Retigabine (Trobalt, Potiga) — General Discussion
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On a sidenote: a tinnitus specialist in Germany (I was refered to him by acclaimed Dr. Dirk De Ridder himself) told me that they know about Retigabin and he sees Trobalt as a legit offlabel-medication option.
He also told me that they had good experiences with Cyclobenzaprin 10-30mg (flexeril)
There are some threads on this board about it.
I dont think that a muscle relaxant/pain blocker will help with severe brain-T
Maybe so...But Autifony are coming out soon and it will be nuclear war on tinnitus...
"Soon" - people with most extreme T probably arent gonna be around for that.
Dont be too sure about that, we dont even know about the results. Spreading hope like that is cruel in case it´s gonna be a bust. But yeah, I would like for it to work.
Just tone down the "cure" shoutings a bit. You once wrote that it´s a shame that gaby killed herself because Trobalt would have cured her...a definitive statement.
Im sure I have at least a gaby grade tinnitus and im almost on 400mg at once and nothing (beside that one time thing) is happening beside some side effects, so it is far away from a cure. But I hope you will prove me wrong when im on 3x400...I wont try it longer than a month when there is not the slightest sign of relief or more milder days.
Dont be too sure about that, we dont even know about the results. Spreading hope like that is cruel in case it´s gonna be a bust. But yeah, I would like for it to work.
Just tone down the "cure" shoutings a bit. You once wrote that it´s a shame that gaby killed herself because Trobalt would have cured her...a definitive statement.
Im sure I have at least a gaby grade tinnitus and im almost on 400mg at once and nothing (beside that one time thing) is happening beside some side effects, so it is far away from a cure. But I hope you will prove me wrong when im on 3x400...I wont try it longer than a month when there is not the slightest sign of relief or more milder days.
I wish I could tell you more...But sadly I can't. Why don't you try just one dose of 400mg? And see what it does? Can't hurt, surely? And by the way, her hyperacusis was destroying her, I said keppra could've cured her.
Yeah, just sayin...you´re doing your best here and it´s a good thing.
im 2-3 days away from 400mg so I will wait, taking the safer route.
im 2-3 days away from 400mg so I will wait, taking the safer route.
Man your going a bit fast imo ... I just arrived at 800 after 3 weeks ... but, yeah I don`t know anymore ... seems the usage has gone berserk and everyone is just following his own will and intention(me included ofcourse) ...
Can I prescibe it in Canada? Im thinking of going to my neurologist for Potiga and kreppa if I can since my Dr said "nothing he can do". All he did was give me certiosteriod nasal spray and ENT test the first week of diagnosing.
I got my T from compacted earwax or trimming my beard with a battery-powered buzzer and heard it in the shower for 5minute. The day after trimming, i trimmed some more and then went on my noisy fan laptop, it was then i felt the T constantly 4 months now. But i did shoot a pellet gun once a week before but i havent noticed anything the day I shot it. My eardrum was red and inflammed and hypersensitive, I also lost 20pounds drinking alot tea. Im trying to eat alot now since that might be a factor. I had antibiotic pills like 6 months before this im not sure if it had anything to do with T started 6 months later.
The ENT said I could get a cochlear implant but Ive read stories that it made T much worse so im holding back on that now.
I got my T from compacted earwax or trimming my beard with a battery-powered buzzer and heard it in the shower for 5minute. The day after trimming, i trimmed some more and then went on my noisy fan laptop, it was then i felt the T constantly 4 months now. But i did shoot a pellet gun once a week before but i havent noticed anything the day I shot it. My eardrum was red and inflammed and hypersensitive, I also lost 20pounds drinking alot tea. Im trying to eat alot now since that might be a factor. I had antibiotic pills like 6 months before this im not sure if it had anything to do with T started 6 months later.
The ENT said I could get a cochlear implant but Ive read stories that it made T much worse so im holding back on that now.
yes don`t do anything invasive ... T can arise weeks after the actual damage was done ... you describe with your shower and noise fan laptop just a continues backdrop to which the T sound suddenly became more apparent ... I used to have a Van ... was completely open ... even driving80mph the whole car was filled with noise ... base sound from the highway i could hear my T ... just because it created a steady backdrop to percieve it ...
if your healthy and fit the requirements to do Retigabine I would say go for it ...
yesterday took my first 400mg dose and this time something has changed ... my sounds has moves more central in the head and the high pitch has transformed into a hiss ... something uch more bearable ... the high pitch still wants to push through but something is blocking it ... let`s see what the rest of the day will bring ...
