Stroke is the third most common cause of death in the United States, but there is no generally accepted specific therapy for most types of strokes. The search for pharmacological treatments that will minimize or prevent ischemic cerebral damage has been hindered by the lack of adequate animal models that simulate the clinical problem and are sufficiently sensitive and reproducible to allow adequate assessment of therapeutic efficacy. We have developed a series of coordinated models of embolic stroke that are specifically designed to allow us to determine, with considerable sensitivity, whether various pharmacological agents can improve neurological function. These methods will also allow us to estimate the frequency of complications that are likely to be encountered. In preliminary studies we found that tissue plasminogen activator (tPA), a thrombolytic agent, appears to substantially reduce neurological damage when given shortly after blood clots enter the cerebral circulation. Drug induced hemorrhagic complications were not observed. We propose to extend these studies to determine the most effective way of using tPA for treatment of acute embolic stroke. Since it is anticipated that tPA will be used in conjunction with heparin, we also propose to study the independent effects of heparin in these carefully controlled animal models and to determine whether any interactions can be anticipated in the combined use of these two agents. Finally, in most previous studies of stroke therapy, reversible ischemia models have been used. However, reversible ischemia represents only a portion of the clinical problem. The embolic stroke models we have developed allow us to study irreversible ischemia in a graded fashion. We propose to study drugs that have been shown to be effective for treatment of reversible ischemia in irreversible embolic stroke. If we can identify therapies that are effective in both types of models, there is an increased probability that these agents will produce beneficial results in clinical trials.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS023814-03
Application #
3407741
Study Section
Neurology B Subcommittee 1 (NEUB)
Project Start
1987-04-01
Project End
1991-03-31
Budget Start
1989-04-01
Budget End
1990-03-31
Support Year
3
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Type
Schools of Medicine
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Lapchak, Paul A; Wei, Jiandong; Zivin, Justin A (2004) Transcranial infrared laser therapy improves clinical rating scores after embolic strokes in rabbits. Stroke 35:1985-8
Lapchak, Paul A; Song, Donghuan; Wei, Jiandong et al. (2004) Coadministration of NXY-059 and tenecteplase six hours following embolic strokes in rabbits improves clinical rating scores. Exp Neurol 188:279-85
Lapchak, Paul A; Song, Donghuan; Wei, Jiandong et al. (2004) Pharmacology of caffeinol in embolized rabbits: clinical rating scores and intracerebral hemorrhage incidence. Exp Neurol 188:286-91
Lapchak, Paul A; Araujo, Dalia M; Zivin, Justin A (2004) Comparison of Tenecteplase with Alteplase on clinical rating scores following small clot embolic strokes in rabbits. Exp Neurol 185:154-9
Lapchak, Paul A; Zivin, Justin A (2003) Ebselen, a seleno-organic antioxidant, is neuroprotective after embolic strokes in rabbits: synergism with low-dose tissue plasminogen activator. Stroke 34:2013-8
Lapchak, Paul A; Araujo, Dalia M; Weir, Christopher J et al. (2003) Effects of intrathecal administration of a cell permeant caspase inhibitor, boc-D-fluoromethylketone (BDFMK), on behavioral deficits following spinal cord ischemia: a dose-response analysis. Brain Res 959:183-90
Lapchak, Paul A; Araujo, Dalia M; Song, Donghuan et al. (2002) Effects of the spin trap agent disodium- [tert-butylimino)methyl]benzene-1,3-disulfonate N-oxide (generic NXY-059) on intracerebral hemorrhage in a rabbit Large clot embolic stroke model: combination studies with tissue plasminogen activator. Stroke 33:1665-70
Lapchak, Paul A; Araujo, Dalia M; Song, Donghuan et al. (2002) The nonpeptide glycoprotein IIb/IIIa platelet receptor antagonist SM-20302 reduces tissue plasminogen activator-induced intracerebral hemorrhage after thromboembolic stroke. Stroke 33:147-52
Lapchak, Paul A; Araujo, Dalia M; Song, Donghuan et al. (2002) Neuroprotective effects of the spin trap agent disodium-[(tert-butylimino)methyl]benzene-1,3-disulfonate N-oxide (generic NXY-059) in a rabbit small clot embolic stroke model: combination studies with the thrombolytic tissue plasminogen activator. Stroke 33:1411-5
Lapchak, Paul A; Araujo, Dalia M; Pakola, Steve et al. (2002) Microplasmin: a novel thrombolytic that improves behavioral outcome after embolic strokes in rabbits. Stroke 33:2279-84

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