Maze learning impairment is associated with stress hemopoiesis induced by chronic treatment of aged rats with human recombinant erythropoietin

Mean cell volume (MCV) of erythrocytes has been reported to increase with a ge in humans, and to be negatively correlated with memory performance in hu mans and rats. We evaluated hematological changes in 21-mo old male Fischer 344 rats undergoing a 3-mo twice weekly subcutaneous injection of human re combinant erythropoietin (EPO). A baseline hematocrit (HCT) was obtained in itially and repeated at monthly intervals to determine the effectiveness of EPO treatment. At 24-mo of age and after 3 mo EPO treatment, the rats were tested for their ability to learn a 14-unit T maze. Following maze testing , blood was drawn for hematologic analyses, including HCT, MCV, maximum swo llen cell volume (MCVS), mean cell transit time (MCTT), and the membrane sh ear modulus of elasticity (G), the latter a derived measure of the relative elasticity of the red cell membrane. After 1 mo EPO treatment, HCT signifi cantly increased compared to saline-injected controls. After 2 mo treatment , HCT began to decline but remained elevated above baseline levels even aft er 3 mo treatment. After 3 mo EPO treatment, MCV was significantly lower in EPO-treated rats compared to controls. These changes imply altered hemopoi esis to produce cells which undergo shrinkage associated with accelerated c ellular aging. The lower MCV would have predicted a shorter MCTT which inst ead was unchanged. This observation suggested the presence of an additional factor contributing to the MCTT. The G, which measures the membrane contri bution to deformability, very significantly increased with EPO treatment. T his finding indicates an increased contribution of membrane properties to t he MCTT after EPO treatment, which cancels the expected decrease in MCTT fo r smaller cells. After 3 mo of EPO treatment, aged rats exhibited significa ntly impaired maze learning compared to controls. A relationship between, c hanges in erythrocyte membrane properties and impaired function was indicat ed by a significant correlation (r=0.67, p <0.04) between G and errors in t he lif-unit T-maze. These findings suggest that stress-induced erythropoies is produces accelerated aging in the red blood cell population that may hav e functional implications (i.e., impaired learning ability).