I have to go to work today at Tomorrowland! ... biggest dance-festival in the world ... just weaponed with my custom earplugs and heaps of retigabine ...
pray for me
Fuckin lucky!! Tomorrow land !yes don`t do anything invasive ... T can arise weeks after the actual damage was done ... you describe with your shower and noise fan laptop just a continues backdrop to which the T sound suddenly became more apparent ... I used to have a Van ... was completely open ... even driving80mph the whole car was filled with noise ... base sound from the highway i could hear my T ... just because it created a steady backdrop to percieve it ...
if your healthy and fit the requirements to do Retigabine I would say go for it ...
yesterday took my first 400mg dose and this time something has changed ... my sounds has moves more central in the head and the high pitch has transformed into a hiss ... something uch more bearable ... the high pitch still wants to push through but something is blocking it ... let`s see what the rest of the day will bring ...
I have to go to work today at Tomorrowland! ... biggest dance-festival in the world ... just weaponed with my custom earplugs and heaps of retigabine ...
pray for me
yes don`t do anything invasive ... T can arise weeks after the actual damage was done ... you describe with your shower and noise fan laptop just a continues backdrop to which the T sound suddenly became more apparent ... I used to have a Van ... was completely open ... even driving80mph the whole car was filled with noise ... base sound from the highway i could hear my T ... just because it created a steady backdrop to percieve it ...
if your healthy and fit the requirements to do Retigabine I would say go for it ...
yesterday took my first 400mg dose and this time something has changed ... my sounds has moves more central in the head and the high pitch has transformed into a hiss ... something uch more bearable ... the high pitch still wants to push through but something is blocking it ... let`s see what the rest of the day will bring ...
I have to go to work today at Tomorrowland! ... biggest dance-festival in the world ... just weaponed with my custom earplugs and heaps of retigabine ...
pray for me
Haha...You'll be fine with some trobalt.
well I can tell you what happens if you don`t eat ...
So yesterday I was working at this this festival ... I had my earplugs... they did a wonderfull job... never got pain... the music sounded like a normal radio playing in the morning with breakfast and the peaks would sound like putting the music at home a bit up to enjoy .. the bases however - my God ... coming home my head was still drilling ... So my H must be very low or something cause I could handle it very well.
in the whole day I ate 1 dadle bar and 2 smal pieces of water melon ...
I was sooo high at the end of the day ...
in the morning took 350 ... some jaw clenching, a bit wooshy in the head but ok ...
arvo I took another 350 ... I became high and couldn`t stop my feet from moving ... felt energized and a bit speedy... moving tongue a lot in my mouth and pressure on lips.
late night I took 400 mg`s ... I was really high ... when holding something my hands were shaking .. my eyes were more open and a lot of jaw clenching and pressure on lips ... had a hard time making choices sometimes ... like if you had two choices I was seriously confused what someone in that some situation would do ... I had to search my bag 4 times - not to see if I had everything - just because i couldn`t even remember what the hell I brought with me .. completely wasted ... not walking really straight and well ... just out of it ...
I could handle all this because i`ve been in far more different worlds when i was young , I knew what was happening. But if you never have done anything in your life ... you would be scared and probably call your doctor to say something is wrong ... and he would lower your mg`s ... alot!
SO. conclusion ... Retigabine definitely contains amphetamine derivatives .. 100% sure
well I can tell you what happens if you don`t eat ...
So yesterday I was working at this this festival ... I had my earplugs... they did a wonderfull job... never got pain... the music sounded like a normal radio playing in the morning with breakfast and the peaks would sound like putting the music at home a bit up to enjoy .. the bases however - my God ... coming home my head was still drilling ... So my H must be very low or something cause I could handle it very well.
in the whole day I ate 1 dadle bar and 2 smal pieces of water melon ...
I was sooo high at the end of the day ...
in the morning took 350 ... some jaw clenching, a bit wooshy in the head but ok ...
arvo I took another 350 ... I became high and couldn`t stop my feet from moving ... felt energized and a bit speedy... moving tongue a lot in my mouth and pressure on lips.
late night I took 400 mg`s ... I was really high ... when holding something my hands were shaking .. my eyes were more open and a lot of jaw clenching and pressure on lips ... couldn`t make sense of nothing anymore ...
like if you had two choices I was seriously confused what someone in that some situation would do ... I had to search my bag 4 times - not to see if I had everything - just because i couldn`t even remember what the hell I brought with me .. completely wasted ... not walking really straight and well ... just out of it ...
I could handle all this because i`ve been in far more different worlds when i was young , I knew what was happening. But if you never have done anything in your life ... you would be scared and probably call your doctor to say something is wrong ... and he would lower your mg`s ... alot!
Well, I never had that happen?
Neither did I, maybe the music was interacting with the drugs effect ..
The other day when i took 400 I actually got sleepy ...
