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Mark Nelson - One of the best experts on this subject based on the ideXlab platform.
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the kv7 channel activator Retigabine suppresses mouse urinary bladder afferent nerve activity without affecting detrusor smooth muscle k channel currents
The Journal of Physiology, 2019Co-Authors: Nathan R Tykocki, Thomas J Heppner, Thomas Dalsgaard, Adrian D Bonev, Mark NelsonAbstract:KEY POINTS: KV 7 channels are a family of voltage-dependent K+ channels expressed in many cell types, which open in response to membrane depolarization to regulate cell excitability. Drugs that target KV 7 channels are used clinically to treat epilepsy. Interestingly, these drugs also cause urinary retention, but it was unclear how. In this study, we focused on two possible mechanisms by which Retigabine could cause urinary retention: by decreasing smooth muscle excitability, or by decreasing sensory nerve outflow. Urinary bladder smooth muscle had no measurable KV 7 channel currents. However, the KV 7 channel agonist Retigabine nearly abolished sensory nerve outflow from the urinary bladder during bladder filling. We conclude that KV 7 channel activation likely affects urinary bladder function by blocking afferent nerve outflow to the brain, which is key to sensing bladder fullness. ABSTRACT: KV 7 channels are voltage-dependent K+ channels that open in response to membrane depolarization to regulate cell excitability. KV 7 activators, such as Retigabine, were used to treat epilepsy but caused urinary retention. Using electrophysiological recordings from freshly isolated mouse urinary bladder smooth muscle (UBSM) cells, isometric contractility of bladder strips, and ex vivo measurements of bladder afferent activity, we explored the role of KV 7 channels as regulators of murine urinary bladder function. The KV 7 activator Retigabine (10 μM) had no effect on voltage-dependent K+ currents or resting membrane potential of UBSM cells, suggesting that these cells lacked Retigabine-sensitive KV 7 channels. The KV 7 inhibitor XE-991 (10 μM) inhibited UBSM K+ currents; the properties of these currents, however, were typical of KV 2 channels and not KV 7 channels. Retigabine inhibited voltage-dependent Ca2+ channel (VDCC) currents and reduced steady-state contractions to 60 mM KCl in bladder strips, suggesting that reduction in VDCC current was sufficient to directly affect UBSM function. To determine if Retigabine altered ex vivo bladder sensory outflow, we measured afferent activity during simulated transient contractions (TCs) of the bladder wall. Simulated TCs caused bursts of afferent activity that were nearly abolished by Retigabine. The effects of Retigabine were blocked by co-incubation with XE-991, suggesting specific activation of KV 7 channels on afferent nerves. These results indicate that Retigabine primarily affects urinary bladder function by inhibiting TC generation and afferent nerve activity, which are key to sensing bladder fullness. Any direct inhibition of UBSM contractility is likely to be from non-specific effects on VDCCs and KV 2 channels.
Jens D. Mikkelsen - One of the best experts on this subject based on the ideXlab platform.
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the pan kv7 kcnq channel opener Retigabine inhibits striatal excitability by direct action on striatal neurons in vivo
Basic & Clinical Pharmacology & Toxicology, 2017Co-Authors: Henrik H Hansen, Frederik Rode, Pia Weikop, Maria D Mikkelsen, Jens D. MikkelsenAbstract:: Central Kv7 (KCNQ) channels are voltage-dependent potassium channels composed of different combinations of four Kv7 subunits, being differently expressed in the brain. Notably, striatal dopaminergic neurotransmission is strongly suppressed by systemic administration of the pan-Kv7 channel opener Retigabine. The effect of Retigabine likely involves the inhibition of the activity in mesencephalic dopaminergic neurons projecting to the striatum, but whether Kv7 channels expressed in the striatum may also play a role is not resolved. We therefore assessed the effect of intrastriatal Retigabine administration on striatal neuronal excitability in the rat determined by c-Fos immunoreactivity, a marker of neuronal activation. When Retigabine was applied locally in the striatum, this resulted in a marked reduction in the number of c-Fos-positive neurons after a strong excitatory striatal stimulus induced by acute systemic haloperidol administration in the rat. The relative mRNA levels of Kv7 subunits in the rat striatum were found to be Kv7.2 = Kv7.3 = Kv7.5 > >Kv7.4. These data suggest that intrastriatal Kv7 channels play a direct role in regulating striatal excitability in vivo.
