Neuropeptide receptors as potential antiepileptic drug targets : focus on the ghrelin axis

Epilepsy is a very serious neurological disorder which is often underrepresented. Around 50 million individuals worldwide have active epilepsy with recurrent seizures and in spite of the medical advances over the years, 30% of these patients remain as drug resistant (Pati 2010). Even after several years of research, there is still a lack of good understanding on the pathophysiology of seizure disorders (Perucca 2011). Investigators in this field believe that there is a great need for novel antiepileptic drugs (AEDs) that act differently than the drugs available on the market. The majority of AEDs act by blocking sodium channels (phenytoin, carbamazepine) or by the augment of GABAergic transmission (phenobarbital, valproic acid). A newer generation of AEDs has expanded therapeutic options, however these are not superior to the older drugs (Hitiris 2006). Patients with mesial temporal lobe epilepsy (mTLE) are among the most pharmacoresistant to these medications (Pati 2010). In order to attempt the rectification of this dilemma, the neuropharmacologist needs to not only try and find AEDs with new mechanisms of action, but to also keep in mind what information is currently available on the pathophysiology of epilepsy. It is clear that during the complicated process of epileptogenesis, several different mechanisms are taking place, thus one should ideally identify new compounds that are capable of targeting different pathways simultaneously. The focus of epilepsy researchers is to identify compounds that are not only capable of attenuating seizures (anticonvulsant), but are also antiepileptogenic (can prevent epilepsy) or disease-modifying (halting its progression).peer-reviewe

Chronopharmacology of antihypertensives

Pharmacological treatments of hypertension are associated with a reduction in cardiovascular risk. The blood pressure of both normotensive and hypertensive patients has a particular pattern associated to the biological clock set according to a circadian rhythm. One of the aims of this study was to test the long acting anti-hypertensive medications, atenolol and perindopril for their chronopharmacological properties in their effect on systolic and diastolic blood pressure levels over a period of 24 hours when administered in the morning or evening. Other aims were to compare blood pressure control in patients on atenolol and perindopril with control and normotensive patients and to obtain hourly systolic and diastolic blood pressure values using the ambulatory blood pressure monitor. An ambulatory blood pressure monitor was applied to the recruited patients for 24 hours and results analysed. Atenolol provides better blood pressure control during the early morning following a morning dose, whilst it results in an elevated blood pressure during the early morning when administered in the evening. Evening administered perindopril did not result in optimum blood pressure control throughout the 24h whilst morning administration resulted in an elevated early morning peak during the critical early morning period.peer-reviewe

Central functions of the ghrelin receptor

The Ghrelin receptor was identified before its natural ligand ghrelin. This receptor is found both centrally and peripherally, and has been shown to affect various processes, such as food intake, gut motility, memory, glucose and lipid metabolism, cardiovascular performances, reproduction, memory, and immunological responses, amongst others. The functions of the ghrelin receptor in the central nervous system are numerous and are still being explored. In this book we specifically focus on the various roles of the ghrelin receptor in the central nervous system. In a first set of chapters, the book will focus on the discovery and the properties of this intriguing constitutively active G-protein coupled receptor, on its multiple intracellular transduction mechanisms and the various subtypes of the currently known ghrelin receptor complexes. Next, the book will elaborate on the mitochondrial mechanisms regulated by the ghrelin receptor, its role in feeding and drug addictive mechanisms, memory, sleep and arousal. The final chapters focus on the potential of this receptor as a target for the treatment of neurological disorders including Parkinson’s disease, epilepsy, anxiety and depression

Anticonvulsant effect of a ghrelin receptor agonist in 6Hz corneally kindled mice

International audienc

Uric acid is released in the brain during seizure activity and increases severity of seizures in a mouse model for acute limbic seizures

Recent evidence points at an important role of endogenous cell-damage induced pro-inflammatory molecules in the generation of epileptic seizures. Uric acid, under the form of monosodium urate crystals, has shown to have pro-inflammatory properties in the body, but less is known about its role in seizure generation. This study aimed to unravel the contribution of uric acid to seizure generation in a mouse model for acute limbic seizures. We measured extracellular levels of uric acid in the brain and modulated them using complementary pharmacological and genetic tools. Local extracellular uric acid levels increased three to four times during acute limbic seizures and peaked between 50 and 100min after kainic acid infusion. Manipulating uric acid levels through administration of allopurinol or knock-out of urate oxidase significantly altered the number of generalized seizures, decreasing and increasing them by a twofold respectively. Taken together, our results consistently show that uric acid is released during limbic seizures and suggest that uric acid facilitates seizure generalization

Modulation of hippocampal activity by vagus nerve stimulation in freely moving rats

BACKGROUND: Vagus Nerve Stimulation (VNS) has seizure-suppressing effects but the underlying mechanism is not fully understood. To further elucidate the mechanisms underlying VNS-induced seizure suppression at a neurophysiological level, the present study examined effects of VNS on hippocampal excitability using dentate gyrus evoked potentials (EPs) and hippocampal electroencephalography (EEG). METHODS: Male Sprague-Dawley rats were implanted with a VNS electrode around the left vagus nerve. A bipolar stimulation electrode was implanted in the left perforant path and a bipolar recording electrode was implanted in the left dentate gyrus for EEG and dentate field EP recording. Following recovery, VNS was applied in freely moving animals, using a duty cycle of 7 s on/18 s off, 30 Hz frequency, 250 micros pulse width, and an intensity of either 0 (SHAM), 25 microA or 1000 microA, while continuously monitoring EEG and dentate field EPs. RESULTS: VNS at 1000 microA modulated dentate field EPs by decreasing the field excitatory post-synaptic potential (fEPSP) slope and increasing the latency and amplitude of the population spike. It additionally influenced hippocampal EEG by slowing theta rhythm from 7 Hz to 5 Hz and reducing theta peak and gamma band power. No effects were observed in the SHAM or 25 microA VNS conditions. CONCLUSION: VNS modulated hippocampal excitability of freely moving rats in a complex way. It decreased synaptic efficacy, reflected by decreased fEPSP slope and EEG power, but it simultaneously facilitated dentate granule cell discharge indicating depolarization of dentate granule cells