The effects of ifenprodil and eliprodil on voltage-dependent Ca2+ channels and in gerbil global cerebral ischaemia.
Ifenprodil and eliprodil are both non-competitive NMDA receptor antagonists which have been shown to inhibit neuronal Ca2+ channel currents. We have examined the effects of these agents on two defined subtypes of voltage-dependent Ca2+ channels and in the gerbil model of global cerebral ischaemia. Recombinantly expressed human alpha 1B-1 alpha 2b beta 1-3 Ca2+ subunits in HEK293 cells, which results in an omega-conotoxin-sensitive neuronal N-type voltage-dependent Ca2+ channel and omega-Aga IVA sensitive Ca2+ channels (P-type) in acutely isolated cerebellar Purkinje neurones were reversibly inhibited by ifenprodil and eliprodil. Human N-type Ca2+ channel currents were inhibited by ifenprodil and eliprodil with IC50 values of 50 microM and 10 microM respectively whereas P-type Ca2+ channel currents were inhibited reversibly by ifenprodil and eliprodil with approximate IC50 values of 60 microM and 9 microM respectively. Maximum current block observed for both channel subtypes was approximately 80% for both ifenprodil and eliprodil. For neuroprotection studies, animals were subjected to 5 min bilateral carotid artery occlusion with or without administration of either ifenprodil or eliprodil (5, 10 or 20 mg/kg i.p.) immediately after surgery followed by two further doses (2.5, 5 or 10 mg/kg, respectively) at 3 and 6 h post-occlusion. Both compounds provided significant protective effects against ischaemia-induced neurodegeneration in the CA1 region of the hippocampus. These results indicate that both ifenprodil and eliprodil protect against ischaemia-induced neurodegeneration when administered post-occlusion and that they also block N and P-type voltage-dependent Ca2+ channels.
Eli Lilly and Co., Lilly Research Centre Ltd., Windlesham, Surrey, UK.
C P
CP
Bath
L N
LN
Farrell
J
J
Gilmore
M A
MA
Ward
C A
CA
Hicks
M J
MJ
O'Neill
D
D
Bleakman
D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D002545:Brain Ischemia / Q000503:physiopathology*; D015220:Calcium Channels / Q000187:drug effects*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005849:Gerbillinae; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D008297:Male; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology*; D011689:Purkinje Cells / Q000187:drug effects; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
D015220:Calcium Channels; D018691:Excitatory Amino Acid Antagonists; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; C010739:ifenprodil; C058083:eliprodil