piperidines and Epilepsy--Reflex

A new class of drugs, the nonimidazole histamine 3 receptor (H3R) antagonists, has been developed in the past decade for treatment of various brain diseases. Pitolisant is such a drug. We studied the pharmacodynamic effect of pitolisant in patients with epilepsy in early Phase II, using the photosensitivity proof of concept model. A total of 14 adult patients (11 females and 3 males; 5 drug naïve) were studied for three days to evaluate the effect of a single oral dose of pitolisant on EEG photosensitivity ranges. All patients showed repeatedly a generalized photoparoxysmal response (PPR) prior to drug administration on placebo Day 1. A statistically significant suppressive effect (standardized photosensitive response [SPR] reduction as measured with paired t-tests) for 20-, 40-, or 60-mg doses of pitolisant was seen in 9/14 (64%) patients of whom 6/14 (43%) showed abolition of the response to intermittent photic stimulation (IPS). Patients on the highest dosage (60 mg) showed the strongest effect with an effect lasting up to 28 h. Thus, full-scale Phase II studies with this novel H3R antagonist, pitolisant, in patients with epilepsy are warranted.

Topics: Administration, Oral; Adult; Animals; Anticonvulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Electroencephalography; Electroshock; Epilepsy, Reflex; Excitatory Amino Acid Agonists; Female; Humans; Kainic Acid; Male; Mice; Piperidines; Time Factors; Young Adult

Post-ictal depression of consciousness occurs after generalized convulsive seizures, and includes analgesia, lasting for hours after electrically or chemically induced seizures in animals. The brain sites and mechanisms, mediating post-ictal analgesia, are unclear. The ventrolateral periaqueductal gray (PAG) is an important neuronal network site for mediating analgesia and also in generalized seizures, particularly in genetically epilepsy-prone rats (GEPRs). Endocannabinoids are implicated in mediating analgesia in several brain sites, including the PAG, and generalized seizures result in endocannabinoid release. This study evaluated if post-ictal analgesia occurs in GEPRs, following audiogenic seizures (AGS), and whether this analgesia involves endocannabinoid actions in PAG. Analgesia was evaluated, using thermal stimulation to evoke nociception, measuring changes in paw withdrawal latencies (PWLs) induced by AGS. Endocannabinoid involvement in post-ictal analgesia in GEPRs was evaluated, using focal bilateral microinjection of a cannabinoid (CB1) receptor antagonist (AM251) into PAG. AGS induced a significant increase in PWLs, lasting for ≥120min. Microinjection of AM251 (100 and 200, but not 50 pmol/side) into PAG significantly decreased post-ictal analgesia in GEPRs. Endocannabinoids are also known to activate transient receptor potential vanilloid (TRPV1) receptors, but PAG microinjection of a TRPV1 receptor antagonist (capsazepine) did not affect post-ictal analgesia in GEPRs. These results indicate that AGS in GEPRs induce post-ictal analgesia, which is the first observation of this phenomenon in a genetic epilepsy model. These findings suggest an important role of PAG in post-ictal analgesia. The results also suggest that CB1 receptors in PAG are critical for mediating post-ictal analgesia in GEPRs.

Topics: Amnesia, Anterograde; Analgesia; Animals; Epilepsy, Reflex; Female; Male; Pain Threshold; Periaqueductal Gray; Piperidines; Pyrazoles; Rats; Receptor, Cannabinoid, CB1; Seizures

Endocannabinoid system and its CB1 receptors are suggested to provide endogeneous protection against seizures. The present study examines whether CB1 receptors contribute to resistance to seizures and kindling epileptogenesis in a model of audiogenic epilepsy. Three groups of Wistar rats were used: rats unsusceptible to audiogenic seizures, rats with acquired resistance to audiogenic seizures and rats with reproducible audiogenic running seizures. Chronic treatment with the CB1 receptor antagonist SR141716 (5 daily dosing of 30mg/kg) did not change innate resistance to audiogenic seizures in non-epileptic rats but reverted acquired seizure resistance in rats which lost their epileptic sensitivity with repeated testing. In the latter rats, audiogenic running seizures reappeared for at least two weeks after the end of treatment. In rats with reproducible seizure response, acutely, SR lengthened audiogenic seizures due to prolongation or appearance, de novo, of post-running limbic clonus without any effect on running seizure per se. This limbic component mimicked audiogenic kindling and indicated propagation of sound-induced brainstem seizure to the limbic forebrain. After chronic SR administration the incidence of the limbic clonus remained to be increased for at least two weeks. The present study supports the hypothesis about a role of CB1 receptors in endogeneous anticonvulsive mechanisms of the brain.

Topics: Acoustic Stimulation; Acute Disease; Animals; Chronic Disease; Disease Models, Animal; Dose-Response Relationship, Drug; Epilepsy, Reflex; Kindling, Neurologic; Limbic System; Male; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Rimonabant; Seizures

Rats become susceptible to audiogenic seizures (AS) when they are exposed to intense noise during a certain critical period of development (priming). Antagonism of N-methyl-D-aspartate (NMDA) receptor NR2B subunit by injecting an antagonist ifenprodil at priming enhanced the later susceptibility to AS. An weak NR2A antagonist, dextromethorphan, did not show such effects while it significantly suppressed the manifestation of AS in already susceptible post-weaning (primed) rats. These results indicate that NR2B plays an important role in the developmental regulation of the auditory system involved in AS but this subunit has a minor relevance to the manifestation of AS in the later life.

Topics: Animals; Dextromethorphan; Disease Susceptibility; Epilepsy, Reflex; Excitatory Amino Acid Antagonists; Female; Male; Piperidines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Seizures

A series of novel arylpiperidines (4a-d) which have highly potent blocking effects for both neuronal Na+ and T-type Ca2+ channels with extremely low affinity for dopamine D2 receptors were synthesized. Among these compounds, 1-(2-hydroxy-3-phenoxy)propyl-4-(4-phenoxyphenyl)-piperidine hydrochloride (4c; SUN N5030) exhibited remarkable neuroprotective activity in a transient middle cerebral artery occlusion (MCAO) model.

Topics: Animals; Anticonvulsants; Calcium Channel Blockers; Calcium Channels, T-Type; Epilepsy, Reflex; Ischemic Attack, Transient; Mice; Mice, Inbred DBA; Neuroprotective Agents; Phenyl Ethers; Piperidines; Sodium Channel Blockers