Sodium channel blocking activity of AM-36 and sipatrigine (BW619C89): in vitro and in vivo evidence.

Abstract

Sodium channel blockers are neuroprotective against cerebral ischemia in animal models. A novel neuroprotective compound AM-36, when screened for activity at the most common receptor and ion channel binding sites, revealed activity at site 2 Na+ channels. Studies then investigated this Na+ channel blocking activity in vitro and in vivo relative to other Na+ channel blockers, including the neuroprotective agent sipatrigine (BW619C89). AM-36 inhibited batrachotoxinin (BTX)-sensitive Na+ channel binding in rat brain homogenates with an IC50 of 0.28 microM. Veratridine (100 microM)-induced neurotoxicity in murine cerebellar granule cells was completely inhibited by AM-36 (1.7 microM) compared to only partial inhibition by sipatrigine (26 microM). Veratridine-stimulated glutamate release, as measured through a microdialysis probe in the cortex of anesthetised rats, was inhibited by 90% by superfusion of AM-36 (1000 microM). In the endothelin-1 (ET-1) model of middle cerebral artery occlusion (MCAo) in conscious rats, both AM-36 (6 mg/kg i.p.) and sipatrigine (10 mg/kg i.p.) 30 min post-MCAo significantly reduced cortical, but not striatal infarct volume. As the refractiveness of the striatum is likely to be dependent on the route and time of drug administration, AM-36 (1 mg/kg i.v.) was administered 3 or 5 h after MCAo and significantly reduced both cortical and striatal infarct volumes. The present studies demonstrate Na+ channel blocking activity of AM-36 both in vitro and in vivo, together with significant neuroprotection when administration is delayed up to 5 h following experimental stroke.

• Authors: J K Callaway, M Castillo-Melendez, S F Giardina, E K Krstew, P M Beart, B Jarrott
• Journal: Neuropharmacology (Neuropharmacology) Vol. 47 Issue 1 Pg. 146-55 (Jul 2004) ISSN: 0028-3908 [Print] England
• PMID: 15165842 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Batrachotoxins
• Neuroprotective Agents
• Piperazines
• Pyrimidines
• Receptors, Cell Surface
• Receptors, Neurotransmitter
• Sodium Channel Blockers
• Sodium Channels
• AM 36
• sipatrigine

Topics

• Animals
• Batrachotoxins (pharmacology)
• Guinea Pigs
• Male
• Mice
• Neuroprotective Agents (pharmacology)
• Piperazines (pharmacology)
• Pyrimidines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptors, Cell Surface (antagonists & inhibitors, physiology)
• Receptors, Neurotransmitter (antagonists & inhibitors, physiology)
• Sodium Channel Blockers (pharmacology)
• Sodium Channels (drug effects, physiology)
• Synaptosomes (drug effects, physiology)