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the neuronal kcnq channel opener Retigabine inhibits locomotor activity and reduces forebrain excitatory responses to the psychostimulants cocaine methylphenidate and phencyclidine
European Journal of Pharmacology, 2007Co-Authors: Henrik H Hansen, Jesper T Andreasen, Pia Weikop, Naheed Mirza, Jorgen Scheelkruger, Jens D. MikkelsenAbstract:Abstract Many central stimulating drugs have a pronounced stimulatory effect on striatal and cortical activity which is associated to enhanced function of mesencephalic dopaminergic neurons. Mesencephalic KCNQ (also termed Kv7) potassium channels suppress the basal activity of dopaminergic neurons in the substantia nigra and ventral tegmental area. These regions have extensive dopaminergic projections to the striatum and cortex, and positive modulation of KCNQ channel function may therefore potentially reduce the reinforcing impact of central stimulating drugs. We studied the effects of the principal neuronal KCNQ channel opener, Retigabine, in rats exposed acutely to cocaine, methylphenidate (dopamine reuptake inhibitors) or phencyclidine (PCP, a psychotomimetic NMDA receptor antagonist). Retigabine (≥ 1.0 mg/kg) inhibited cocaine, methylphenidate and PCP-stimulated locomotor activity. Also, Retigabine reduced spontaneous locomotor activity. The inhibitory effect of Retigabine on psychostimulant-induced locomotor activity was accompanied by a marked reduction in c-Fos expression, in particular the nucleus accumbens and primary motor cortex were responsive to Retigabine pre-treatment. Notably, Retigabine also reduced basal extracellular levels of striatal dopamine metabolites and partially prevented dopamine overflow in the striatum induced by dopamine reuptake blockade. In combination, these data suggest that Retigabine reduces striatal and cortical excitability, thereby attenuating excitatory effects of central stimulating drugs in dopamine-rich areas of the rat forebrain. KCNQ channel openers may therefore be of potential relevance in the treatment of addiction states caused by abuse of psychostimulants.
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the kcnq channel opener Retigabine inhibits the activity of mesencephalic dopaminergic systems of the rat
Journal of Pharmacology and Experimental Therapeutics, 2006Co-Authors: Henrik H Hansen, Lars Christian Biilmann Ronn, Pia Weikop, Christina Ebbesen, Claus Mathiesen, Olivier Waroux, Jacqueline Scuveemoreau, Vincent Seutin, Jens D. MikkelsenAbstract:Homo- and heteromeric complexes of KCNQ channel subunits are the molecular correlate of the M-current, a neuron-specific voltage-dependent K + current with a well established role in control of neural excitability. We investigated the effect of KCNQ channel modulators on the activity of dopaminergic neurons in vitro and in vivo in the rat ventral mesencephalon. The firing of dopaminergic neurons recorded in mesencephalic slices was robustly inhibited in a concentration-dependent manner by the KCNQ channel opener N -(2-amino-4-(4-fluorobenzylamino)-phenyl) carbamic acid ethyl ester (Retigabine). The effect of Retigabine persisted in the presence of tetrodotoxin and simultaneous blockade of GABA A receptors, small-conductance calcium-activated K + (SK) channels, and hyperpolarization-activated (I h ) channels, and it was potently reversed by the KCNQ channel blocker 4-pyridinylmethyl-9(10 H )-anthracenone (XE991), indicating a direct effect on KCNQ channels. Likewise, in vivo single unit recordings from dopaminergic neurons revealed a prominent reduction in spike activity after systemic administration of Retigabine. Furthermore, Retigabine inhibited dopamine synthesis and c-Fos expression in the striatum under basal conditions. Retigabine completely blocked the excitatory effect of dopamine D 2 autoreceptor antagonists. Again, the in vitro and in vivo effects of Retigabine were completely reversed by preadministration of XE991. Dual immunocytochemistry revealed that KCNQ4 is the major KCNQ channel subunit expressed in all dopaminergic neurons in the mesolimbic and nigrostriatal pathways. Collectively, these observations indicate that Retigabine negatively modulates dopaminergic neurotransmission, likely originating from stimulation of mesencephalic KCNQ4 channels.
