Tamoxifen as an effective neuroprotectant in an endovascular canine model of stroke.
ABSTRACT Tamoxifen has been shown to be a potent neuroprotectant against stroke in rodents. Because other neuroprotectant medications have failed in human trials, a study of tamoxifen in a large-animal model was necessary to further assess the drug's effectiveness. For this study, the authors developed an endovascular model of anterior circulation infarction in canines to mimic the human clinical condition. They assessed the following hypotheses: 1) that they will be able to consistently produce an internal carotid artery (ICA) terminus infarction and 2) that tamoxifen is an effective neuroprotectant against stroke in canines.
In 24 male beagles (weight 9-11 kg), bilateral femoral artery cutdowns were performed, and the vertebral artery and left ICA were each selectively catheterized. Under fluoroscopic guidance, a microcatheter was introduced via the vertebral artery, guiding the catheter into the basilar artery, posterior communicating artery, and ICA terminus. A 1-ml clot was injected in the terminus, occluding the middle cerebral artery (MCA) and anterior cerebral artery (ACA) origin. In the first 12 canines, the occlusions were confirmed by angiography. A Canine Stroke Score (CSS) was assigned (score range 0-18 [0 = intact on examination, 18 = comatose]). The animals were then killed and their brains stained with 2,3,5-triphenyltetrazolium chloride (TTC). The subsequent 12 canines underwent a blinded randomized study in which the authors compared the results of tamoxifen (5 mg/kg) infused intravenously 1 hour after clot injection with an equal volume of vehicle (dimethylsulfoxide). After 3 hours, the animals underwent MR imaging, were extubated, and clinical examinations were performed. The canines were killed at 8 hours after clot injection, and TTC staining was used.
In the first group, infarct volume and CSSs were consistent with the extent of the occlusion of the angiographic vessels. An occlusion of the ACA, MCA, and posterior cerebral artery resulted in larger infarcts and higher stroke scores than occlusion of the ACA and MCA. In the second group, tamoxifen significantly reduced infarct size and improved clinical outcomes. In tamoxifen-treated animals, the mean infarct volume reduction was 40% (p < 0.05) and the mean CSS was significantly less than vehicle-treated animals (p < 0.001). There were significant correlations among MR imaging-determined volume, TTC-determined volume, and neurological clinical outcome (p < 0.05).
Using this endovascular model of stroke, the authors were able to consistently produce an infarction in the canines that was similar in scope to a carotid terminus occlusion in humans. Also, angiography could predict subsequent clinical course and infarct size. Tamoxifen was effective at significantly improving the canine neurological deficits and reducing the size of the stroke. This study took the first step in demonstrating the effectiveness of a promising human neuroprotectant in a large animal.
- SourceAvailable from: Robert F Spetzler[show abstract] [hide abstract]
ABSTRACT: Advancements in computer science and magnet design have resulted in the recent development of high resolution NMR imaging systems. Using our primate model we evaluated the ability of NMR scanning to detect early changes following middle cerebral artery (MCA) occlusion. Serial NMR scans documented progressive changes secondary to edema and swelling beginning ninety minutes after MCA occlusion. NMR was also able to readily demonstrate the area of cerebral infarct 10 days after a six hour episode of MCA occlusion. Soft tissue contrast and image resolution were superb. Correlation with pathologic sections was excellent.Stroke 01/1984; 14(2):185-91. · 6.16 Impact Factor
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ABSTRACT: An experimental model of cerebral infarction is created in rats by intracarotid injection of their homologous blood clots. This is the first small animal model in which embolization was achieved by homologous blood clots. The infarcts were produced predominantly in the territory of the middle cerebral artery. The low mortality rate and excellent reproduction rate make possible the correlative study of morphological, biochemical, and metabolic parameters at selected points in time to reconstruct the pathogenesis and natural history of focal cerebral ischemia and its relation to blood elements.Stroke 13(4):505-8. · 6.16 Impact Factor
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ABSTRACT: P-glycoprotein, an active transporter that pumps a diverse range of hydrophobic compounds out of cells, has recently been proposed to function as, or regulate, a volume-activated, anion-selective channel (Valverde, M.A., Diaz, M., Sepulveda, F. V., Gill, D. R., Hyde, S. C., and Higgins, C. F. (1992) Nature 355, 830-833). In this study a number of compounds known to inhibit P-glycoprotein-mediated drug pumping were tested for their effect on the osmotically activated release from HeLa cells of I-, a known substrate of volume-activated anion channels, and taurine, a sulfonic amino acid that serves as an important organic osmolyte in many cell-types. Tamoxifen, 4-iodotamoxifen, and pyrrolidino-4-iodotamoxifen (idoxifene) were potent blockers of osmotically activated I- and taurine efflux. Other known P-glycoprotein inhibitors (verapamil, cyclosporin A, pimozide, trifluoperazine, ICI 164, and ICI 182) were less effective. For all compounds tested the effect on taurine release was the same as that on I- release, consistent with the hypothesis that swelling-activated taurine release is via anion-selective channels. There was no positive correlation between the effect of the inhibitors on osmotically activated solute release and their effect on P-glycoprotein-mediated drug transport. In contrast, there was a strong positive correlation between the IC50 values for the effect of the inhibitors on volume-activated solute release and those for their effect on calmodulin. These data raise doubts as to whether the effect of P-glycoprotein inhibitors on volume-activated channels is a consequence of their interaction with P-glycoprotein and indicate a possible role for calmodulin, or a cell component having at least some physical similarities, in controlling channel activity.Journal of Biological Chemistry 12/1994; 269(47):29389-94. · 4.65 Impact Factor