But I think the essence of Trobalt that helps with the epilepsy makes you sleepy and also make you hungry and they counteract it with amphetamines cause they make you awake and and stop you from being hungry ..
The other day when i took 400 I actually got sleepy ...
But I think the essence of Trobalt that helps with the epilepsy makes you sleepy and also make you hungry and they counteract it with amphetamines cause they make you awake and and stop you from being hungry ..
Oh, trobalt made me terribly hungry...Seriously....I put on weight because of it. Annoying to say the least.
In 1980, Brown and Adams [40] described the existence of a low-threshold, depolarization-activated potassium current that they referred to as the "M-current" because it was inhibited by the cholinergic agonist muscarine. The M-current is active in the voltage range for action potential initiation and is therefore of particular importance in regulating the dynamics of the neuronal firing [41]. The M-current turns on slowly following membrane depolarization, and it does not inactivate with sustained depolarization. Although the current was originally described in bullfrog sympathetic neurons, it is also present in brain neurons in the hippocampus, neocortex, and elsewhere [42]. In hippocampal pyramidal cells, M-current contributes to the medium duration (0.1 seconds) afterhyperpolarization that occurs after a single action potential or bursts of action potentials [43]. Depolarizing stimuli activate the M-current, which acts as a brake on repetitive action potential discharges and burst responses, so that neurons generate a regular, stimulus-graded spike output [44]. Thus, the M-current is uniquely suited to suppress bursting and epileptiform activity while permitting maintenance of responses to ordinary excitatory inputs [45].
The molecular identity of the potassium channels that underlie the M-current was uncovered as a result of studies in the late 1990s on a rare type of idiopathic generalized epilepsy [46,47]. This form of epilepsy, benign familial neonatal convulsions, was found to be due to diverse mutations in novel potassium channel subunits, referred to as KCNQ2 (Kv7.2) and KCNQ3 (Kv7.2), which are homologous to a heart potassium channel subunit KvLQT1 (KCNQ1/Kv7.1). The potassium channel family that includes the cardiac KvLQT1 subunit and its KCNQ homologs is now referred to as Kv7 [48]. Shortly after the discovery of KCNQ2 and KCNQ3, it was demonstrated that the M-current channel is formed by these subunits as heteromultimers [49]. M-current can also be generated by KCNQ2 and KCNQ3 homomultimers and possibly also by heteromultimers with other KCNQ subunits, such as KCNQ5, which to date has not been linked to a human disease [50–54]. KCNQ2 mRNA is found throughout the rodent central nervous system, with high expression levels in the hippocampus, neocortex, and cerebellum [42], and KCNQ2 protein has high expression levels in hippocampus, neocortex, and amygdala [55]. KCNQ3 is also expressed in the hippocampus, neocortex, thalamus, and cerebellum [56].
The first immunocytochemical studies of KCNQ channels indicated that they have a somatodendritic distribution and are also expressed presynaptically [57]. Functional M-channels (most likely KCNQ2/KCNQ3 heteromers) are expressed by hippocampal interneurons as well as by principal cells [58]. More recent immunocytochemical studies and patch clamp recordings from different regions of the neuron have confirmed the somatic distribution of the channels in hippocampal neurons, but the channels were unexpectedly found to be absent from distal dendrites [59] (however see Yue and Yaari [45]). In other studies, immunohistochemical staining has demonstrated colocalization of KCNQ2 with voltage-dependent sodium channels at nodes of Ranvier [60]. In addition, immunoreactivity for KCNQ2 and KCNQ3 has been detected at axon initial segments [47,61•]. There is an emerging recognition of the similarities between nodes of Ranvier and axon initial segments, which are sites of action potential initiation and propagation, respectively [62]. The two axonal domains have similar molecular compositions: both are enriched in voltage-dependent sodium channels as well as various adhesion molecules and cytoskeletal proteins that serve to complex sodium channels, including the adaptor protein ankyrin-G. KCNQ2 and KCNQ3 have an ankyrin-G binding motif similar to that present in sodium channels, which is believed to mediate the interaction and retention of both channel types at the plasmalemma of the node and axon initial segment [61•].
The new information on the subcellular localization of M-current channels has allowed a refinement in the understanding of the role the channels play in regulating neuronal excitability and the inhibition of epileptiform discharges. In hippocampal pyramidal neurons, spikes are probably initiated in the axon distal to the initial segment [63]. The initial segment therefore lies between the somatodendritic compartment and the true spike-initiation site. M-channels at this pivotal location are well positioned to gate transmission of somatodendritic depolarizations to the site of action potential generation. Because M-channels are slow to activate, rapid depolarizations are relatively unaffected by the axon initial-segment M-current. In contrast, more prolonged somatodendritic depolarizations, such as those that occur during epileptiform activity, would be attenuated and less likely to activate action-potential firing at the spike-initiation zone. In addition, initial-segment M-channels may block retrograde spike invasion into the somatodendritic compartments, electrically isolating the axon from the remainder of the neuron. Spikes generate an afterdepolarization (driven by subthreshold-persistent sodium current), which triggers further spiking so that bursting occurs. The M-current limits the size and duration of the afterdepolarization, preventing its escalation into a somatic spike burst [44].