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Retigabine chemical synthesis to clinical application
Cns Drug Reviews, 2006Co-Authors: Gordon Blackburnmunro, Jens D. Mikkelsen, Naheed Mirza, W Dalbybrown, R E BlackburnmunroAbstract:Retigabine [{"type":"entrez-nucleotide","attrs":{"text":"D23129","term_id":"427051","term_text":"D23129"}}D23129; N‐(2‐amino‐4‐(4‐fluorobenzylamino)‐phenyl)carbamic acid ethyl ester] is an antiepileptic drug with a recently described novel mechanism of action that involves opening of neuronal KV7.2–7.5 (formerly KCNQ2‐5) voltage‐activated K+ channels. These channels (primarily KV7.2/7.3) enable generation of the M‐current, a subthreshold K+ current that serves to stabilize the membrane potential and control neuronal excitability. In this regard, Retigabine has been shown to have a broad‐spectrum of activity in animal models of electrically‐induced (amygdala‐kindling, maximal electroshock) and chemically‐induced (pentylenetetrazole, picrotoxin, NMDA) epileptic seizures. These encouraging results suggest that Retigabine may also prove useful in the treatment of other diseases associated with neuronal hyperexcitability. Neuropathic pain conditions are characterized by pathological changes in sensory pathways, which favor action potential generation and enhanced pain transmission. Although sometimes difficult to treat with conventional analgesics, antiepileptics can relieve some symptoms of neuropathic pain. A number of recent studies have reported that Retigabine can relieve pain‐like behaviors (hyperalgesia and allodynia) in animal models of neuropathic pain. Neuronal activation within several key structures within the CNS can also be observed in various animal models of anxiety. Moreover, amygdala‐kindled rats, which have a lowered threshold for neuronal activation, also display enhanced anxiety‐like responses. Retigabine dose‐dependently reduces unconditioned anxiety‐like behaviors when assessed in the mouse marble burying test and zero maze. Early clinical studies have indicated that Retigabine is rapidly absorbed and distributed, and is resistant to first pass metabolism. Tolerability is good in humans when titrated up to its therapeutic dose range (600‐1200 mg/day). No tolerance, dependence or withdrawal potential has been reported, although adverse effects can include mild dizziness, headache, nausea and somnolence. Thus, Retigabine may prove to be useful in the treatment of a diverse range of disease states in which neuronal hyperexcitability is a common underlying factor.
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The KCNQ channel activator Retigabine blocks haloperidol-induced c-Fos expression in the striatum of the rat.
Neuroscience Letters, 2004Co-Authors: Jens D. MikkelsenAbstract:Retigabine activates inward potassium rectifying KCNQ channels. This stabilizes the membrane potential via hyperpolarization in vitro and Retigabine has also been shown to inhibit convulsions in vivo. This study was carried out to determine whether Retigabine inhibited haloperidol-dependent activation of neurons in the striatum as measured by expression of c-Fos. Groups of male rats were treated with Retigabine (10 mg/kg i.p.), haloperidol (1 mg/kg i.p.), or the two in combination (at 15 min interval) and fixed 60 min after haloperidol treatment. Haloperidol produced a large increase in the number of c-Fos-positive nuclei in different degrees in all parts of the striatum. Pretreatment with Retigabine completely blocked haloperidol-induced c-Fos in both the ventral and dorsal striatum suggesting that Retigabine via activation of the KCNQ channel interacts with haloperidol and inhibits neuronal excitation in the striatum.
Chris Rundfeldt - One of the best experts on this subject based on the ideXlab platform.
