Present address: Genzyme Virotech GmbH, Loewenplatz 5, 65428 Rüsselsheim, Germany.
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
Article first published online: 14 SEP 2004
European Journal of Neuroscience
Volume 20, Issue 7, pages 1761–1768, October 2004
How to Cite
Mauler, F., Hinz, V., Horváth, E., Schuhmacher, J., Hofmann, H. A., Wirtz, S., Hahn, M. G. and Urbahns, K. (2004), 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. European Journal of Neuroscience, 20: 1761–1768. doi: 10.1111/j.1460-9568.2004.03615.x
- Issue published online: 14 SEP 2004
- Article first published online: 14 SEP 2004
- Received 4 March 2004, accepted 12 July 2004
- brain water content;
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 µm 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.