with and without therapy. A rat focal ischemia model will be used. Acute chances will be measured with microdialysis and intermediate-to-chronic outcomes will be monitored with MRI. We will test the effects of glutamate antagonists (MK801 and NBQX) and inhibitors of lactic acidosis (dichloroacetate).

Thesaurus Terms: cerebral ischemia/hypoxia, disease model, glutamate, neuroprotectant, stroke brain disorder che- motherapy, brain mapping, cytotoxicity, dichloroacetate, in- hibitor/antagonist, lactic acidosis, nonhuman therapy evalua- tion, reperfusion laboratory rabbit, laboratory rat, magnetic resonance imaging, microdialysis

Institution:

Fiscal Year: Department: Project Start: Project End: ICD:

IRG:

Massachusetts General Hospital 55 Fruit St Boston, MA 02114 1999

01-Jul-95 30-Apr-00 National Inst Of Neurological

Disorders and Stroke NEUA

~ROJECT TITLE

MECHANISMS OF HEMORRHAGE AND EDEMA IN TPA STROKE THERAPY

Grant Number: 3R01NS37074-02S1 PI Name: Lo, Eng H.

Abstract: DESCRIPTION (Adapted from Applicant's Ab7 stract): A spontaneously hypertensive rat model of throm- boembolic stroke has been developed in our laboratory that presents with parenchymal hemorrhage, hemorrhagic infarc- tioh and edema after tPA reperfusion. Autologous platelet and fibrin rich clots amenable to TtPA dissolution are used. A unique aspect of the model involves the use of in vivo im- aging to rapidly screen for successful occlusions in the MCA territory, thereby reducing model variability and improving statistical power. In this proposal, we will use the model to (I) elucidate the conditions of stroke that predispose towards thrombolysis-induced hemorrhage and edema, (ii) examine

the pathophysiologic mechanisms that underlie the occur- rence of these complications, and (iii) test in vivo MRI meth- ods to assess the risks of these complications. For the first aim, we will compare rates of hemorrhage and edema that re- sult from distal vessel occlusions vs. proximal vesel occlu- sions. To clarify the role of hypertension we will compare our spontaneously hypertensive rat model with hybrid border- line hypertensive rates and normotensive Wistar-Kyoto rats. Additionall, hyperglycemic rats will be compared against normoglycemic rats. For the second aim we hypothesize that after thrombolytic reperfusion free radical cascades and sec- ondary excitotoxicity damage cerebrovasculature that are al- ready weakened by ischemia, thus leading to hemorrhage and edema. To thest this hypothesis we will antagnozie these mechanisms with the free radical scavenger (PBN, the NMDA antagonist MK801, the NO synthase inhibitor L-NA, and a novel immunoliposome to reseal vascular membrane lesions. Prevention of tPA0induced hemorrhage and/or edema will be the primary endpoint. Neuroprotection against ischemia will also be assessed as a secondary endpoint. For the third aim we will test MRI methods that measure the permeability of vascular walls. Since the likelihood of reperfusion injury is related to the degree of vascular damage, this method should have predictive value by assessing cerebrovascular integrity prior to thrombolytic therapy.

Thesaurus Terms: brain edema, cardiovascular disorder chemotherapy, cerebral hemorrhage, drug adverse effect, hy- pertension, plasminogen activator, reperfusion, stroke free radical, free radical scavenger, neuroprotectant, neurotoxin, vascular endothelium permeability laboratory rat, magnetic resonance imaging, spontaneous hypertensive rat

Institution:

Fiscal Year: Department: Project Start Project End: ICD:

IRG:

Massachusetts General Hospital 55 Fruit St Boston, MA 02114 1999

01 -Jan-98 31-Dec-01 National Inst Of Neurological

Disorders and Stroke NEUA

677