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investigations into the mechanism of action of the new anticonvulsant Retigabine interaction with gabaergic and glutamatergic neurotransmission and with voltage gated ion channels
Drug Research, 2011Co-Authors: Chris Rundfeldt, Rainer NetzerAbstract:Retigabine (N-(2-amino-4-(4 -fluorobenzylamino)phenyl) carbamic acid ethyl ester, CAS 150812-12-7,D-23129) is a novel anticonvulsant currently undergoing phase II clinical trials. The compound was shown to possess broad spectrum and potent anticonvulsant properties both in vitro and in vivo. The mechanism of action of this drug is currently not fully understood. In previous studies a potent opening effect on K + channels and an increased release of newly synthesized γ-aminobutyric acid (GABA) were reported. The aim of this study was to investigate the interaction of Retigabine with GABA, kainate and N-methyl-D-aspartate (NMDA) induced currents as well as with voltage gated Na + and Ca ++ channels. Retigabine concentration dependently potentiated GABA induced currents in rat cortical neurones. Significant effects were only seen with concentrations of 10 µmol/l and above. The action of Retigabine was not antagonised by flumazenil indicating interaction with other than benzodiazepine binding sites. In comparison with the K + channel opening effect which can be seen at concentrations as low as 0.1 µmol/l the contribution of this mechanism to the anticonvulsant activity of Retigabine may be minor. Inhibitory effects observed on voltage activated Na + and Ca ++ channels as well as on kainate induced currents were only observed at the highest concentration tested (100 µmol/l) and can be considered non specific. No significant interaction with NMDA induced currents was observed.
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the anti hyperalgesic activity of Retigabine is mediated by kcnq potassium channel activation
Naunyn-schmiedebergs Archives of Pharmacology, 2004Co-Authors: Rita Dost, Angelika Rostock, Chris RundfeldtAbstract:Retigabine (N-(2-amino-4-(4-fluorobenzylamino)-phenyl) carbamic acid ethyl ester) has a broad anticonvulsant spectrum and is currently in clinical development for epilepsy. The compound has an opening effect on neuronal KCNQ channels. At higher concentrations an augmentation of gamma-aminobutyric acid (GABA) induced currents as well as a weak blocking effect on sodium and calcium currents were observed. The goal of this study was to characterise the activity of Retigabine in models of acute and neuropathic pain and to investigate if the potassium channel opening effect of Retigabine contributes to its activity.
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a neurochemical study of the novel antiepileptic drug Retigabine in mouse brain
Pharmacological Research, 2000Co-Authors: Graeme J Sills, Chris Rundfeldt, Elaine Butler, Gerard Forrest, G G Thompson, Martin J BrodieAbstract:The novel antiepileptic drug, Retigabine, has been reported to have multiple mechanisms of action, including potentiation of γ -aminobutyric acid (GABA) and glutamate synthesis. We have investigated its effects on several GABA- and glutamate-related neurochemical parameters in mouse brain. Mice were administered Retigabine either as a single dose or daily for 5 days. At 4 h after dosing, brains were removed and analysed for GABA, glutamate, and glutamine concentrations and for the activities of GABA-transaminase and glutamic acid decarboxylase. Single doses of Retigabine significantly lowered brain concentrations of glutamate and glutamine. Repeated treatment significantly reduced the activity of GABA-transaminase. The drug was essentially without effect on all other parameters investigated. These results suggest that Retigabine blocks GABA metabolism rather than enhancing GABA synthesis. In addition, the drug may also lower brain concentrations of the excitatory neurotransmitter glutamate and its precursor, glutamine. These effects may contribute to the antiepileptic action of Retigabine.
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flupirtine and Retigabine prevent l glutamate toxicity in rat pheochromocytoma pc 12 cells
European Journal of Pharmacology, 2000Co-Authors: Jan Seyfried, Chris Rundfeldt, Bernd O Evert, Jorg B Schulz, Karl A Kovar, Thomas Klockgether, Ullrich WullnerAbstract:Abstract Flupirtine is an analgesic drug thought to have NMDA receptor antagonistic and antiapoptotic effects. We investigated the effects of Ethyl-2-amino-6-(4-(4-fluorbenzyl)amino)-pyridine-3-carbamamic acid, maleate (flupirtine) and the related compound N -(2-amino-4-(4-fluorobenzylamino)-phenyl)-carbamic acid, ethyl ester) (Retigabine) (Desaza-flupirtine) on the toxicity of l -glutamate and l -3,4-dihydroxyphenylalanine ( l -DOPA) in rat pheochromocytoma PC 12 cells in vitro. Both drugs (10 μM) markedly decreased nonreceptor-mediated necrotic cell death in PC 12 cultures treated with l -glutamate (10 mM) for 72 h. In contrast, apoptosis induced by l -DOPA (250 μM) after 48 h was not affected by either substance. While l -DOPA elicited massive generation of reactive oxygen intermediates, l -glutamate-induced cell death was accompanied by only slightly increased levels of reactive oxygen intermediates. Flupirtine and Retigabine exerted anti-oxidative effects in PC 12 cultures independent of their ability to prevent cell death. Further examination of the protective action of flupirtine and Retigabine against l -glutamate toxicity showed that it had no influence on monoamine oxidase (monoamine: oxygen oxidoreductase (deaminating), EC 1.4.3.4., MAO) activity. Thus, flupirtine and Retigabine provided protection against cystine deprivation and l -glutamate toxicity but did not protect against l -glutamate under cystine-free conditions indicating that both compounds are sufficiently effective to compensate the oxidative stress elicited by cystine deprivation but not excessive activity of monoamine oxidase after l -glutamate treatment.
