The pre-ischaemic neuroprotective effect of a novel polyamine antagonist, N1-dansyl-spermine in a permanent focal cerebral ischaemia model in mice.

Abstract

The polyamine sites on the NMDA receptor complex offer a therapeutic target for focal ischaemia, potentially devoid of most side effects associated with NMDA antagonists. In this study, we investigated the effect of a novel polyamine antagonist, N(1)-dansyl-spermine (0.5-10 mg kg(-1)) in a permanent focal cerebral ischaemia model in mice, and compared its effect to that of MK-801 (0.3-3 mg kg(-1)) following administration 30 min prior to ischaemia. A battery of histological and behavioural tests was employed following permanent middle cerebral artery occlusion to assess any neuroprotective effect. Following middle cerebral artery occlusion, N(1)-dansyl-spermine (1-5 mg kg(-1)) and MK-801 (1 or 3 mg kg(-1)) caused a comparable and significant reduction in the percentage hemisphere lesion volume. Similarly, both drugs significantly reduced oedema and neurological deficit score to a similar extent. Locomotor activity in MCAO mice was not significantly improved by MK-801 or N(1)-dansyl-spermine, although N(1)-dansyl-spermine induced a trend towards significant improvement. Significant improvement in rotarod performance was observed at neuroprotective doses with both drugs. Upon comparison of the profile of effects, N(1)-dansyl-spermine at least matched the effectiveness of MK-801 as a neuroprotective agent in this model. In addition, in sham-operated control mice, N(1)-dansyl-spermine was well tolerated, in contrast to the pronounced adverse effects of MK-801 on locomotor activity and rotarod performance. In conclusion, this study has shown that N(1)-dansyl-spermine is as effective a neuroprotective drug as MK-801 in this model. Moreover, in contrast to MK-801, N(1)-dansyl-spermine could be a promising therapeutic candidate for stroke as it is well tolerated at neuroprotective doses in sham-operated animals.

• Authors: Jun Li, Martin C Henman, Karen M Doyle, Daniel Strbian, Brian P Kirby, Turgut Tatlisumak, Graham G Shaw
• Journal: Brain research (Brain Res) Vol. 1029 Issue 1 Pg. 84-92 (Dec 10 2004) ISSN: 0006-8993 [Print] Netherlands
• PMID: 15533319 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Dansyl Compounds
• Excitatory Amino Acid Antagonists
• N(1)-dansylspermine
• Neuroprotective Agents
• Polyamines
• Receptors, N-Methyl-D-Aspartate
• Spermine
• Dizocilpine Maleate

Topics

• Analysis of Variance
• Animals
• Behavior, Animal (drug effects)
• Brain Damage, Chronic (pathology, prevention & control)
• Brain Ischemia (drug therapy, pathology)
• Dansyl Compounds (pharmacology, therapeutic use)
• Disease Models, Animal
• Dizocilpine Maleate (pharmacology)
• Dose-Response Relationship, Drug
• Excitatory Amino Acid Antagonists (pharmacology, therapeutic use)
• Male
• Mice
• Motor Activity (drug effects)
• Neuroprotective Agents (pharmacology, therapeutic use)
• Polyamines (antagonists & inhibitors)
• Receptors, N-Methyl-D-Aspartate (antagonists & inhibitors)
• Rotarod Performance Test
• Spermine (analogs & derivatives, pharmacology, therapeutic use)