Exploration of P-type Ca2+ channels as drug targets for the treatment of epilepsy or ischemic stroke.
We investigated the neuroprotective efficacy of the P-type Ca2+ channel antagonist daurisoline against electroshock-induced convulsions in rats and mice, hypoxic/hypoglycemic-induced damage in rat hippocampal slices and brain damage induced by occlusion of the middle cerebral artery (MCA) in rats. Daurisoline applied intravenously (i.v.) (bolus of 1-60 mg/kg) reduced the spontaneous activity of rat cerebellar Purkinje cells in a dose-dependent manner, a result demonstrating activity in the brain with systemic administration of the compound. While this effect reversed rapidly in about 10-20 min following bolus-application of the drug at doses of up to 30 mg/kg, a dose of 60 mg/kg consistently induced a depression of respiration followed by death of the animals. Daurisoline administered at 10-30 mg/kg did not prevent electroshock-induced convulsions in mice or rats, nor did it reduce the neuronal damage in hippocampal slices induced by a hypoxic/hypoglycemic insult in vitro by MCA occlusion in vivo. These observations do not support the hypothesis that P-type Ca2+ channels are promising drug targets for the acute treatment of epileptic convulsions and/or ischemic stroke.
Lingenhöhl
K
K
Ciba, CNS Research, Basel, Switzerland.
Small
D L
DL
Monette
R
R
Buchan
A M
AM
Morley
P
P
Allegrini
P R
PR
Fröst
L W
LW
Sauer
D
D
Schmutz
M
M
Knöpfel
T
T
D000470:Alkaloids / Q000627:therapeutic use*; D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D044182:Benzylisoquinolines; D001921:Brain / Q000187:drug effects / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy*; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D004827:Epilepsy / Q000188:drug therapy*; D005071:Evoked Potentials / Q000187:drug effects; D008297:Male; D051379:Mice; D018613:Microscopy, Confocal; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D011689:Purkinje Cells / Q000187:drug effects; D051381:Rats
D000470:Alkaloids; D000927:Anticonvulsants; D044182:Benzylisoquinolines; D002121:Calcium Channel Blockers; D018696:Neuroprotective Agents; C023968:daurisoline