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.
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| 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.
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| Authors | Frank Mauler, Volker Hinz, Ervin Horváth, Joachim Schuhmacher, Heiko A Hofmann, Stephan Wirtz, Michael G Hahn, Klaus Urbahns |
| Journal | The European journal of neuroscience (Eur J Neurosci) Vol. 20 Issue 7 Pg. 1761-8 (Oct 2004) ISSN: 0953-816X [Print] France |
| PMID | 15379997 (Publication Type: Journal Article) |
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