracellular acidification that will cause a reduction of intracellular chloride and a shift of GABA actions. The effects of high concentrations of lactate, and particularly of pyruvate (4-5 mM), as used are relevant primarily to pathologic conditions; these concentrations not being found in the brain in normal ''control'' conditions. Slices in glucose-containing medium may not be ideal, but additional energy substrates neither correspond to physiologic conditions nor alter GABA actions. In keeping with extensive observations in a wide range of animal species and brain structures, GABA depolarizes immature neurons and the reduction of the intracellular concentration of chloride ([Cl ) ] i ) is a basic property of brain maturation that has been preserved throughout evolution. In addition, this developmental sequence has important clinical implications, notably concerning the higher incidence of seizures early in life and their long-lasting deleterious sequels. Immature neurons have difficulties exporting chloride that accumulates during seizures, leading to permanent increase of [Cl ) ] i that converts the inhibitory actions of GABA to excitatory and hampers the efficacy of GABA-acting antiepileptic drugs.

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Dibenzylamine - a novel blocker of the voltage-dependent K + current in myocardial mouse cells

Cited by 4 publications

References 20 publications

Depolarizing Actions of GABA in Immature Neurons Depend Neither on Ketone Bodies Nor on Pyruvate

Depolarizing Actions of GABA in Immature Neurons Depend Neither on Ketone Bodies Nor on Pyruvate

Voltage‐Dependent Block of N‐Methyl‐d‐Aspartate Receptors by the Novel Anticonvulsant Dibenzylamine, a Bioactive Constituent of l‐(+)‐β‐Hydroxybutyrate

Excitatory action of GABA on immature neurons is not due to absence of ketone bodies metabolites or other energy substrates

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