Summary:It is estimated 20-25% of the epileptic patients fails to achieve good control with the different antiepileptic drugs (AEDs) treatments, developing refractory epilepsy (RE). Discovered first in cancer, the activity of P-glycoprotein (P-gp) and others ABC transporters as multidrug-resistance-associated proteins (MRPs) and breast cancer resistant protein (BCRP) are directly related with the refractoriness. We have observed the overexpression of these all transporters in the brain of patients with RE, and according with other authors, all these data suggests an active drug efflux from brain. Both constitutive and seizure induced brain P-gp overexpression was also suggested. As confirmation of these clinical evidences, different models of experimental epilepsy have demonstrated P-gp overexpression on blood brain barrier (BBB) and brain parenchyma cells, as astrocytes and neurons. In our model, early P-pg detection in vesselrelated cells and later additional P-gp detection in neurons, correlated with the gradual loss of protective effect of phenytoin. The progressive neuronal P-gp expression, depending on intensity and time-constancy of seizure-injury, was in agreement with the development of "P-gp-positive seizure-axis" proposed by Kwan & Brodie, who also showed that the development of RE directly correlated with the number and frequency of seizures before initiation of drug therapy. P-gp expression in excretory organs suggests that P-gp have a central role in drug elimination.Persistent low levels of AEDs in plasma and P-gp brain overexpression in several RE pediatric patients were reported. We also observed in adult RE patients, an increased liver clearance of 99m Tc-hexakis-2-methoxyisobutylisonitrile ( 99m Tc-MIBI) (a P-gp substrate), and the surgically treated cases showed Pgp brain overexpression. These results suggest the systemic hyperactivity of P-gp in RE patients, including brain P-gp overexpression should be suspected when persistent subtherapeutic levels of AEDs in plasma are detected. P-gp neuronal expression described in both clinical and experimental reports indicates that additional mechanisms could be operative from seizure-affected P-gp-positive neurons, due to AEDs targets are expressed at membrane level. An alternative mechanism was demonstrated in P-gp-expressed cells that exhibit lower membrane potential ( ψ 0 = −10 to -20) compared to normal physiological ψ 0 of -60 mV. Under this situation and irrespective to the P-gp pharmacoresistant property or type of drug treatment selected, P-gp-expressed neurons could increase their sensitivity to new seizures perhaps as an epileptogenic mechanism. The understanding of properties of these ABC transporters can offer new tools for better selection of more effective preventive or therapeutic strategies and avoid the invasive surgical treatments for RE. Key Words: Refractory epilepsy-MDR-BCRP-MVP99m Tc-MIBI.

Epilepsy is a common neurological disorder. About one-third of epilepsy patients have a multidrug resistance (MDR) phenotype and develop refractory epilepsy (RE). Changes in the properties of the antiepileptic drugs (AEDs) targets resulting in reduced drug sensitivity, can't explain the MDR phenotype. This particular refractoriness is now attributed to overexpression of multidrug transporters in brain, leading to impaired access of AEDs to CNS targets, and it was documented in both human as well as in experimental models of RE. Single nucleotide polymorphism (SNP) identified in the MDR1-ABCB1 gene (C3435T/CC-genotype) is associated with increased intestinal expression of P-glycoprotein (P-gp) that affects levels of AEDs in plasma. The functional studies of P-gp using P-gp inhibitors could show the still unclear clinical impact of ABCB1 polymorphisms on AEDs resistance. Some drug-drug interactions previously believed to be cytochrome P450 (CYP) mediated are now also considered to be due to the modulation of multidrug-transporters. Because in certain cases pharmacoresistance can be overcome by add-on therapy, co-administered P-gp inhibitors could contribute to the effectiveness of AEDs treatment in RE. And in this regard, perhaps we can postulate to P-gp as a new clinical therapeutic target in multidrug-refractory epilepsy.

Neuronal damage secondary to brain injuries such as cerebral hypoxia, seizures as well as neurodegenerative process, may include pro-inflammatory changes. The activation of a common mechanism related to survival or cell death, mediated by the stabilization and trans-activation of Hypoxia-Inducible Factor 1 (HIF-1), has been observed in these conditions. HIF-1 may induce over expression of P-glycoprotein, the product multidrug-resistance gene (MDR-1), both on blood-brain barrier as well as on the cerebral damaged cells, producing the refractoriness to therapeutic strategies for neuroprotection. However, in these same cells, HIF-1 can also induce the expression of erythropoietin receptor (Epo-R). Irrespective of its known properties on hematopoiesis, it was proposed that erythropoietin can trigger neuroprotective mechanisms mediated by Epo-R activation. Brain hypoxia, epilepsy, neurodegeneration and inflammation, can share the induction of Epo-R and several other growth factor receptors as well as signal transductions pathways after HIF-1 transactivation. Perhaps, the use of the intranasal route for the exogenous administration of Epo, (or other biological compounds) could help neuroprotection as well as to repair the brain areas damaged.

Highly expressed Erythropoietin Receptor (EPO-R) has been detected in several nonhematopoietic hypoxic cells, including cells from different brain areas in response to many different types of cell injury. In brain, hypoxia-ischemia (HI) can induce a wide spectrum of biologic responses, where inflammation and apoptosis are the main protagonists. Inflammation, as a primary brain insult, can induce a chronic hypoxic condition, producing the continuous cycle of inflammation-hypoxia that increases the apoptotic-cell number. It has also been demonstrated that administration of erythropoietin (EPO) prevented the neuronal death induced by HI, as well as the induction of lipid peroxidation in the hippocampus in a rodent model of Alzheimer's disease. Anti-apoptotic, anti-inflammatory, anti-oxidant, and/or cell-proliferative effects of EPO, have been observed in all type of cells expressing EPO-R, resulting in a potential tool for neuroprotection, neuroreparation, or neurogenesis of brain damaged areas. The nasal route is an alternative way of drugs administration that has been successfully exploited for bypassing the blood brain barrier, and subsequently delivering EPO and other molecules to central nervous system. Intranasal administration of EPO could be a new therapeutic opportunity in several brain damages that includes hypoxia, inflammation, neurodegenerative process, and apoptosis.