title: Selective intermediate-/small-conductance calcium-activated potassium channel (KCNN4) blockers are potent and effective therapeutics in experimental brain oedema and traumatic brain injury caused by acute subdural haematoma.
abstract: Early deterioration and death after brain injury is often the result of oedema in the injured and peri-lesional tissue. So far, no pharmacotherapy is available that exhibits significant brain oedema-reducing efficacy in patients. We selected two low molecular weight compounds from different chemical classes, a triazole (1-[(2-chlorophenyl)diphenylmethyl]-1,2,3-triazole) and a cyclohexadiene (methyl 4-[4-chloro-3-(trifluoromethyl)phenyl]-6-methyl-3-oxo-1,4,7-tetrahydroisobenzofuran-5-carboxylate) to characterize their pharmacological properties on KCNN4 channels (intermediate/small conductance calcium-activated potassium channel, subfamily N, member 4) in vitro as well as in vivo. In vitro we replaced potassium by rubidium (Rb+) and determined Rb+ fluxes evoked by 10 micro m of the calcium ionophore A23187 on C6BU1 rat glioma cells. Compared with known KCNN4 blockers, such as clotrimazole (IC50=360 +/- 12 nm) and charybdotoxin (IC50=3.3 +/- 1.9 nm), the triazole and cyclohexadiene were considerably more potent than clotrimazole and displayed similar potencies (IC50=12.1 +/- 8.8 and 13.3 +/- 4.7 nm, respectively). In the rat acute subdural haematoma model, both the triazole and cyclohexadiene displayed reduction of brain water content (-26% at 0.3 mg/kg and -24% at 0.01 mg/kg) and reduction of the intracranial pressure (-46% at 0.1 mg/kg and -60% at 0.003 mg/kg) after 24 h when administered as a 4-h infusion immediately after brain injury. When infarct volumes were determined after 7 days, the triazole as well as the cyclohexadiene displayed strong neuroprotective efficacy (-52% infarct volume reduction at 1.2 mg/kg and -43% at 0.04 mg/kg, respectively). It is concluded that blockade of KCNN4 channels is a new pharmacological approach to attenuate acute brain damage caused by traumatic brain injury.
authors.affiliation: CNS Research, Bayer Health Care, Aprather Weg 18a, 42096 Wuppertal, Germany. Frank.Mauler@bayerhealthcare.com
authors.forename: Frank
authors.initials: F
authors.lastname: Mauler
authors.forename: Volker
authors.initials: V
authors.lastname: Hinz
authors.forename: Ervin
authors.initials: E
authors.lastname: Horváth
authors.forename: Joachim
authors.initials: J
authors.lastname: Schuhmacher
authors.forename: Heiko A
authors.initials: HA
authors.lastname: Hofmann
authors.forename: Stephan
authors.initials: S
authors.lastname: Wirtz
authors.forename: Michael G
authors.initials: MG
authors.lastname: Hahn
authors.forename: Klaus
authors.initials: K
authors.lastname: Urbahns
mesh_terms: D000818:Animals; D001923:Brain Chemistry; D001929:Brain Edema / Q000628:therapy*; D001930:Brain Injuries / Q000628:therapy*; D000001:Calcimycin / Q000494:pharmacology; D045744:Cell Line, Tumor; D002544:Cerebral Infarction / Q000473:pathology; D018999:Charybdotoxin / Q000627:therapeutic use; D003022:Clotrimazole / Q000627:therapeutic use*; D017931:DNA Primers; D004912:Erythrocytes / Q000502:physiology; D005910:Glioma / Q000235:genetics; D006408:Hematoma, Subdural / Q000628:therapy*; D006801:Humans; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D026902:Potassium Channel Blockers / Q000627:therapeutic use*; D024681:Potassium Channels, Calcium-Activated; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012413:Rubidium / Q000097:blood; D014867:Water / Q000032:analysis
chemical_list: D017931:DNA Primers; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496923:KCNN4 protein, human; D026902:Potassium Channel Blockers; D024681:Potassium Channels, Calcium-Activated; D014867:Water; D018999:Charybdotoxin; D000001:Calcimycin; D003022:Clotrimazole; D012413:Rubidium