Postischemic (6-Hour) treatment with recombinant human tissue plasminogen activator and proteasome inhibitor PS-519 reduces infarction in a rat model of embolic focal cerebral ischemia.

Abstract

BACKGROUND AND PURPOSE:

The proteasome inhibitor PS-519 blocks activation of nuclear factor-kappaB, a major mediator of inflammation. We tested the hypothesis that combination treatment of recombinant human tissue plasminogen activator (rhtPA) and PS-519 extends the therapeutic window for treatment of stroke with rhtPA without increasing incidence of hemorrhagic transformation.

METHODS:

The middle cerebral artery (MCA) of male Wistar rats (n=56) was occluded by an embolus. After embolization, animals were randomly divided into the following groups: PS-519 treatment groups: PS-519 was given at 2, 4, or 6 hours after MCA occlusion; rhtPA treatment groups: rhtPA was given at 2 or 4 hours after MCA occlusion; combination treatment groups: PS-519 and rhtPA were given at 2, 4, or 6 hours after MCA occlusion; control group: the same volume of saline was given at 2 hours after MCA occlusion.

RESULTS:

Administration of PS-519 alone at 2 or 4 hours, but not 6 hours, significantly (P<0.05) reduced infarct volume and improved neurological recovery compared with the control group. Administration of rhtPA alone at 2 hours, but not 4 hours, significantly (P<0.05) reduced infarct volume and improved neurological recovery compared with the control group. Furthermore, combination treatment with rhtPA and PS-519 even at 6 hours significantly (P<0.05) reduced infarct volume, improved neurological recovery, and did not increase the incidence of hemorrhagic transformation compared with the control group or the group treated with PS-519 alone.

CONCLUSIONS:

Our data suggest that combination treatment with PS-519 and rhtPA extends the neuroprotective effect to at least 6 hours after embolization.

• Authors: L Zhang, Z G Zhang, R L Zhang, M Lu, J Adams, P J Elliott, M Chopp
• Journal: Stroke (Stroke) Vol. 32 Issue 12 Pg. 2926-31 (Dec 01 2001) ISSN: 1524-4628 [Electronic] United States
• PMID: 11739997 (Publication Type: Journal Article)

Chemical References

• Cysteine Proteinase Inhibitors
• Fibrinolytic Agents
• Multienzyme Complexes
• PS519
• Recombinant Proteins
• Peroxidase
• Tissue Plasminogen Activator
• Cysteine Endopeptidases
• Proteasome Endopeptidase Complex
• Acetylcysteine

Topics

• Acetylcysteine (administration & dosage, analogs & derivatives)
• Animals
• Behavior, Animal (drug effects)
• Blood Pressure (drug effects)
• Body Weight (drug effects)
• Brain Ischemia (complications, drug therapy, metabolism, pathology)
• Cell Count
• Cerebral Hemorrhage (etiology, pathology, prevention & control)
• Cerebral Infarction (etiology, pathology, prevention & control)
• Cysteine Endopeptidases
• Cysteine Proteinase Inhibitors (administration & dosage)
• Disease Models, Animal
• Drug Administration Schedule
• Drug Therapy, Combination
• Fibrinolytic Agents (administration & dosage, adverse effects)
• Humans
• Intracranial Embolism (complications, drug therapy, pathology)
• Male
• Multienzyme Complexes (antagonists & inhibitors)
• Neurologic Examination
• Peroxidase (metabolism)
• Proteasome Endopeptidase Complex
• Rats
• Rats, Wistar
• Recombinant Proteins (administration & dosage, adverse effects)
• Time Factors
• Tissue Plasminogen Activator (administration & dosage, adverse effects)