SB 201823-A, a neuronal Ca2+ antagonist is neuroprotective in two models of cerebral ischaemia.
We have characterised the Ca2+ channel blocking properties of a new non-peptide Ca2+ channel antagonist, SB 201823-A, in cultures of rat sensory neurones. The IC50 for SB 201823-A against total Ca2+ current in sensory neurones was 4.9 microM. SB 201823-A showed little selectivity for sub-types of neuronal Ca2+ channel but was selective for Ca2+ channels over Na+ and K+ channels. Efficacy against other types of cation channel such as agonist gated channels was not assessed. SB 201823-A was neuroprotective in vivo when administered post-ischaemia in one focal and one global model of neuronal ischaemia. In the rat photothrombotic focal lesion model, SB 201823-A administered i.p. 10 min post-ischaemia resulted in a dramatic reduction in lesion volume. In the gerbil bilateral carotid artery occlusion global model, SB 201823-A dosed i.p. 30 min post-occlusion resulted in both histological and functional improvements when compared to vehicle treated animals. These data suggest that such novel neuronal Ca2+ channel antagonists may have potential in ameliorating both the pathological and functional consequences of stroke in man.
Benham
C D
CD
SmithKline Beecham Pharmaceuticals, The Pinnacles, Harlow, Essex, U.K.
Brown
T H
TH
Cooper
D G
DG
Evans
M L
ML
Harries
M H
MH
Herdon
H J
HJ
Meakin
J E
JE
Murkitt
K L
KL
Patel
S R
SR
Roberts
J C
JC
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D002341:Carotid Artery Thrombosis / Q000503:physiopathology; D004594:Electrophysiology; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism; D005849:Gerbillinae; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism*; D010880:Piperidines / Q000627:therapeutic use*; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D002121:Calcium Channel Blockers; D010880:Piperidines; D015222:Sodium Channels; C085883:SB 201823-A; D011188:Potassium