Kv7 (KCNQ) channel openers induce hypothermia in the mouse

Kristensen, Line V.; Sandager‐Nielsen, Karin; Hansen, Henrik H.

doi:10.1016/j.neulet.2010.11.024

Cited by 18 publications

(7 citation statements)

References 31 publications

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“…Results of this study show that administration of the non-selective channel openers flupirtine and retigabine dose-dependently reduced basal body temperature and the SIH response, while reducing locomotor activity levels. These findings are in line with the previous findings, and suggest that non-selective Kv7 channel openers may exert anxiolytic, hypothermic and sedative effects (Korsgaard et al, 2005;Kristensen et al). Also, our results confirm the earlier findings that flupirtine expresses lower potency to enhance Kv7 function compared to retigabine (Korsgaard et al, 2005).…”

Section: Discussionsupporting

confidence: 93%

Kv7 channel modulators reduce the stress-induced hyperthermia response and cause locomotor sedation in rats

Narain¹,

Mirza²,

Olivier³

et al. 2012

Journal of Thermal Biology

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Section: Discussionsupporting

confidence: 93%

Kv7 channel modulators reduce the stress-induced hyperthermia response and cause locomotor sedation in rats

Narain¹,

Mirza²,

Olivier³

et al. 2012

Journal of Thermal Biology

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“…However, in contrast to cannabinoids and GABA agonists, VSN16R is well tolerated in animals, even following direct injection into the brain. Likewise, BMS‐204352, which is highly hydrophobic and readily enters the brain, also has a large therapeutic window in rodents (Gribkoff et al, ; Kristensen et al, ). As BK Ca channels are activated in depolarizing conditions, it is possible that the BK Ca channel conformation targeted by VSN16R may only be active in certain states.…”

Section: Discussionmentioning

confidence: 99%

Big conductance calcium‐activated potassium channel openers control spasticity without sedation

Baker

Pryce

Visintin

et al. 2017

British J Pharmacology

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Background and PurposeOur initial aim was to generate cannabinoid agents that control spasticity, occurring as a consequence of multiple sclerosis (MS), whilst avoiding the sedative side effects associated with cannabis. VSN16R was synthesized as an anandamide (endocannabinoid) analogue in an anti‐metabolite approach to identify drugs that target spasticity.Experimental ApproachFollowing the initial chemistry, a variety of biochemical, pharmacological and electrophysiological approaches, using isolated cells, tissue‐based assays and in vivo animal models, were used to demonstrate the activity, efficacy, pharmacokinetics and mechanism of action of VSN16R. Toxicological and safety studies were performed in animals and humans.Key ResultsVSN16R had nanomolar activity in tissue‐based, functional assays and dose‐dependently inhibited spasticity in a mouse experimental encephalomyelitis model of MS. This effect occurred with over 1000‐fold therapeutic window, without affecting normal muscle tone. Efficacy was achieved at plasma levels that are feasible and safe in humans. VSN16R did not bind to known CB1/CB2/GPPR55 cannabinoid‐related receptors in receptor‐based assays but acted on a vascular cannabinoid target. This was identified as the major neuronal form of the big conductance, calcium‐activated potassium (BKCa) channel. Drug‐induced opening of neuronal BKCa channels induced membrane hyperpolarization, limiting excessive neural‐excitability and controlling spasticity.Conclusions and ImplicationsWe identified the neuronal form of the BKCa channel as the target for VSN16R and demonstrated that its activation alleviates neuronal excitability and spasticity in an experimental model of MS, revealing a novel mechanism to control spasticity. VSN16R is a potential, safe and selective ligand for controlling neural hyper‐excitability in spasticity.

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“…They also affect action potential threshold and resting membrane potential (Marrion, 1997;Delmas and Brown, 2005;Hu et al, 2007;Shah et al, 2008). Potentiation of IM has been proposed as a way to attenuate neuronal excitability and could be therefore beneficial in treating diseases characterized by neuronal hyperexcitability, such as epilepsy, neuropathic pain or bipolar disorders (Jentsch, 2000;Rogawski and Bazil, 2008;Wickenden and McNaughton-Smith, 2009;Kristensen et al, 2012). A well-known IM activator is Retigabine (RTG) (Rundfeldt, 1997), which effectively suppresses epileptiform activity in vitro (Armand et al, 1999;2000) in a dose-and developmental-dependent manner (Forcelli et al, 2012), and in a broad range of animal models of epilepsy and pain in several preclinical pain models (Blackburn- Munro and Jensen, 2003;Munro et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

The new KCNQ2 activator 4‐Chlor‐N‐(6‐chlor‐pyridin‐3‐yl)‐benzamid displays anticonvulsant potential

Boehlen

Schwake

Dost

et al. 2013

British J Pharmacology

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BACKGROUND AND PURPOSEKCNQ2-5 channels are voltage-gated potassium channels that regulate neuronal excitability and represent suitable targets for the treatment of hyperexcitability disorders. The effect of Chlor-N-(6-chlor-pyridin-3-yl)-benzamid was tested on KCNQ subtypes for its ability to alter neuronal excitability and for its anticonvulsant potential. EXPERIMENTAL APPROACHThe effect of 4-Chlor-N-(6-chlor-pyridin-3-yl)-benzamid was evaluated using whole-cell voltage-clamp recordings from CHO cells and Xenopus laevis oocytes expressing different types of KCNQ channels. Epileptiform afterdischarges were recorded in fully amygdala-kindled rats in vivo. Neuronal excitability was assessed using field potential and whole cell recording in rat hippocampus in vitro. KEY RESULTS4-Chlor-N-(6-chlor-pyridin-3-yl)-benzamid caused a hyperpolarizing shift of the activation curve and a pronounced slowing of deactivation in KCNQ2-mediated currents, whereas KCNQ3/5 heteromers remained unaffected. The effect was also apparent in the Retigabine-insensitive mutant KCNQ2-W236L. In fully amygdala-kindled rats, it elevated the threshold for induction of afterdischarges and reduced seizure severity and duration. In hippocampal CA1 cells, 4-Chlor-N-(6-chlor-pyridin-3-yl)-benzamid strongly damped neuronal excitability caused by a membrane hyperpolarization and a decrease in membrane resistance and induced an increase of the somatic resonance frequency on the single cell level, whereas synaptic transmission was unaffected. On the network level, 4-Chlor-N-(6-chlor-pyridin-3-yl)-benzamid caused a significant reduction of g and q oscillation peak power, with no significant change in oscillation frequency. CONCLUSION AND IMPLICATIONSOur data indicate that 4-Chlor-N-(6-chlor-pyridin-3-yl)-benzamid is a potent KCNQ activator with a selectivity for KCNQ2 containing channels. It strongly reduces neuronal excitability and displays anticonvulsant activity in vivo. Abbreviations

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Kv7 (KCNQ) channel openers induce hypothermia in the mouse

Cited by 18 publications

References 31 publications

Kv7 channel modulators reduce the stress-induced hyperthermia response and cause locomotor sedation in rats

Kv7 channel modulators reduce the stress-induced hyperthermia response and cause locomotor sedation in rats

Big conductance calcium‐activated potassium channel openers control spasticity without sedation

The new KCNQ2 activator 4‐Chlor‐N‐(6‐chlor‐pyridin‐3‐yl)‐benzamid displays anticonvulsant potential

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