Imatinib for Acute Ischemic Stroke
Abstract & Commentary
By Alan Z. Segal, MD Associate Professor of Clinical Neurology, Weill Cornell Medical College, Attending Neurologist, NewYork-Presbyterian Hospital. Dr. Segal reports no financial relationships relevant to this field of study.
Synopsis: Blockage of the harmful effects of tissue plasminogen activator by imatinib (Gleevec) might improve ischemic stroke outcomes.
Source: Su EJ, Fredriksson L, Geyer M, et al. Activation of PDGF-CC by tissue plasminogen activator impairs blood-brain barrier integrity during ischemic stroke. Nat Med 2008;14:731-737.
Tissue plasminogen activator (tPA) remains the only FDA-approved medication for acute ischemic stroke and is limited in its scope to a very brief 3-hour time window. Attempts to use tPA beyond 3 hours have failed due to decreased efficacy and increased hemorrhage rates. Further studies suggest that although tPA may be effective in its thrombolytic properties, it may have other deleterious effects on ischemic stroke. Animal studies using a middle cerebral artery occlusion (MCAO) model have shown that in situations in which tPA was inhibited or genetically deficient, stroke outcomes are improved. tPA may play a role in ischemia-induced blood brain barrier (BBB) dysfunction and contribute to hemorrhagic conversion of stroke, especially when given at later time intervals. tPA may cause increased cerebrovascular permeability through a receptor-mediated action on the extravascular (CNS) aspect of the neurovascular unit. This unit is comprised of endothelial cells, astrocytes, microglia, neurons, and smooth muscle cells. In the present study, a potential substrate for tPA, platelet derived growth factor-CC (PDGF-CC) is identified. tPA activates PDGF-C at its N-terminus, producing PDGF-CC. This molecule then binds to PDGF-a receptors on perivascular astrocytes, producing increased vascular permeability and potentially hemorrhage.
The authors demonstrated that the intraventricular administration of either tPA or PDGF-CC produced an increase in permeability as measured by Evans blue dye extravasation into the brain tissue of non-ischemic mice. When antibodies to PDGF-CC were added, the tPA effect was blunted, proving that PDGF-CC acted downstream of tPA. The effect was not observed when tPA was administered by an IV mechanism, implying that tPA had to be exposed to astrocytes in brain tissue, on the abluminal side of the blood vessel, that is, across the BBB. Immunohistochemical staining and electron microscopy confirmed that the PDGF-a receptors were closely associated with arterioles throughout the cerebral cortex. This distribution was found to closely correlate with endogenous expression of tPA.
The study furthermore showed that in tPA deficient mice, PDGF-a activation was eliminated. More importantly, the data showed that when mice were treated with the PDGF-a inhibitor imatinib, there was a 33% reduction in Evans blue extravasation after MCAO. Infarct volumes were reduced by 34% in mice treated with imatinib. Among mice treated with tPA at 5 hours following MCAO, those treated at 1 hour with imatinib had 50% lower rates of hemorrhagic transformation compared to untreated mice.
Commentary
As the authors note, the ill effects of tPA seem to be most potent beyond 3 hours when there has been sufficient breakdown of the BBB to allow tPA extravasation into the extravascular tissues. As the data showed, the effect of tPA on PDGF-CC was only observed in mice treated intraventricularly, not intravenously. These results do not apply to patients treated within 3 hours with IV tPA but rather offer new possibilities beyond this time window.
Imatinib is already widely used for treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors (GIST), acting as an inhibitor of tyrosine kinase mediated second messenger systems. Given the data outlined here, it appears that this agent might be benficial in stroke. Imatinib reduces infarct volumes in animal models, and by maintaining the integrity of the microvasculature, imatinib may reduce the hemorrhagic complications of thrombolysis. Time windows may still remain an issue. In the mouse models studied above, imatinib was given at one-hour post-MCAO, a time point too early to be clinically feasible. As the authors note, imatinib, alone or in combination with tPA, is now being planned in a clinical trial sponsored by the Karolinska Insitute in Stockholm. The specifics of this protocol are not currently available.
Blockage of the harmful effects of tissue plasminogen activator by imatinib (Gleevec) might improve ischemic stroke outcomes.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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