Hyperforin effects on GABA

[dzaocom]

Hello. I'm interested how St.John's wort main alkaloid hyperforin affects GABA concentration in body. Wikipedia says that hyperforin inhibits GABA reuptake so that definitely increases GABA concentration, but at the same time it antagonizes GABA receptor that decreases GABA concentration (which I don't understand how it does, by what mechanism). So if hyperforin is responsible for both of this processes, than what is the outcome? Is overall GABA concentration increased or decreased with hyperforin? Thanks.

 

[neurotic]

in theory, an antagonist wouldn't reduce the concentration of a neurotransmitter, but rather prevent it from activating the receptors that are being antagonized

 

[dzaocom]

in theory, an antagonist wouldn't reduce the concentration of a neurotransmitter, but rather prevent it from activating the receptors that are being antagonized

So certain receptor sites of GABA are antagonized by hyperforin. And if GABA can't activate the receptors that are antagonized, then it doesn't matter if GABA reuptake is inhibited or no. But the receptor sites which aren't antagonized can be altered by reuptake inhibition and increase Cl ion flow right?

 

[dopamimetic]

It depends on the particular system & genetics. There are always downstream mechanisms.. so by antagonizing a receptor, it might give rise to up regulation. Also because the transmission is blocked, there could be more output of the transmitter..

Reuptake inhibition coupled with antagonism could in a simple picture cancel out each other. So possibly it does slightly increase overall GABA transmission w/o strong tolerance development.. but without studies this is pure guessing.

 

[belligerent drunk]

You have to remember that it's all in dynamic motion. An antagonist does block the receptor, but it doesn't block it completely, unless in very high concentrations. GABA still binds and activates the receptor, otherwise you'd be dead, so as per normal its concentration affects how much the receptor is activated. So by inhibiting reuptake and thus increasing GABA concentration, you increase GABA-mediated activation and by (partially) blocking the site, you decrease it. Which effect is stronger, as in whether the net effect is incease or decrease in channel opening, is impossible to tell without experimental data.

 

[dzaocom]

Thanks for answers. Same problem arises with glutamate and NMDA receptor. Hyperforin also inhibits glutamate reuptake with much higher quantities than other monoamines, but at the same time antagonizes NMDA receptor. Glutamate acts as NMDA agonist so here's another problem. Maybe reuptake inhibition of glutamate is much stronger than binding affinity of hyperforin to NMDA receptor. What do you think about this?

 

[belligerent drunk]

It is close to impossible to tell theoretically with a certain degree of certainty. You need to know the binding affinity of hyperforin for the NMDA receptor and also the extent of reuptake inhibition, both of which need to be done experimentally. I haven't explored the literature on this subject, but you may find something if you browse articles regarding these aspects.

 

[dopamimetic]

Without the data, you can't say anything... if it's stronger at glutamate reuptake inhibition than at NMDA antagonism, it will be a glutamatergic (with more pronounced AMPA action than NMDA because of the partial NMDA antagonism), otherwise it will behave slightly dissociative / anti-excitatory.

Edit: belligerent drunk, you were faster

But hyperforin looks really promising thinking of all it's divergent activities.. Anyone sampled pure hyperforin yet?

 

[Nagelfar]

in theory, an antagonist wouldn't reduce the concentration of a neurotransmitter, but rather prevent it from activating the receptors that are being antagonized

Many inverse agonists are referred to, even in literature, as antagonists; and thus get confused with neutral antagonists, are we sure we're not speaking of inverse agonism in this instance?

 

[belligerent drunk]

Many inverse agonists are referred to, even in literature, as antagonists; and thus get confused with neutral antagonists, are we sure we're not speaking of inverse agonism in this instance?

http://www.ingentaconnect.com/content/ben/cmc/2010/00000017/00000005/art00001

Hyperforin (10 μM) has antagonistic effects on NMDA receptors, inhibiting the NMDA-induced calcium influx into cortical neurons [66]. NMDA-induced choline (Ch) release is dependent not just on calcium influx but also on phospholipase A2 activation, which can lead to phospholipid hydrolysis and membrane breakdown [67]. In rat hippocampal slices, hyperforin was able to completely abolish NMDA-induced Ch release from phospholipids. The ability of hyperforin to inhibit NMDA-induced Ch release indicates it possesses protective effects on membrane phospholipids. Interesting enough, hyperforin has been shown to have effects on the fluidity of the plasma membrane [68, 69]. Furthermore, hyperforin (3 μM) was also able to prevent NMDA-induced water gain by 39% [66]. Hyperforin’s antagonistic effects on this receptor, though the exact mechanism remains unknown, may aid in preventing harmful processes under excitotoxic condition

According to this wording, I think hyperforin should be a neutral antagonist rather than an inverse agonist. Also, this and some other studies suggest that hyperforin has antidepressant and neuroprotective properties thanks to its NMDA antagonism, suggesting that its antagonism is stronger than reuptake inhibition of NMDA, so there's one answer to your question.