Although M-channels in central and peripheral neurons have been localized by immunocytochemistry to nodes [60,64], they have not yet been demonstrated anatomically on nerve terminals. Nevertheless, the selective M-current blocker linopirdine can enhance the depolarization-induced release of various neurotransmitters in brain slices [65] and isolated nerve terminals [66], suggesting a presynaptic localization. Recent evidence supports the view that presynaptic M-channels serve to inhibit neurotransmitter release [67,68]. For example, in cultured hippocampal neurons, activation of M-channels reduces the frequency of spontaneous EPSCs [69]. Although calcium influx is conventionally believed to be the exclusive trigger for neurotransmitter release, there is evidence that release is modulated by voltage [70]. Therefore, the control of neurotransmitter release by M-current may simply be the result of changes in axon terminal membrane potential.
Given the critical role of M-current in regulating the transition to bursting, it is of interest that mutations inKCNQ2, and rarely KCNQ3, are associated with benign familial neonatal convulsions, a condition that is characterized by frequent unprovoked seizures beginning in the first days of life and resolving after weeks to months. The mutations reside predominantly in the pore region or the long cytoplasmic C-terminus, and also in the S4 voltage sensor and the S1–S2 region [47]. In many cases, the mutations cause nearly a complete loss of function of the homomeric expressed channels, but in heteromeric KCNQ2/KCNQ3 channels there is a 20% to 25% reduction in current. Thus, only a relatively small reduction in current leads to the epileptic phenotype. Complete elimination of the current is lethal in genetically altered mice [71]. Heterozygous animals develop normally and lack spontaneous epileptic activity but are more susceptible to pentylenetetrazol-induced seizures. Similar phenotypes are observed in mice homozygous or heterozygous for the spontaneous Szt1 mutation, which involves the region of the Kcnq2 gene that encodes the C-terminus of KCNQ2, as well as other genes [72,73].
Because reducing M-current enhances neuronal excitability and predisposes to seizures, enhancing M-current might be expected to protect against seizures [41]. Experimental support for this concept was first provided when it was shown that retigabine (a powerful AED) could open potassium channels in cultured neuronal cells [74]. Retigabine was subsequently found to be a specific opener of M-current channels [75–77], with effects on KCNQ2–5 and the most potent activity on KCNQ3. The main action of retigabine is to shift the current–voltage curve for activation of the channels to the left so that they open at more hyperpolarized membrane potentials [78,79]. In addition, retigabine increases the rate at which the channels activate and slows the rate at which they deactivate. These effects appear to be due to an interaction of retigabine with a key tryptophan residue in the S5 domain of the channel [80••81]. This residue is not present in the cardiac KvLQT1 channel, which is resistant to retigabine, thus accounting for a lack of cardiotoxicity of the drug. Wuttke et al. [80••] have proposed that retigabine binds to a hydrophobic pocket in the cytoplasmic domains of S5 and S6, thus stabilizing the open state of the channel (see also Maljevic et al. [47]).
Inhibition of excitatory transmitter output at synapses is a key mode of action of AEDs [1], and modulation of synaptic release is the likely action for the other two targets discussed in this review. Modulation of presynaptic release by M-channels could also represent an important way in which M-channel openers such as retigabine protect against seizures. However, it is certainly not the only mechanism, as retigabine was able to abolish nonsynaptic bursting in hippocampal neurons [82]. The mechanisms of neuronal synchronization in this situation are obscure, but because synaptic transmission was absent in these experiments, the action of retigabine must relate to its effects on intrinsic neuronal excitability. In rodents, KCNQ2 and KCNQ3 show a gradual maturation so that the characteristic adult axonal distribution of the channels is not present in the early postnatal period [55,56]. Understanding the human developmental expression patterns of these channels will provide insights into the response to KCNQ openers in infants and children.
Validation of KCNQ potassium channels as an AED target has come from several recent clinical trials of retigabine [83]. A phase 2 dose-ranging study in 399 patients with partial seizure demonstrated a dose-dependent reduction in seizures [84•]. Two unpublished phase 3 trials (Retigabine Efficacy and Safety Trials for Partial Onset Epilepsy [RESTORE] 1 and 2) in 305 and 593 patients, respectivly, have confirmed the results of the phase 2 study.
