OBJECTIVETo study the effects of a spin trap agent and a CD18 antibody administered after stroke induction on intracerebral hemorrhaging. The drugs can prevent leukocyte adhesion.METHODSA rabbit embolic stroke model that produces intracerebral hemorrhage was used.RESULTSA time course study showed that hemorrhaging was grossly apparent in approximately 50% of the subjects at 5 hours and in 75% at 24 hours after embolization. MDL 101,002, a spin trap agent, administered IV 5 minutes after embolization, significantly decreased the volume of hemorrhage. It also improved the behavior score relative to vehicle-treated rabbits. The CD18 antibody tended to decrease hemorrhage volume.CONCLUSIONThe beneficial effect of MDL 101,002 may be caused by inhibition of free radical injury to brain tissue, thereby protecting brain microvessel integrity. Acute therapy for intracerebral hemorrhage may be feasible.

01 May 1999·Experimental NeurologyQ2 · MEDICINE

Novel Free Radical Spin Traps Protect against Malonate and MPTP Neurotoxicity

Q2 · MEDICINE

Article

Author: Russell T. Matthews ; Gerald Mueller ; Peter Klivenyi ; M.Flint Beal ; Marike Wermer ; Lichuan Yang ; Craig E. Thomas

Both malonate and 1-methyl-4-phenyl-1,2,5,6 tetrahydropyridine (MPTP) are neurotoxins which cause energy depletion, secondary excitotoxicity, and free radical generation. Malonate is a reversible inhibitor of succinate dehydrogenase, while MPTP is metabolized to 1-methyl-4-phenylpyridinium, an inhibitor of mitochondrial complex I. We examined the effects of pretreatment with the cyclic nitrone free radical spin trap MDL 101,002 on malonate and MPTP neurotoxicity. MDL 101,002 produced dose-dependent neuroprotection against malonate-induced striatal lesions. MDL 101, 002 produced significant protection against MPTP induced depletions of dopamine and its metabolites. MDL 101,002 also significantly attenuated MPTP-induced increases in striatal 3-nitrotyrosine concentrations. The free radical spin trap tempol also produced significant protection against MPTP neurotoxicity. These findings provide further evidence that free radical spin traps produce neuroprotective effects in vivo and suggest that they may be useful in the treatment of neurodegenerative diseases.

01 Jun 1998·Life SciencesQ3 · MEDICINE

MDL 101,002, a free radical spin trap, is efficacious in permanent and transient focal ischemia models

Q3 · MEDICINE

Article

Author: Debbie R McCarty ; James V Ficorilli ; Hsien C Cheng ; Paula A Chmielewski ; Craig E Thomas ; Carrie G Markgraf ; Nelson L Velayo ; Michael P Johnson

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.

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Indication	Highest Phase	Country/Location	Organization	Date
Stroke	Discovery	US	Hoechst Marion Roussel, Inc.	-

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