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the novel anticonvulsant Retigabine activates m currents in chinese hamster ovary cells tranfected with human kcnq2 3 subunits
Neuroscience Letters, 2000Co-Authors: Chris Rundfeldt, Rainer NetzerAbstract:Abstract Retigabine (D-23129) is a novel antiepileptic compound with broad spectrum and potent anticonvulsant properties, both in vitro and in vivo. The compound was shown to activate a K + current in neuronal cells. The pharmacology of the induced current displays concordance with the published pharmacology of the M-channel, which recently was correlated to the KCNQ2/3 K + channel heteromultimere. We examined the effect of Retigabine on KCNQ2/3 expressed in Chinese hamster ovary cells. The compound concentration-dependently activated a K + current in transfected cells clamped at −50 mV. The activation was induced by a shift of the opening threshold to more negative potentials. The effect was not mediated by an interaction with the cAMP modulatory site and could be partially blocked by the M-channel antagonist linopirdine. The data display that Retigabine is the first described M-channel agonist and support the hypothesis that M-channel agonism is a new mode of action for anticonvulsant drugs. Since the function of this channel is reduced in a hereditary epilepsy syndrome, Retigabine may be the first anticonvulsant to directly target the deficit observed in a channelopathy.
Lyudmil Peychev - One of the best experts on this subject based on the ideXlab platform.
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EXPERIMENTAL EVALUATION OF MEDIAN EFFECTIVE DOSE OF Retigabine (TROBALT ® ) IN THE MAXIMAL ELECTROSHOCK TEST AND MAXIMAL PENTYLENETETRAZOLE TEST IN RATS
2020Co-Authors: Elisaveta G. Apostolova, V. Kokova, Lyudmil PeychevAbstract:Retigabine is a novel antiepileptic drug that influences M-type potassium currents. It is active in broad range of animal seizure models. PURPOSE. The aim of the present study is to determine the median effective dose (ED50) of Retigabine in two seizure models – maximal electroshock (MES) test and maximal pentylenetetrazole (MPTZ) test in rats. METHODS. Male Wistar rats (10 groups of 6 rats) were treated orally with Retigabine in doses 5, 7, 12, 20, 25 mg/kg (MES test) and 35, 60, 70, 90, 100 mg/kg (MPTZ test) respectively. ED50 MES and ED50 MPTZ were evaluated 30 minutes after p.o. administration of Retigabine (Trobalt ® , tab. 200 mg) by the method of Litchfield and Wilcoxon. PTZ was injected i.p. in dose 100 mg/kg. RESULTS. Our results showed ED50 Retigabine = 18 mg/kg in the MES test and ED50 Retigabine = 64 mg/kg in the i.p. MPTZ test. The drug supress electrically and chemically induced seizures – models of generalized tonic – clonic seizures. CONCLUSIONS. Retigabine inhibits generalized seizures in MES test (18 mg/kg, p.o.) and in i.p. MPTZ test (64 mg/kg, p.o).
