Both neuronal expression of P-glycoprotein and Erythropoietin Receptor can be induced in vitro by glutamate, as well as in vivo by Status epilepticus.

AUZMENDI JA; RAMOS AJ; LAZAROWSKI A

Ciudad Autónoma de Buenos Aires

Congreso; IV International Congress in Translational Medicine; 2018

UBA-IMBS

Purpose: Neuronal expression of P-glycoprotein (P-gp) has been described to be related with both experimental and clinical pharmacotresistant epilepsy [Lazarowski et al. Epilepsia 2007; 48,140- 149]. Epileptic seizures are not been related with expression of erythropoietin receptor (Epo-R) in neurons yet. Normal neurons don´t express P-gp and Epo-R. In a model of cobalt chloride-induced brain hypoxia developed by our group, P-gp and Epo-R were co-expressed in neurons, and intranasal administration of erythropoietin (Epo), increased neuronal survival andreduced brain damage [Merelli et al. Neurotox Res. 2011;20:182-92]. Our aim was demonstrate that glutamateexitotoxicity in vitro and Status Epilepticus (SE) in vivo can induce P-gp and Epo-R expression in neurons. Methods: In vitro, we worked whit culture of primary cortical neuronal obtained from E17 embryo rats, which after ten days, were exposed to five minutes of high glutamate concentration (300 μm). In vivo, status epilepticus (SE) was induced on 250g Wistar rats by lithium chloride plus pilocarpine treatment, and stopped with diazepam after 20 min of SE. Neuronal death was evaluated in vitro by MTT assay and nuclear recount and P-gp functional activity using rhodamine123; P-gp and Epo-R were identified by immunofluorescence in both models. Results: In vitro, we found P-gp and EpoR expression in neurons is dependent on the increasing concentration of glutamate. In vivo SE increased the neuronal and astroglial expression of P-gp, while Epo-R only was observed expressed in neurons. Our results indicate that epileptic stress induce the neuronal expression of P-gp related with pharmacoresistance, but also induce the expression of Epo-R, that is a clear hypoxic marker. Conclusion: We don´t know if the pharmacological doses of erythropoietin could prevent or reverts the P-gp mediated pharmacoresistance observed in refractory epilepsy, however, we speculate that EPO administration could reduce the neuronal loss as we previously described during brain hypoxia.