The efficacy of retigabine in these various clinical trials strongly supports the concept that positive modulation of M-current (reduction in the threshold for activation) can confer seizure protection. However, retigabine has some known pharmacologic actions distinct from its effects on KCNQ channels; most notably, it potentiates GABAA receptor responses at similar or perhaps slightly higher concentrations than are effective on potassium channels [85]. Therefore, it is of interest that a structurally dissimilar KCNQ activator, ICA-27243, which is more selective and does not affect GABAA receptor responses, also exhibits anticonvulsant activity [86–88]. This confirms the validity of KCNQ channels as an anticonvulsant target, at least in animal models. An additional orally bioavailable selective KCNQ activator, ICA-105665, with activity in chemoconvulsant (pentylenetetrazol), electroshock, and kindling models, is entering clinical development (Rigdon, personal communication).
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Conclusions
The discovery of the new AED targets discussed in this review was based on the availability of anticonvulsant molecules identified as having protective activity in animal seizure models. With these molecules in hand, a program of research was initiated that eventually led to the identification of the novel targets. In the case of α2δ and SV2A, affinity ligands were used to localize the distribution of the targets and as fishhooks to snare the target for either automated sequencing or determination of molecular weight. Proof that the target is relevant to anticonvulsant activity was ultimately based on the use of genetically engineered mice. In the case of Kv7/KCNQ/M potassium channels, the target was discovered through cellular electrophysiology informed by genetic studies in a rare idiopathic epilepsy syndrome. The knowledge of the targets has been utilized to discover follow-on compounds with improved properties that act by similar mechanisms. Pregabalin, an analog of gabapentin, has already reached the market. Levetiracetam spawned the analog brivaracetam, which was identified specifically as a result of its high affinity for the levetiracetam binding site. There are a host of KCNQ openers in various stages of development, some of which are structurally related to retigabine and others that are not [42,69]. Clearly, the new set of targets discussed in this review are providing opportunities for the rational discovery of AEDs in a way that was not possible when animal models were the only tool.
A common theme for the three molecular targets discussed in this review is that they are all localized to nerve terminals, where they play diverse roles in regulating neurotransmitter release. Actions on presynaptic mechanisms are likely to be the primary way in which AEDs that target α2δ and SV2A confer seizure protection. Because Kv7/KCNQ/M potassium channels are also localized presynaptically, where they regulate release, AEDs that open these channels also likely act in part through regulation of release (although effects on somatodendritic and axon initial segment channels are likely relevant as well). The concept that AEDs act presynaptically to modulate transmitter release contrasts with conventional notions that AEDs confer seizure protection by inhibiting repetitive action-potential generation, influencing rhythm-generating mechanisms, or enhancing postsynaptic inhibition. The discovery and characterization of the new targets focuses attention on presynaptic mechanisms as a key mode of action for AEDs. In fact, it is likely that sodium channel–blocking AEDs, including phenytoin, carbamazepine, and lamotrigine, ultimately confer seizure protection by affecting excitatory neurotransmitter output at synapses [1].
The identification of AEDs that act on new targets has not yet led to a "magic bullet" that reliably eliminates seizures in drug-refractory patients. Nevertheless, newer AEDs have provided improvements in safety, tolerability, and pharmacokinetics, and they offer a broader range of options. It remains to be seen whether the agents in the development pipeline that act through the targets discussed in this review, including brivaracetam and retigabine, will offer more substantial benefits.
The molecular identity of the potassium channels that underlie the M-current was uncovered as a result of studies in the late 1990s on a rare type of idiopathic generalized epilepsy [46,47]. This form of epilepsy, benign familial neonatal convulsions, was found to be due to diverse mutations in novel potassium channel subunits, referred to as KCNQ2 (Kv7.2) and KCNQ3 (Kv7.2), which are homologous to a heart potassium channel subunit KvLQT1 (KCNQ1/Kv7.1). The potassium channel family that includes the cardiac KvLQT1 subunit and its KCNQ homologs is now referred to as Kv7 [48]. Shortly after the discovery of KCNQ2 and KCNQ3, it was demonstrated that the M-current channel is formed by these subunits as heteromultimers [49]. M-current can also be generated by KCNQ2 and KCNQ3 homomultimers and possibly also by heteromultimers with other KCNQ subunits, such as KCNQ5, which to date has not been linked to a human disease [50–54]. KCNQ2 mRNA is found throughout the rodent central nervous system, with high expression levels in the hippocampus, neocortex, and cerebellum [42], and KCNQ2 protein has high expression levels in hippocampus, neocortex, and amygdala [55]. KCNQ3 is also expressed in the hippocampus, neocortex, thalamus, and cerebellum [56].
