Intranasal administration of Human Recombinant Erythropoietin (rHuEpo) improves the spontaneous motor activity in hypoxic rats in spite of brain MDR-1 overexpression

CALTANA L, MERELLI A, RAMOS AJ; LOPEZ L, LAZAROWSKI A, BRUSCO A

Washington Convention Center: Hall A-C ; USA

Congreso; 2008 Meeting Society for Neuroscience; 2008

Society for Neuroscience

Brain hypoxia-ischemic-stroke is the major problem for human health inducing long-term disability without therapeutic options. Hypoxic damage, range from reduction of aerobic metabolism including ultraestructural changes, loss of function and/or cell death. Under hypoxic damage, hypoxia-inducible factor-1á (HIF-1á) upregulation may induce genes such as EPO and EPO-R, related with O2 supply and/or cell survival. HIF-1á can also induce MDR-1 gene expression conferring potential pharmacoresistance to neuroprotective therapeutics. Under these conditions the use of rHuEpo has not been enough studied.Our aim was evaluate the effects of rHuEpo administration intraperitoneal (i.p) or intranasal (IN) on the spontaneous motor activity (SMA) in rats undergone to focal cortical hypoxia, and its relationship with MDR-1, HIF-1á and EPO-R brain expression.Adult male Wistar rats (n=18) were anaesthetized, placed in a stereotaxic device and intracerebrally injected with 2 ul of 50 mM CoCl2. The site of injection, confirmed by histological analysis, was layer 2-3 of right fronto-parietal cortex (Bregma -1.30mm). rHuEpo 950U-i.p. (n=6) or 24U-IN (n=6) was administered; the remaining 6 rats were treated with saline (i.p.). Other three sham-operated rats were used as controls. Reticulocytes (%) were studied after rHuEpo administration during 5 days. SMA (open field) was evaluated 1 day before and during 5 days after injury. Immunostainning, MDR-1, HIF-1á and EPO-R were performed in brain slides.Our results showed that rHuEpo induced an increased reticulocyte value only in rats i.p. administered. MDR-1, HIF-1á and EPO-R were highly expressed in hypoxic brains as compared with their contralateral hemisphere and control ones. SMA decreased in CoCl2 injected-rats but remained normal when CoCl2 injected-rats were treated with rHuEpo (p<0.01) in both i.p. and IN.In spite of the MDR-1 gene overexpression observed, these results suggest that a single dose of IN-rHuEpo prevents the impairment in SMA as compared with saline treatment and does not induce peripheral erythropoietic effects as shown for ip-rHuEpo administered group.