RESUMO
Up-regulation of efflux transporters in brain capillaries may lead to the decreased therapeutic efficacy of antiepileptic drugs in patients with Drug Resistant Epilepsy. Adenosine receptor activation in brain capillaries can modulate blood-brain barrier permeability by decreasing the protein levels and function of efflux transporters. Therefore, we aimed to investigate whether the activation of adenosine receptors improves convulsions outcome in carbamazepine (CBZ) resistant animals and modulates the protein levels of efflux transporters (P-GP, MRP1, MRP2) in brain capillaries. We employed the window-pentylenetetrazol (PTZ) kindling model to develop CBZ resistant rats by CBZ administration during the post-kindling phase, and tested if these animals displayed subsequent resistance to other antiepileptic drugs. Crucially, we investigated if the administration of a broad-spectrum adenosine agonist (NECA) improves convulsions control in CBZ resistant rats. Of potential therapeutic relevance, in CBZ resistant rats NECA restored the anticonvulsant effect of CBZ. We also evaluated how the resistance to CBZ and the activation of adenosine receptors with NECA affect protein levels of efflux transporters in brain capillaries, as quantified by western blot. While CBZ resistance was associated with the up-regulation of both P-GP/MRP2 in brain capillaries, with the administration of NECA in CBZ resistant rats, we observed a decrease of P-GP and an increase of MRP2 levels, in brain capillaries. Since the activation of adenosine receptors improves the outcome of convulsions probably through the modulation of the efflux transporters protein levels in brain capillaries, adenosine agonists could be useful as an adjunct therapy for the control of Drug Resistant Epilepsy.
Assuntos
Anticonvulsivantes/administração & dosagem , Encéfalo/metabolismo , Capilares/metabolismo , Carbamazepina/administração & dosagem , Excitação Neurológica/efeitos dos fármacos , Excitação Neurológica/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Receptores Purinérgicos P1/metabolismo , Animais , Encéfalo/irrigação sanguínea , Encéfalo/efeitos dos fármacos , Modelos Animais de Doenças , Epilepsia Resistente a Medicamentos/induzido quimicamente , Epilepsia Resistente a Medicamentos/metabolismo , Masculino , Pentilenotetrazol/administração & dosagem , Ratos Wistar , Convulsões/metabolismoRESUMO
During critical periods of neurodevelopment, the immature brain is susceptible to neuronal hyperexcitability, alterations such as hyperthermia, hypoxia, brain trauma or a preexisting neuroinflammatory condition can trigger, promote and prolong epileptiform activity and facilitate the development of epilepsy. The goal of the present study was to evaluate the long-term neuroprotective effects Magnolia officinalis extract, on a model of recurrent status epilepticus (SE) in immature rats. Sprague-Dawley rats were treated with kainic acid (KA) (3 mg/kg, dissolved in saline solution) beginning at day 10 P N every 24 h for five days (10 P N-14PN). Two experimental groups (KA) received two treatments for 10 days (14-24 P N): one group was treated with 300 mg/kg Magnolia Officinalis (MO) (KA-MO), and another was treated with 20 mg/kg of celecoxib (Clbx) (KA-Clbx) as a control drug. A SHAM control group at day 90 P N was established. Seizure susceptibility was analyzed through an after-discharge threshold (ADT) evaluation, and electroencephalographic activity was recorded. The results obtained from the ADT evaluation and the analysis of the electroencephalographic activity under basal conditions showed that the MO and Clbx treatments protected against epileptiform activity, and decreases long-term excitability. All rats in the KA-MO and KA-Clbx groups presented a phase I seizure on the Racine scale, corresponding to the shaking of a wet dog. In contrast, the KA group showed phase V convulsive activity on the Racine scale. Similarly, MO and Clbx exerted neuroprotective effects on hippocampal neurons and reduced gliosis in the same areas. Based on these results, early intervention with MO and Clbx treatments to prevent the inflammatory activity derived from SE in early phases of neurodevelopment exerts neuroprotective effects on epileptogenesis in adult stages.