The first immunocytochemical studies of KCNQ channels indicated that they have a somatodendritic distribution and are also expressed presynaptically [57]. Functional M-channels (most likely KCNQ2/KCNQ3 heteromers) are expressed by hippocampal interneurons as well as by principal cells [58]. More recent immunocytochemical studies and patch clamp recordings from different regions of the neuron have confirmed the somatic distribution of the channels in hippocampal neurons, but the channels were unexpectedly found to be absent from distal dendrites [59] (however see Yue and Yaari [45]). In other studies, immunohistochemical staining has demonstrated colocalization of KCNQ2 with voltage-dependent sodium channels at nodes of Ranvier [60]. In addition, immunoreactivity for KCNQ2 and KCNQ3 has been detected at axon initial segments [47,61•]. There is an emerging recognition of the similarities between nodes of Ranvier and axon initial segments, which are sites of action potential initiation and propagation, respectively [62]. The two axonal domains have similar molecular compositions: both are enriched in voltage-dependent sodium channels as well as various adhesion molecules and cytoskeletal proteins that serve to complex sodium channels, including the adaptor protein ankyrin-G. KCNQ2 and KCNQ3 have an ankyrin-G binding motif similar to that present in sodium channels, which is believed to mediate the interaction and retention of both channel types at the plasmalemma of the node and axon initial segment [61•].
The new information on the subcellular localization of M-current channels has allowed a refinement in the understanding of the role the channels play in regulating neuronal excitability and the inhibition of epileptiform discharges. In hippocampal pyramidal neurons, spikes are probably initiated in the axon distal to the initial segment [63]. The initial segment therefore lies between the somatodendritic compartment and the true spike-initiation site. M-channels at this pivotal location are well positioned to gate transmission of somatodendritic depolarizations to the site of action potential generation. Because M-channels are slow to activate, rapid depolarizations are relatively unaffected by the axon initial-segment M-current. In contrast, more prolonged somatodendritic depolarizations, such as those that occur during epileptiform activity, would be attenuated and less likely to activate action-potential firing at the spike-initiation zone. In addition, initial-segment M-channels may block retrograde spike invasion into the somatodendritic compartments, electrically isolating the axon from the remainder of the neuron. Spikes generate an afterdepolarization (driven by subthreshold-persistent sodium current), which triggers further spiking so that bursting occurs. The M-current limits the size and duration of the afterdepolarization, preventing its escalation into a somatic spike burst [44].
Although M-channels in central and peripheral neurons have been localized by immunocytochemistry to nodes [60,64], they have not yet been demonstrated anatomically on nerve terminals. Nevertheless, the selective M-current blocker linopirdine can enhance the depolarization-induced release of various neurotransmitters in brain slices [65] and isolated nerve terminals [66], suggesting a presynaptic localization. Recent evidence supports the view that presynaptic M-channels serve to inhibit neurotransmitter release [67,68]. For example, in cultured hippocampal neurons, activation of M-channels reduces the frequency of spontaneous EPSCs [69]. Although calcium influx is conventionally believed to be the exclusive trigger for neurotransmitter release, there is evidence that release is modulated by voltage [70]. Therefore, the control of neurotransmitter release by M-current may simply be the result of changes in axon terminal membrane potential.
Given the critical role of M-current in regulating the transition to bursting, it is of interest that mutations inKCNQ2, and rarely KCNQ3, are associated with benign familial neonatal convulsions, a condition that is characterized by frequent unprovoked seizures beginning in the first days of life and resolving after weeks to months. The mutations reside predominantly in the pore region or the long cytoplasmic C-terminus, and also in the S4 voltage sensor and the S1–S2 region [47]. In many cases, the mutations cause nearly a complete loss of function of the homomeric expressed channels, but in heteromeric KCNQ2/KCNQ3 channels there is a 20% to 25% reduction in current. Thus, only a relatively small reduction in current leads to the epileptic phenotype. Complete elimination of the current is lethal in genetically altered mice [71]. Heterozygous animals develop normally and lack spontaneous epileptic activity but are more susceptible to pentylenetetrazol-induced seizures. Similar phenotypes are observed in mice homozygous or heterozygous for the spontaneous Szt1 mutation, which involves the region of the Kcnq2 gene that encodes the C-terminus of KCNQ2, as well as other genes [72,73].
