title: Inhibition of the potassium channel KCa3.1 by senicapoc reverses tactile allodynia in rats with peripheral nerve injury.
abstract: Neuropathic pain is a debilitating, chronic condition with a significant unmet need for effective treatment options. Recent studies have demonstrated that in addition to neurons, non-neuronal cells such as microglia contribute to the initiation and maintenance of allodynia in rodent models of neuropathic pain. The Ca2+- activated K+channel, KCa3.1 is critical for the activation of immune cells, including the CNS-resident microglia. In order to evaluate the role of KCa3.1 in the maintenance of mechanical allodynia following peripheral nerve injury, we used senicapoc, a stable and highly potent KCa3.1 inhibitor. In primary cultured microglia, senicapoc inhibited microglial nitric oxide and IL-1β release. In vivo, senicapoc showed high CNS penetrance and when administered to rats with peripheral nerve injury, it significantly reversed tactile allodynia similar to the standard of care, gabapentin. In contrast to gabapentin, senicapoc achieved efficacy without any overt impact on locomotor activity. Together, the data demonstrate that the KCa3.1 inhibitor senicapoc is effective at reducing mechanical hypersensitivity in a rodent model of peripheral nerve injury.
authors.affiliation: Neuroinflammation Disease Biology Unit, Lundbeck Research USA Inc., 215 College Rd, Paramus, NJ 07652, USA. Electronic address: staalro@yahoo.com.
authors.forename: Roland G W
authors.initials: RGW
authors.lastname: Staal
authors.affiliation: Neuroinflammation Disease Biology Unit, Lundbeck Research USA Inc., 215 College Rd, Paramus, NJ 07652, USA.
authors.forename: Tanzilya
authors.initials: T
authors.lastname: Khayrullina
authors.affiliation: Neuroinflammation Disease Biology Unit, Lundbeck Research USA Inc., 215 College Rd, Paramus, NJ 07652, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Psychogenics Inc., 765 Old Saw Mill River Rd #104, Tarrytown, NY 10591, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Davis
authors.affiliation: Neuroinflammation Disease Biology Unit, Lundbeck Research USA Inc., 215 College Rd, Paramus, NJ 07652, USA.
authors.forename: Shaun M
authors.initials: SM
authors.lastname: Fallon
authors.affiliation: Molecular Pharmacology, Bioanalysis & Operations, Lundbeck Research USA Inc., 215 College Road, Paramus, NJ 07652, USA.
authors.forename: Manuel
authors.initials: M
authors.lastname: Cajina
authors.affiliation: Molecular Pharmacology, Bioanalysis & Operations, Lundbeck Research USA Inc., 215 College Road, Paramus, NJ 07652, USA.
authors.forename: Megan E
authors.initials: ME
authors.lastname: Nattini
authors.affiliation: Psychogenics Inc., 765 Old Saw Mill River Rd #104, Tarrytown, NY 10591, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Hu
authors.affiliation: Molecular Pharmacology, Bioanalysis & Operations, Lundbeck Research USA Inc., 215 College Road, Paramus, NJ 07652, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Molecular Pharmacology, Bioanalysis & Operations, Lundbeck Research USA Inc., 215 College Road, Paramus, NJ 07652, USA.
authors.forename: Suresh Babu
authors.initials: SB
authors.lastname: Poda
authors.affiliation: Neuroinflammation Disease Biology Unit, Lundbeck Research USA Inc., 215 College Rd, Paramus, NJ 07652, USA.
authors.forename: Stevin
authors.initials: S
authors.lastname: Zorn
authors.affiliation: Molecular Pharmacology, Bioanalysis & Operations, Lundbeck Research USA Inc., 215 College Road, Paramus, NJ 07652, USA.
authors.forename: Gamini
authors.initials: G
authors.lastname: Chandrasena
authors.affiliation: Neuroinflammation Disease Biology Unit, Lundbeck Research USA Inc., 215 College Rd, Paramus, NJ 07652, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Dale
authors.affiliation: Neuroinflammation Disease Biology Unit, Lundbeck Research USA Inc., 215 College Rd, Paramus, NJ 07652, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Cambpell
authors.affiliation: Neurodegeneration Disease Biology Unit, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
authors.forename: Lars Christian
authors.initials: LC
authors.lastname: Biilmann Rønn
authors.affiliation: Neurodegeneration Disease Biology Unit, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
authors.forename: Gordon
authors.initials: G
authors.lastname: Munro
authors.affiliation: Neuroinflammation Disease Biology Unit, Lundbeck Research USA Inc., 215 College Rd, Paramus, NJ 07652, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mӧller
mesh_terms: D000081:Acetamides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D006801:Humans; D006930:Hyperalgesia / Q000150:complications* / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors*; D008124:Locomotion / Q000187:drug effects; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D059348:Peripheral Nerve Injuries / Q000150:complications*; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D014320:Triphenylmethyl Compounds / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000081:Acetamides; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496923:KCNN4 protein, human; D026902:Potassium Channel Blockers; D014320:Triphenylmethyl Compounds; D011188:Potassium; C472774:senicapoc
keywords: Calcium-activated potassium channel; Chronic constriction injury; Gabapentin; ICA-17043; K(Ca)3.1; KCNN4; Microglia; Neuropathic pain; Senicapoc; Tactile allodynia; Von Frey