Topic: retigabine

The image shows the morphology of pyramidal neuron filled with biocytin during the recording from mutant cell.This study focuses on understanding the pathophysiological mechanisms of KCNQ-DEE, a severe form of neonatal epilepsy associated with variants in genes of the KCNQ family. KCNQ genes encode subunits of KV7 voltage-gated potassium channels. Each channel is formed by four subunits and particularly heterotetrametric KV7.2/KV7.3 or KV7.5/KV7.3 channels, carrying the so-called M-current, play a crucial role in modulating neuronal excitability in the central nervous system. Most pathogenic v

Recent evidence suggests an anti-hypertensive effect for the pineal neurohormone melatonin (MT) as it promotes vasorelaxation through concentration-, receptor-, and vessel-dependent mechanisms. Interestingly, Kv7.4 activation results to be a downstream effect of several vasorelaxants that activate the cAMP signalling cascade. Furthermore, positive modulation of Kv7.4 also appears to be the mechanism by which hydrogen sulphide (H2S) mediates vasorelaxation. In fact, the H2S-donor sodium hydrogen sulphide (NaHS) promoted endothelial-independent relaxations of rat aortic rings by facilitating Kv7

Kv7.2 and Kv7.3 are voltage-gated potassium channels subunits mainly expressed in neurons where they underlie the M-current (IKM), a sub-threshold K+ current controlling action potentials generation and frequency. The Kv7.2/7.3 channel opener retigabine is an antiseizures drug used until 2017 when it was withdrawn from the market for safety reasons. Since then, no Kv7 activator is currently available for clinical use. We used a drug repurposing strategy to identify novel Kv7.2/3 activators. A library of 5600 compounds, mostly represented by clinically-approved drugs, was screened in CHO cells

Blood-brain barrier (BBB) disruption and the consequent alteration of solute and ion transport play a pivotal role in the onset and progression of many neurological diseases, including epilepsy. Among the players that have been shown to modulate BBB function, our group recently demonstrated that Kv7 channels, a family of voltage-gated potassium channels, are critical modulators of barrier permeability, both in physiological conditions and experimental models of seizures. Accumulating evidence suggest that the renin-angiotensin system (RAS) is altered during epilepsy and affects BBB permeabilit

Dravet Syndrome is a developmental and epileptic encephalopathy, with intractable seizures and other comorbidities; due to loss of function variants in SCN1A, the disease mostly manifests because of the impairment of the functionality of inhibitory interneurons. Trying to address the unmet clinical needs of patients carrying missense variants, we used a transgenic mouse model carrying the recurrent variant p.(Ala1783Val) in Scn1a. This mouse closely recapitulates the clinical phenotype, allowing to more deeply explore the epileptogenesis and find new precision medicine approaches.We carried ou

Seizures arise from disruption in mechanisms that control neuronal excitability and the M-current is one such mechanism. This low-threshold potassium current modulates neuronal excitability and suppresses repetitive firing. M-channels assemble as tetramers of Kv7 subunits and mutations in the KCNQ2 gene, encoding Kv7.2, are linked to epilepsy and intellectual disabilities. Despite this common epileptogenic mechanism, understanding M-channel regulation remains limited. We identified type 1 TARPs, well-known Transmembrane AMPA-receptors Regulatory proteins, as new interactors of the Kv7.2 subuni