Because reducing M-current enhances neuronal excitability and predisposes to seizures, enhancing M-current might be expected to protect against seizures [41]. Experimental support for this concept was first provided when it was shown that retigabine (a powerful AED) could open potassium channels in cultured neuronal cells [74]. Retigabine was subsequently found to be a specific opener of M-current channels [75–77], with effects on KCNQ2–5 and the most potent activity on KCNQ3. The main action of retigabine is to shift the current–voltage curve for activation of the channels to the left so that they open at more hyperpolarized membrane potentials [78,79]. In addition, retigabine increases the rate at which the channels activate and slows the rate at which they deactivate. These effects appear to be due to an interaction of retigabine with a key tryptophan residue in the S5 domain of the channel [80••81]. This residue is not present in the cardiac KvLQT1 channel, which is resistant to retigabine, thus accounting for a lack of cardiotoxicity of the drug. Wuttke et al. [80••] have proposed that retigabine binds to a hydrophobic pocket in the cytoplasmic domains of S5 and S6, thus stabilizing the open state of the channel (see also Maljevic et al. [47]).
Inhibition of excitatory transmitter output at synapses is a key mode of action of AEDs [1], and modulation of synaptic release is the likely action for the other two targets discussed in this review. Modulation of presynaptic release by M-channels could also represent an important way in which M-channel openers such as retigabine protect against seizures. However, it is certainly not the only mechanism, as retigabine was able to abolish nonsynaptic bursting in hippocampal neurons [82]. The mechanisms of neuronal synchronization in this situation are obscure, but because synaptic transmission was absent in these experiments, the action of retigabine must relate to its effects on intrinsic neuronal excitability. In rodents, KCNQ2 and KCNQ3 show a gradual maturation so that the characteristic adult axonal distribution of the channels is not present in the early postnatal period [55,56]. Understanding the human developmental expression patterns of these channels will provide insights into the response to KCNQ openers in infants and children.
Validation of KCNQ potassium channels as an AED target has come from several recent clinical trials of retigabine [83]. A phase 2 dose-ranging study in 399 patients with partial seizure demonstrated a dose-dependent reduction in seizures [84•]. Two unpublished phase 3 trials (Retigabine Efficacy and Safety Trials for Partial Onset Epilepsy [RESTORE] 1 and 2) in 305 and 593 patients, respectivly, have confirmed the results of the phase 2 study.
The efficacy of retigabine in these various clinical trials strongly supports the concept that positive modulation of M-current (reduction in the threshold for activation) can confer seizure protection. However, retigabine has some known pharmacologic actions distinct from its effects on KCNQ channels; most notably, it potentiates GABAA receptor responses at similar or perhaps slightly higher concentrations than are effective on potassium channels [85]. Therefore, it is of interest that a structurally dissimilar KCNQ activator, ICA-27243, which is more selective and does not affect GABAA receptor responses, also exhibits anticonvulsant activity [86–88]. This confirms the validity of KCNQ channels as an anticonvulsant target, at least in animal models. An additional orally bioavailable selective KCNQ activator, ICA-105665, with activity in chemoconvulsant (pentylenetetrazol), electroshock, and kindling models, is entering clinical development (Rigdon, personal communication).
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Conclusions
The discovery of the new AED targets discussed in this review was based on the availability of anticonvulsant molecules identified as having protective activity in animal seizure models. With these molecules in hand, a program of research was initiated that eventually led to the identification of the novel targets. In the case of α2δ and SV2A, affinity ligands were used to localize the distribution of the targets and as fishhooks to snare the target for either automated sequencing or determination of molecular weight. Proof that the target is relevant to anticonvulsant activity was ultimately based on the use of genetically engineered mice. In the case of Kv7/KCNQ/M potassium channels, the target was discovered through cellular electrophysiology informed by genetic studies in a rare idiopathic epilepsy syndrome. The knowledge of the targets has been utilized to discover follow-on compounds with improved properties that act by similar mechanisms. Pregabalin, an analog of gabapentin, has already reached the market. Levetiracetam spawned the analog brivaracetam, which was identified specifically as a result of its high affinity for the levetiracetam binding site. There are a host of KCNQ openers in various stages of development, some of which are structurally related to retigabine and others that are not [42,69]. Clearly, the new set of targets discussed in this review are providing opportunities for the rational discovery of AEDs in a way that was not possible when animal models were the only tool.
A common theme for the three molecular targets discussed in this review is that they are all localized to nerve terminals, where they play diverse roles in regulating neurotransmitter release. Actions on presynaptic mechanisms are likely to be the primary way in which AEDs that target α2δ and SV2A confer seizure protection. Because Kv7/KCNQ/M potassium channels are also localized presynaptically, where they regulate release, AEDs that open these channels also likely act in part through regulation of release (although effects on somatodendritic and axon initial segment channels are likely relevant as well). The concept that AEDs act presynaptically to modulate transmitter release contrasts with conventional notions that AEDs confer seizure protection by inhibiting repetitive action-potential generation, influencing rhythm-generating mechanisms, or enhancing postsynaptic inhibition. The discovery and characterization of the new targets focuses attention on presynaptic mechanisms as a key mode of action for AEDs. In fact, it is likely that sodium channel–blocking AEDs, including phenytoin, carbamazepine, and lamotrigine, ultimately confer seizure protection by affecting excitatory neurotransmitter output at synapses [1].
