MDL 101,002, a free radical spin trap, is efficacious in permanent and transient focal ischemia models.
The present work describes the neuroprotective effects of the free radical spin trap, MDL 101,002, in models of permanent and transient focal ischemia. Permanent focal ischemia was carried out by occlusion of the distal segment of the middle cerebral artery (MCA) and CCA's in Spontaneously Hypertensive (SH) and Wistar rats. Transient focal ischemia was undertaken by occluding the origin of the MCA for 180 min by the intraluminar monofilament method in Wistar rats. With permanent distal MCA occlusion in SH rats, 100 mg/kg i.v. at 30 min post-ischemia resulted in a significant 40% reduction in infarct volume. Similarly, a 75 mg/kg bolus + 45 mg/kg-h dose of MDL 101,002 given i.v. at 5 min post-ischemia resulted in a 90% or 60% decrease in infarct volume in the mixed permanent/transient distal MCA model with Wistar rats using 120 or 180 min of CCA occlusion, respectively. When full reperfusion was established, after 180 min of occlusion in the proximal MCA model, a dose of 40 mg/kg + infusion and 75 mg/kg + infusion resulted in a significant 50% and 70% decrease in ischemic damage, respectively. MDL 101,002 is clearly an effective neuroprotective agent in all models examined. This work would suggest that this novel cyclic nitrone spin trap affords effective neuroprotection and is useful for the treatment of ischemic stroke.
CNS Research, Hoechst Marion Roussel, Inc, Cincinnati, Ohio 45215, USA. johnson_michael_p@lilly.com
M P
MP
Johnson
D R
DR
McCarty
N L
NL
Velayo
C G
CG
Markgraf
P A
PA
Chmielewski
J V
JV
Ficorilli
H C
HC
Cheng
C E
CE
Thomas
D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D002545:Brain Ischemia / Q000188:drug therapy*; D016166:Free Radical Scavengers; D007546:Isoquinolines / Q000494:pharmacology / Q000627:therapeutic use*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D009589:Nitrogen Oxides / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D013113:Spin Labels
C091566:3,4-dihydro-3,3-dimethylisoquinoline-N-oxide; D016166:Free Radical Scavengers; D007546:Isoquinolines; D018696:Neuroprotective Agents; D009589:Nitrogen Oxides; D013113:Spin Labels