Increased cerebral infarct volumes in polyglobulic mice overexpressing erythropoietin

There is increasing evidence that erythropoietin (Epo) has a protective fun ction in cerebral ischemia. When used for treatment, high Epo plasma levels associated with increases in blood viscosity, however, may counteract bene ficial effects of Epo in brain ischemia. The authors generated two transgen ic mouse lines that overexpress human Epo preferentially, but not exclusive ly, in neuronal cells. In mouse line tg21, a fourfold increase of Epo prote in level was found in brain only, whereas line tg6 showed a dramatic increa se of cerebral and systemic transgene expression resulting in hematocrit le vels of 80%. Cerebral blood flow (CBF), as determined by bolus tracking mag netic resonance imaging, was not altered in the tg6 line. The time-to-peak interval for the tracer, however, increased approximately threefold in poly globulic tg6 mice. Immunohistochemical analysis revealed an increase in dil ated vessels in tg6 mice, providing an explanation for unaltered CBF in pol yglobulic animals. Permanent occlusion of the middle cerebral artery (pMCAO ) led to similar perfusion deficits in wild-type, tg6, and tg21 mice. Compa red with wild-type controls, infarct volumes were not significantly smaller (22%) in tg21 animals 24 hours after pMCAO, but were 49% enlarged (P < 0.0 5) in polyglobulic tg6 mice. In the latter animals, elevated numbers of Mac -1 immunoreactive cells in infarcted tissue suggested that leukocyte infilt ration contributed to enlarged infarct volume. The current results indicate that moderately increased brain levels of Epo in tg21 transgenic mice were not sufficient to provide significant tissue protection after pMCAO. The r esults with tg6 mice indicate that systemic chronic treatment with Epo asso ciated with elevated hematocrit might deteriorate outcome after stroke eith er because of the elevated hematocrit or other chronic effects.