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.
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.
Mauler
Frank
F
CNS Research, Bayer Health Care, Aprather Weg 18a, 42096 Wuppertal, Germany. Frank.Mauler@bayerhealthcare.com
Hinz
Volker
V
Horváth
Ervin
E
Schuhmacher
Joachim
J
Hofmann
Heiko A
HA
Wirtz
Stephan
S
Hahn
Michael G
MG
Urbahns
Klaus
K
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
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