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COMPARATIVE STUDY OF THE ANTINOCICEPTIVE EFFECT OF ETIFOXINE AND Retigabine IN RATS
Knowledge International Journal, 2018Co-Authors: Vesela Kokova, Elisaveta G. Apostolova, Lyudmil Peychev, Zhivko Zhivko, Kostadin KanalevAbstract:Introduction: Etifoxine is a nonbenzodiazepine anxiolytic and anticonvulsant drug. It enhances GABAergic transmission directly by binding to β2 and/or β3 subunits of the GABAA receptor complex and indirectly via stimulation of neurosteroid production after the activation of 18 kDa translocator protein (TSPO). Retigabine is an anticonvulsant drug which activates low-threshold voltage-gated potassium channels. Anticonvulsant drugs reduce hyperexcitability and are currently extensively studied for possible antinociceptive activity. The aim of this study is to compare the antinociceptive effect of etifoxine and Retigabine in rats. Materials and methods: The research included forty male Wistar rats, divided into five groups (n = 8). They were treated intraperitoneally with: 1st group (control) – saline 0,1ml/100g bw, 2nd group–metamizole natrii 150 mg/kg bw, 3rd group – etifoxine 50 mg/kg bw, 4th group –Retigabine 5 mg/kg bw and 5th group – Retigabine 15 mg/kg bw. The antinociceptive effect was evaluated with hot plate test and analgesy-meter test. The statistical analysis was performed using SPSS.17. Results: Etifoxine did not prolong the latency time in hot plate test and did not increase the withdrawal latency in analgesy-meter test, compared to the animals treated with saline. In hot plate test, Retigabine in dose 15 mg/kg bw significantly increased the latency time at the second and third hour, compared to the control group (p<0.05). In analgesy-meter test, a significant increase of the withdrawal latency between Retigabine and control animals occurred only at dose 15 mg/kg bw at first hour after single administration (p<0.05). Conclusions: The obtained experimental data show that etifoxine in dose 50 mg/kg bw does not have antinociceptive effect. Single administration of Retigabine 15 mg/kg bw reduced painful thermal and mechanical stimuli in rats. The presence of KCNQ channels in the neuronal pathways of pain suggests that the antinociceptive effect of Retigabine is maybe based on the activation of low-threshold potassium channels.
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Retigabine diminishes the effects of acetylcholine, adrenaline and adrenergic agonists on the spontaneous activity of guinea pig smooth muscle strips in vitro
Autonomic Neuroscience: Basic and Clinical, 2016Co-Authors: Elisaveta G. Apostolova, Plamen Zagorchev, Vesela Kokova, Lyudmil PeychevAbstract:Abstract Purpose The aim of this study is to evaluate the effect of Retigabine on the smooth muscle response to acetylcholine, adrenaline, α-and β-adrenoceptor agonists. Methods We studied the change in the spontaneous smooth muscle contraction of guinea pig gastric corpus strips before and after 20-min treatment with 2 μM Retigabine. We also evaluated the effect of Retigabine on the smooth muscle response to 10 μM acetylcholine, 1 and 10 μM adrenaline, 1 μM methoxamine, 0.1 μM p-iodoclonidine and 10 μM isoproterenol. Results We observed a significant reduction in the effects of all studied mediators and agonists when they were added to organ baths in the presence of Retigabine. Retigabine diminished the effect of acetylcholine on the spontaneous smooth muscle activity. The effect was fully antagonized by XE-991 (Kv7 channel blocker), which supports our hypothesis about the role of KCNQ channels in the registered changes. The increase in the contraction force after adding of 1 μM adrenaline, methoxamine, and 0.1 μM p-iodoclonidine was also significantly smaller in presence of Retigabine. However, comparing the effect of 10 μM adrenaline on the contractility before and after treatment with Retigabine, we observed increased contractility when Retigabine was present in the organ baths. Conclusion A possible explanation for the observed diminished effects of mediators and receptor agonists is that the effect of Retigabine on smooth muscle contractility is complex. The membrane hyperpolarization, the interaction between Kv7 channels and adrenoceptors, and the influence on signaling pathways may contribute to the summary smooth muscle response.
