Recovery of Motor Spontaneous Activity After Intranasal Delivery of Human

MERELLI A, CALTANA L, GIRIMONTI P, RAMOS AJ, LAZAROWSKI A, BRUSCO A.

NEUROTOXICITY RESEARCH

SPRINGER

Lugar: New York; Año: 2010

1029-8428

Stroke is a major human health problem inducing long-term disability without any efficient therapeutic option being currently available. Under hypoxia,hypoxia-inducible factor-1á (HIF-1á) activates several genes as erythropoietinreceptor (Epo-R) related with O(2) supply, and the multidrug-resistance gene(MDR-1) related with drug-refractory phenotype. Brain cortical injection ofCoCl(2) produces focal hypoxia-like lesion with neuronal and glial alterations,as well as HIF-1á stabilization and MDR-1 overexpression. Intranasal (IN) drugdelivery can by-pass blood-brain barrier (BBB) where MDR-1 is normally expressed.We evaluated the effects of IN-rHu-Epo administration on spontaneous motoractivity (SMA) and the brain pattern expression of HIF-1á, MDR-1, and Epo-R inour cobalt-induced hypoxia model. Adult male Wistar rats were injected bystereotaxic surgery in frontoparietal cortex, with CoCl(2) (2 ìl-50 mM; n = 20)or saline (controls; n = 20). Ten rats of each group were treated with IN-rHu-Epo24 U or IN-saline. In addition, erythropoietic stimulation was evaluated byreticulocytes (Ret) account during three consecutive days, after intraperitoneal (i.p.)-recombinant-human Epo (rHu-Epo) (950 U; n = 6) or IN-rHu-Epo (24 U; n = 6)administration. SMA was evaluated by open field and rotarod tests, before andafter surgical procedures during five consecutive days. Histological andimmunostaining studies of HIF-1á, MDR-1, and Epo-R were performed on brainslides. A significant difference in SMA was observed in the hypoxic rats ofIN-rHu-Epo-administered group as compared with Co-Saline-treated subjects andcontrols (p < 0.001). HIF-1á, EPO-R, and MDR-1 were overexpressed in the hypoxic cortex areas, while in contralateral hemisphere or controls, they were negatives.Reticulocytes were only increased in intraperitoneal (i.p.)-rHu-Epo-administered group. In spite of MDR-1 overexpression being detected in neurons, thecoexpression of Epo-R could explain the positive effects observed on SMA ofIN-rHu-Epo-administered group.