Activation of adenosine receptors modulates the efflux transporters in brain capillaries and restores the anticonvulsant effect of carbamazepine in carbamazepine resistant rats developed by window-pentylenetetrazole kindling.

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.

[Central nervous system neuromodulation for the treatment of epilepsy. II. Mechanisms of action and perspectives]. / Neuromodulation du système nerveux central dans le traitement des épilepsies. II . Mécanismes d'action et perspectives.

OBJECTIVES: Review of available evidence of the mechanisms of action underlying the anticonvulsant effect of current applied to various CNS structures. MATERIAL AND METHODS: Studies were conducted from observations of patients with drug-resistant seizures and treated with neuromodulation. Seizures originated from various cortical areas with secondary generalization or were initially generalized without a focal origin, either clinically or on EEG or SEEG. Intracranial recordings and SEEG were performed using subdural grids or depth electrodes implanted either for recordings or therapeutic deep brain stimulation (DBS). In a group of mesial temporal lobe epilepsy patients investigated with subdural or SEEG electrodes, the epileptogenic focus area was stimulated for 15 days before anterior temporal lobectomy. The surgical specimen was examined using standard and electronic microscopy and autoradiography in order to identify several neurotransmitter receptors. They also were compared to other surgical specimens from epileptic patients who had intracerebral recordings but without stimulation (epileptic controls) and to autopsy specimens from subjects with no history of epilepsy (nonepileptic controls). RESULTS: High-frequency (HF) stimulation increases the after-discharge threshold of the stimulated site and alters the cycles of potentials evoked by a test stimulation using a paradigm of coupled stimulations. HF stimulation also decreases local cerebral blood flow in the stimulated area as demonstrated on SPECT. Parahippocampal cortex HF stimulation significantly increases the GABAergic benzodiazepine receptor density in the stimulated area. In addition, centromedianum (CM) thalamic nucleus HF stimulation suppresses thalamic and cortical spike-waves, as well as secondary synchronous discharges visible on EEG. Conversely, low-frequency (3-Hz) bilateral CM stimulation induces a typical absence clinically and on EEG. CONCLUSION: High-frequency stimulation is responsible for an inhibition of local and propagated epileptogenesis. Low-frequency stimulation may trigger or enhance epileptogenesis when applied on epileptogenic regions.