The identification of AEDs that act on new targets has not yet led to a "magic bullet" that reliably eliminates seizures in drug-refractory patients. Nevertheless, newer AEDs have provided improvements in safety, tolerability, and pharmacokinetics, and they offer a broader range of options. It remains to be seen whether the agents in the development pipeline that act through the targets discussed in this review, including brivaracetam and retigabine, will offer more substantial benefits.
@Danny Boy
what is the above text related to.. ? .. too much to read .. give the essential and I might read all of it ..
btw, I`m now on 1200mgs ... and something is changing.. sometimes it`s there but, sometimes i`m surprised it is gone but than suddenly i hear it again .. lot`s of things, but all very inconsistent untill now ..
But I have other news to .. went to another ENT today .. my lord she is good ... she actually discovered I have TMJ !!
for so many year I go one place to another and she tells me after sitting 2minutes in a chair and have some microscope down my nose in my throat! .. I was so high in her office on trobalt .. was funny ..
so i want to continue with Trobalt at highest dose till end of the week and then taper down and start her little treatment ... and than see what happens and taper up again with Trobalt
what is the above text related to.. ? .. too much to read .. give the essential and I might read all of it ..
btw, I`m now on 1200mgs ... and something is changing.. sometimes it`s there but, sometimes i`m surprised it is gone but than suddenly i hear it again .. lot`s of things, but all very inconsistent untill now ..
But I have other news to .. went to another ENT today .. my lord she is good ... she actually discovered I have TMJ !!
for so many year I go one place to another and she tells me after sitting 2minutes in a chair and have some microscope down my nose in my throat! .. I was so high in her office on trobalt .. was funny ..
so i want to continue with Trobalt at highest dose till end of the week and then taper down and start her little treatment ... and than see what happens and taper up again with Trobalt
@Danny Boy
what is the above text related to.. ? .. too much to read .. give the essential and I might read all of it ..
btw, I`m now on 1200mgs ... and something is changing.. sometimes it`s there but, sometimes i`m surprised it is gone but than suddenly i hear it again .. lot`s of things, but all very inconsistent untill now ..
But I have other news to .. went to another ENT today .. my lord she is good ... she actually discovered I have TMJ !!
for so many year I go one place to another and she tells me after sitting 2minutes in a chair and have some microscope down my nose in my throat! .. I was so high in her office on trobalt .. was funny ..
so i want to continue with Trobalt at highest dose till end of the week and then taper down and start her little treatment ... and than see what happens and taper up again with Trobalt
Haha...You know you like getting high on trobalt. It's more of a history lesson lol
but is it a big improvement on ur T?@Danny Boy
what is the above text related to.. ? .. too much to read .. give the essential and I might read all of it ..
btw, I`m now on 1200mgs ... and something is changing.. sometimes it`s there but, sometimes i`m surprised it is gone but than suddenly i hear it again .. lot`s of things, but all very inconsistent untill now ..
But I have other news to .. went to another ENT today .. my lord she is good ... she actually discovered I have TMJ !!
for so many year I go one place to another and she tells me after sitting 2minutes in a chair and have some microscope down my nose in my throat! .. I was so high in her office on trobalt .. was funny ..
so i want to continue with Trobalt at highest dose till end of the week and then taper down and start her little treatment ... and than see what happens and taper up again with Trobalt
and the last visit i had with my ent i asked him that if i might have tmj from all my nasal problems and ear tube dysfuntion from my ears popping etc.. he just gave me idiot smurk and said no...without even trying to see
TMJ is quite a dead end. Don´t spend too much money on useless jaw splints and additional costs at the orthodontist.
Why not ? Well just cause it didn't work for someone doesn't mean it won't work at all , in fact TMJ is one of the common causes of tinnitus
You´re welcome to try it. Once T starts (no matter whats the cause) its almost irreversible in 99% of the cases.
In Nils case, he has had T for years, wearing a splint won´t be a magic trick and will let it disappear.
Sure, it always gives one some hope when the doctors says you have TMJ and this and that and you have something to hold on to. I was there too, I spent more than 500€ on jaw diagnostics and splints.
AND in my case it even made sense because I was diagnosed with TMJ after I had some wisdom teeth pulled and my monster T started.
Still, it didn´t help a bit. So if you have some fresh issues with your jaw and your T is new, sure its worth checking it out.
I can see where you're going , splints are useless , most of the time , tmj requires more than just a splint , but yeah a t sufferer will do anything to find the cause of his t any hope will still be hope, and how's the trobalt going with you?
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