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activation of kcnq channels located on the skeletal muscle membrane by Retigabine and its influence on the maximal muscle force in rat muscle strips
Naunyn-schmiedebergs Archives of Pharmacology, 2016Co-Authors: Plamen Zagorchev, Elisaveta G. Apostolova, Vesela Yu Kokova, Lyudmil PeychevAbstract:Retigabine is a new antiepileptic drug with the main mechanism of action: activation of voltage-gated potassium channels (Kv7) represented in many tissues including the excitable cells—neuronal and muscular. The aim of this article is to determine the role of potassium channels located on the skeletal muscle membrane in the in vivo and in vitro reduction of muscle contractile activity induced by Retigabine. We studied the effects of Retigabine on the motor function in vivo using a bar holding test and exploratory activity using open field test in rats. Electrical field stimulation (EFS) was applied to skeletal muscle strips in vitro in order to evaluate muscular activity. We registered a significant decrease in the muscle tone and exploratory activity of rats, treated orally with 60 mg/kg bw Retigabine. In vitro experiments showed decrease in the maximal muscle force of strips in the presence of Retigabine in the medium after both indirect (nerve-like) and direct (muscle-like) stimulation. The effects were fully antagonized by XE-991 (Kv7 channel blocker), which supports our hypothesis about the relation between these types of potassium channels and the observed change in the muscle force. Based on these results, we can conclude that skeletal muscle Kv7 channels play a significant role in the myorelaxation and reduced muscle force registered after treatment with Kv7 channels openers (e.g., Retigabine). The hyperpolarization of skeletal muscle membrane caused by accelerated K+ efflux may be the underlying cause for the effect of Retigabine on the muscle tone.
Frederik Rode - One of the best experts on this subject based on the ideXlab platform.
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the pan kv7 kcnq channel opener Retigabine inhibits striatal excitability by direct action on striatal neurons in vivo
Basic & Clinical Pharmacology & Toxicology, 2017Co-Authors: Henrik H Hansen, Frederik Rode, Pia Weikop, Maria D Mikkelsen, Jens D. MikkelsenAbstract:: Central Kv7 (KCNQ) channels are voltage-dependent potassium channels composed of different combinations of four Kv7 subunits, being differently expressed in the brain. Notably, striatal dopaminergic neurotransmission is strongly suppressed by systemic administration of the pan-Kv7 channel opener Retigabine. The effect of Retigabine likely involves the inhibition of the activity in mesencephalic dopaminergic neurons projecting to the striatum, but whether Kv7 channels expressed in the striatum may also play a role is not resolved. We therefore assessed the effect of intrastriatal Retigabine administration on striatal neuronal excitability in the rat determined by c-Fos immunoreactivity, a marker of neuronal activation. When Retigabine was applied locally in the striatum, this resulted in a marked reduction in the number of c-Fos-positive neurons after a strong excitatory striatal stimulus induced by acute systemic haloperidol administration in the rat. The relative mRNA levels of Kv7 subunits in the rat striatum were found to be Kv7.2 = Kv7.3 = Kv7.5 > >Kv7.4. These data suggest that intrastriatal Kv7 channels play a direct role in regulating striatal excitability in vivo.
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functional effects of the kcnq modulators Retigabine and xe991 in the rat urinary bladder
European Journal of Pharmacology, 2010Co-Authors: Frederik Rode, Julie Svalo, Majid Sheykhzade, Lars Christian Biilmann RonnAbstract:Abstract The anticonvulsant Retigabine has previously been reported to inhibit bladder overactivity in rats in vivo but the mechanism and site of action are not known. In the present study we investigated the effect of Retigabine in isolated rat bladder tissue. Bladders from Sprague–Dawley rats were cut transversally into rings and mounted on an isometric myograph. The average tension, the amplitude and frequency of bladder muscle twitches were measured. The bladder tissue was stimulated with carbachol, KCl (5, 10 and 60 mM), and by electric field stimulation. Dose–response curves were obtained with increasing concentrations of the KCNQ(2–5) selective positive modulator, Retigabine or with the KCNQ(1–5) negative modulator XE991. Retigabine experiments were repeated in the presence of 10 µM XE991. Retigabine reduced both the contractility and the overall tonus of bladder tissue independent of the mode of stimulation with EC50 values ranging from 3.3 µM (20 mM KCl) to 8.3 µM (0.2 µM carbachol). In support of a KCNQ-specific effect, Retigabine had only weak effects after 60 mM KCl pre treatment and all Retigabine effects could be reversed by XE991. XE991 increased both the amplitude and mean tension of the bladder but was more potent at increasing the number rather than the size of the stimulated twitches. In conclusion, this study demonstrates an efficacious KCNQ dependent effect of Retigabine and XE991 on rat bladder contractility.
