Repetitive cortical spreading depression in a gyrencephalic feline brain: inhibition by the novel benzoylamino-benzopyran SB-220453.
Transient cortical depolarization is implicated in the pathology of migraine. SB-220453 is a potent anti-convulsant which inhibits neurogenic inflammation and cortical spreading depression (SD)-evoked nitric oxide release via a novel but unknown mechanism. This study further investigates the effects of SB-220453 on generation and propagation of repetitive SD in the anaesthetized cat. Vehicle or SB-220453 1, 3 or 10 mg/kg was administered intraperitoneally 90 min prior to induction of SD in the suprasylvian gyrus (SG). Changes in d.c. potential were recorded in the SG and the adjacent marginal gyrus (MG). In vehicle-treated animals (n = 7), a brief exposure (6 min) to KCl induced a median (25-75% range) number of five (four to six) and three (two to four) depolarizations over a duration of 55 min (32-59 min) and 51 min (34-58 min) in the SG and MG, respectively. SB-220453 produced dose-related inhibition of the number of events and period of repetitive SD activity. SB-220453 also reduced SD-induced repetitive pial vasodilatation but had no effect on resting haemodynamics. However, when SD events were observed in the presence of SB-220453, it had no effect on metabolic coupling. These results show that SB-220453 produces marked inhibition of repetitive SD in the anaesthetized cat. SB-220453 may therefore have therapeutic potential in treatment of SD-like activity in migraine.
Smith
M I
MI
Department of Neuroscience Research, SmithKline Beecham Pharmaceuticals, Harlow, UK.
Read
S J
SJ
Chan
W N
WN
Thompson
M
M
Hunter
A J
AJ
Upton
N
N
Parsons
A A
AA
D000700:Analgesics / Q000097:blood / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000097:blood / Q000494:pharmacology*; D001549:Benzamides / Q000097:blood / Q000494:pharmacology*; D001578:Benzopyrans / Q000097:blood / Q000494:pharmacology*; D002415:Cats; D013181:Cortical Spreading Depression / Q000187:drug effects*; D004353:Drug Evaluation, Preclinical; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008576:Meningeal Arteries / Q000187:drug effects / Q000648:ultrastructure; D008881:Migraine Disorders / Q000188:drug therapy* / Q000503:physiopathology; D009569:Nitric Oxide / Q000378:metabolism; D010841:Pia Mater / Q000098:blood supply; D011189:Potassium Chloride / Q000633:toxicity; D014664:Vasodilation / Q000187:drug effects
D000700:Analgesics; D000927:Anticonvulsants; D001549:Benzamides; D001578:Benzopyrans; C118706:tonabersat; D009569:Nitric Oxide; D011189:Potassium Chloride