The effects of ifenprodil and eliprodil on voltage-dependent Ca 2+ channels and in gerbil global cerebral ischaemia

The effects of ifenprodil and eliprodil on voltage-dependent Ca 2+ channels and in gerbil global... Ifenprodil and eliprodil are both non-competitive NMDA receptor antagonists which have been shown to inhibit neuronal Ca 2+ channel currents. We have examined the effects of these agents on two defined subtypes of voltage-dependent Ca 2+ channels and in the gerbil model of global cerebral ischaemia. Recombinantly expressed human α 1B-1 α 2b β 1–3 Ca 2+ subunits in HEK293 cells, which results in an ω-conotoxin-sensitive neuronal N-type voltage-dependent Ca 2+ channel and ω-Aga IVA sensitive Ca 2+ channels (P-type) in acutely isolated cerebellar Purkinje neurones were reversibly inhibited by ifenprodil and eliprodil. Human N-type Ca 2+ channel currents were inhibited by ifenprodil and eliprodil with IC 50 values of 50 μM and 10 μM respectively whereas P-type Ca 2+ channel currents were inhibited reversibly by ifenprodil and eliprodil with approximate IC 50 values of 60 μM and 9 μM 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 Ca 2+ channels. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Journal of Pharmacology Elsevier

The effects of ifenprodil and eliprodil on voltage-dependent Ca 2+ channels and in gerbil global cerebral ischaemia

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Publisher
Elsevier
Copyright
Copyright © 1996 Elsevier Ltd
ISSN
0014-2999
D.O.I.
10.1016/0014-2999(95)00846-2
Publisher site
See Article on Publisher Site

Abstract

Ifenprodil and eliprodil are both non-competitive NMDA receptor antagonists which have been shown to inhibit neuronal Ca 2+ channel currents. We have examined the effects of these agents on two defined subtypes of voltage-dependent Ca 2+ channels and in the gerbil model of global cerebral ischaemia. Recombinantly expressed human α 1B-1 α 2b β 1–3 Ca 2+ subunits in HEK293 cells, which results in an ω-conotoxin-sensitive neuronal N-type voltage-dependent Ca 2+ channel and ω-Aga IVA sensitive Ca 2+ channels (P-type) in acutely isolated cerebellar Purkinje neurones were reversibly inhibited by ifenprodil and eliprodil. Human N-type Ca 2+ channel currents were inhibited by ifenprodil and eliprodil with IC 50 values of 50 μM and 10 μM respectively whereas P-type Ca 2+ channel currents were inhibited reversibly by ifenprodil and eliprodil with approximate IC 50 values of 60 μM and 9 μM 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 Ca 2+ channels.

Journal

European Journal of PharmacologyElsevier

Published: Mar 28, 1996

References

  • Cerebral hypoxia
    Brierley, J.B.
  • Excitotoxic cell death
    Choi, D.
  • CGS 19755, a competitive NMDA receptor antagonist, reduces calcium-calmodulin binding and improves outcome after global cerebral ischemia
    Grotta, J.C.; Picone, C.M.; Ostrow, P.T.; Strong, R.A.; Earls, R.M.; Yao, L.P.; Rhoades, H.M.; Dedman, J.R.
  • Excitatory amino acid antagonists and their potential for the treatment of ischaemic brain damage in man
    McCulloch, J.

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