OK, you Kv fundis, I NEED HELP PLEASE!
@rtwombly
@locoyeti
@cdog
@jazz (as overall super-scientist!)
....anyone else guys???
@benryu has seemingly "gone" unfortunately.
And yes, this may be a bit step-by-step tedious, but you know me by now. I need to be "sequential" and "pedantic" due to my birth in the old days, half a century ago when "Tweets" came from birds, etc.
Disclaimer: First up, on all this I stuff I may be totally wrong and out to lunch - so please correct me if that is the case. I knew zero about neuro-molecular dynamics some months ago. Don't be shy!!!
So what I am trying to figure out is if Keppra is similar enough to AUT00063 or even Retigabine in action, to be a potential (and safer) Tinnitus drug worthy of trial. Due to prior false hopes when discovering that a 'correct looking' Kv drug "X" was an anatgonist (suppressor) instead of an agonist (activator), I wanted to make sure Keppra and Retigabine at least were in the same camp with
that essential action. *[By the way, can one only use "agonist" and "antagonist" with neurotransmitters from the synaptic clefts??? Or is it OK to use the terms with ionic stuff like K+, Na+, Ca+ etc.? In case not, I will switch to "activation" and "inhibition" henceforth in their stead].
Some introductory reminder phrases may be of help here, (key note points, to me = in blue/bold):
Excitation or inhibition of the membrane.....
Whether excitation or inhibition occurs depends on what chemical served as the neurotransmitter and the result that it had. For example, if the neurotransmitter causes the Na+ channels to open, the neuron membrane becomes depolarized, and the impulse is carried through that neuron. If the K+ channels open, the neuron membrane becomes hyperpolarized, and inhibition occurs. The impulse is stopped dead if an action potential cannot be generated.
Retigabine action…(Potassium channel opener!)..... A novel class of drugs – potassium (Kþ) channel openers or activators – has recently been shown to cause anticonvulsive and neuroprotective effects by activating hyperpolarizing Kþ currents, and therefore, may show efficacy for treating tinnitus.
In my simple English, if Retigabine is an "activator" and "door kicker" to the hyperpolarization state (wherein 'inhibition' occurs), I would then phrase the question thus: We want
opening of the K+ gates and elimination of the hypperpolarization state ~ which is the over-compensation calming condition that stops the neuron from reaching a new immediate resting potential, and thence the ability for subsequent depolarization and (another) action potential thereafter.
Ironically, in a certain way this sounds like a WTF???...We want
more "activation"??? We want to "un-inhibit" the neuron so that it can reach action potential, depolarize, and fire again more easily??? But hell isn't tinnitus an "over-firing" condition that does not stop? Etc., etc., etc.
But let's not go there here, as indeed our basic premise with Retigabine and the Kv7 and Kv3 (presumably) scene, is that we want the "stuck gates" re-opened and the K+ ions to flow again. My old "kick the doors down" analogy.
So in one word, we want ACTIVATION of Kv channel, not INHIBITION....Right?????
OK, if I am correct, then look at
Keppra...
Hah! If you can. The definitive study seems to be the one out of Tiawan, and maybe the Tiawanese have a thing for complex English, but I just plain cannot follow what the hell they are talking about. The Retigabine studies were all
much easier for me to put together and understand to a fairly reasonable degree. Here's the main reference link:
http://www.jpp.krakow.pl/journal/archive/12_09/pdf/37_12_09_article.pdf
*[Unfortunately I have not found it yet in non pdf format, so it's a pain in the arse to cut and paste as formatting goes to hell. I have had to re-do all this next stuff below manually].
Tah dah!...And the initial, introductory simple summary, is:
Levetiracetam (LEV) is an S-enantiomer pyrrolidone derivative with established antiepileptic efficacy in generalized epilepsy and partial epilepsy. However, its effects on ion currents and membrane potential remain largely unclear. We investigated the effect of LEV on differentiated NG108-15 neurons. In these cells treated with dibutyryl cyclic AMP, the expression level of the KV3.1 mRNA was elevated. With the aid of patch clamp technology, we found that LEV could suppress the amplitude of delayed rectifier K+ current (IK(DR)) in a concentration-dependent manner with an IC50 value of 37 µM. LEV (30 µM) shifted the steady-state activation of IK(DR) to a more positive potential by 10 mV, without shifting the steady-state inactivation of IK(DR). Neither Na+, nor erg (ether-a-go-go-related)-mediated K+ and ATP-sensitive K+ currents were affected by LEV (100 µM). LEV increased the duration of action potentials in current clamp configuration. Simulation studies in a modified Hodgkin-Huxley neuron and network unraveled that the reduction of slowly inactivating IK(DR) resulted in membrane depolarization accompanied by termination of the firing of action potentials in a stochastic manner. Therefore, the inhibitory effects on slowly inactivating IK(DR) (KV3.1-encoded current) may constitute one of the underlying mechanisms through which LEV affect neuronal activity in vivo.
I mean??? Maybe I am just dumbed down or something, but in one place it sounds like LEV may be an "activator" and in another an "inhibitor"! And looking through the main text was equally frustrating.
Here's a few snippets....
...Another report suggested the inhibition of voltage-operated potassium current by LEV, as an antiepileptic mechanism.
...Voltage-gated K+ (KV) channels play a major role in determining the excitability of neurons. These channels are responsible for setting the resting potential, repolarizing membranes during action potentials, regulating action potential duration and frequency (15). Among them, delayed rectifiers are ubiquitous in neurons. In fast-spiking neurons, a causal relationship between KV3, especially KV3.1, and the delayed rectifier K+ current (IK(DR)), has now been well established.
So does LEV enhance or suppress Kv3.1 and/or the "delayed rectification"?????
The explanation for Fig.10 (below) may help, as I thought I was getting closer to an answer...but then lost it again!
View attachment 4145
*See the text for the explanation - maybe you brighter wickets can "get it"!
OK, nearly there! Here is an extract of the final summary at the end of the paper:
...The major findings of this study are as follows. First, in differentiated NG108-15 neuronal cells, LEV inhibited the amplitude of IK(DR) in a concentration-dependent manner. Second, LEV could produce a depolarized shift in the steadystate activation curve of IK(DR). Third, neither INa nor IK(erg) was affected after application of LEV. Fourth, LEV could prolong the duration of APs in these cells. Fifth, the simulation model predicted that the decreased conductance of IK(DR) with a depolarized shift in activation curve of IK(DR), which reflected the LEV action, could terminate the firing of APs in modeled neurons and in a simulated network of neurons with HH kinetics. Taken together, the inhibition by LEV of IK(DR) can be one of the ion mechanisms underlying LEV-induced change in functional activity of neurons.
Once again, it seemed to me that I could read into this any which way, as either an "inhibitor" or an "activator". Maybe you can see the "truth"?! If so PLEASE TELL ME IN SIMPLE ENGLISH...Maybe the original Chinese would have been as good to me!
Take care, and hoping for some "enlightenment" here....Thanks!
Zimichael
again...and good work @Viking! I will be watching your input closely as this could be a much safer route than Trobalt, though my gut sense is it may not be quite as "potent" on tinnitus. I hope I'm wrong.
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