Neuroprotective effects of N-methyl-D-aspartate receptor antagonist on aspartate induced neurotoxicity in the spinal cord in vivo.
OBJECTIVE
Much evidence has been gathered to show that neurotoxicity of excitatory amino acids is mainly activated through an N-methyl-D-aspartate (NMDA) receptor cascade. We evaluated the protective effects of NMDA receptor antagonists, MK-801 and CGS19755 on spinal cord neurons using the NMDA receptor mediated neurotoxicity model in vivo.


METHODS
New Zealand white rabbits underwent an infrarenal aortic isolation. Group A animals (n = 7) received segmental aspartate (50 mM) infusion for 10 minutes. Group B animals (n = 6) were pretreated with MK-801 (6mg/kg), a noncompetitive NMDA receptor antagonist, that was administrated intravenously for 3 hours beginning 1 hour before the segmental infusion of aspartate (50 mM) of 10 minutes. Group C animals (n = 6) received pretreatment with CGS19755 (30mg/kg), a competitive NMDA receptor antagonist, that was administrated in the same fashion as group B, followed by the segmental infusion of aspartate (50 mM). Neurologic status was scored at 12, 24, and 48 hours after operation using the Tarlov score. All the animals were sacrificed for histologic assessment at 48 hours.


RESULTS
Group A animals exhibited paraplegia or paraparesis with marked neuronal necrosis. Group B and C animals showed significantly better neurologic function compared with group A (p = 0.0013, A vs. B) (p = 0.0011, A vs. C). Pathohistological change was not observed in group B and C animals.


CONCLUSIONS
NMDA receptor antagonists can have protective effects on spinal cord neurons against aspartate induced neurotoxicity. This model may be useful in assaying protective agents in the spinal cord against neuronal injury mediated by NMDA receptors in vivo.
Cho
Yasunori
Y
Department of Cardiovascular Surgery, Keio University, Tokyo, Japan.
Ueda
Toshihiko
T
Mori
Atsuo
A
Shimizu
Hideyuki
H
Yozu
Ryohei
R
D000818:Animals; D001224:Aspartic Acid / Q000633:toxicity; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology / Q000627:therapeutic use*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D010264:Paraplegia / Q000139:chemically induced; D010875:Pipecolic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D011817:Rabbits; D013116:Spinal Cord / Q000187:drug effects*
D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D010875:Pipecolic Acids; D001224:Aspartic Acid; C053672:selfotel; D016291:Dizocilpine Maleate