RGD Reference Report - 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. - Rat Genome Database

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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.

Authors: Mauler, Frank  Hinz, Volker  Horváth, Ervin  Schuhmacher, Joachim  Hofmann, Heiko A  Wirtz, Stephan  Hahn, Michael G  Urbahns, Klaus 
Citation: Mauler F, etal., Eur J Neurosci. 2004 Oct;20(7):1761-8. doi: 10.1111/j.1460-9568.2004.03615.x.
RGD ID: 329969897
Pubmed: PMID:15379997   (View Abstract at PubMed)
DOI: DOI:10.1111/j.1460-9568.2004.03615.x   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Acute Subdural Hematoma treatmentISOKcnn4 (Rattus norvegicus)329969897; 329969897 RGD 
Acute Subdural Hematoma treatmentIMP 329969897 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Kcnn4  (potassium calcium-activated channel subfamily N member 4)

Genes (Mus musculus)
Kcnn4  (potassium intermediate/small conductance calcium-activated channel, subfamily N, member 4)

Genes (Homo sapiens)
KCNN4  (potassium calcium-activated channel subfamily N member 4)


Additional Information