Inhibition of TBPS binding probably also plays a role in its anxiolysis:
Pharmacological profile of an essential oil derived from Melissa officinalis with anti-agitation properties: focus on ligand-gated channels.
A dual radioligand binding and electrophysiological study, focusing on a range of ligand-gated ion channels, was performed with a chemically-validated essential oil derived from Melissa officinalis (MO), which has shown clinical benefit in treating agitation. MO inhibited binding of [35S] t-butylbicyclophosphorothionate (TBPS) to the rat forebrain gamma-aminobutyric acid (GABA)(A) receptor channel (apparent IC50 0.040+/-0.001 mg mL(-1)), but had no effect on N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropianate (AMPA) or nicotinic acetylcholine receptors. Electrophysiological analyses with primary cultures of rat cortical neurons demonstrated that MO reversibly inhibited GABA-induced currents in a concentration-dependent manner (0.01-1 mg mL(-1)), whereas no inhibition of NMDA- or AMPA-induced currents was noted. Interestingly, MO elicited a significant dose-dependent reduction in both inhibitory and excitatory transmission, with a net depressant effect on neurotransmission (in contrast to the classical GABA(A) antagonist picrotoxinin which evoked profound epileptiform burst firing in these cells). The anti-agitation effects in patients and the depressant effects of MO in in-vitro we report in neural membranes are unlikely to reflect a sedative interaction with any of the ionotropic receptors examined here.
On the importance of TBPS:
"35S-TBPS binding is a sensitive index of the function of the GABAergic synapses. Since TBPS inhibits the GABAergic neurotransmission by a direct blockage of the GABA-gated chloride channels, the inhibition of 35S-TBPS binding to the chloride channel by these anxiolytic drugs implies an increased ability to generate chloride current, resulting in enhanced function of the GABAergic synapses." [Anxiety: psychobiological and clinical perspectives]
I'm a little confused by the results (italicized) concerning inhibition of GABA-induced currents at certain doses. From what I can tell, most anxiolytics enhance the Cl current. Does this imply that part of MO's MOA is having an effect detrimental to GABA enhancement (though the net effect is still depressant)? And might this be the reason it's only a "weak" anxiolytic?
Also of note is that MO exhibits radical-scavenging properties (
19760174).
Edited by chrono, 25 September 2010 - 10:32 AM.
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