作者: Bhattacharya, Anindya ; Missault, Stephan ; Van Eetveldt, Annemie ; Dedeurwaerdere, Stefanie ; Kumar-Singh, Samir ; Bielen, Kenny ; Ceusters, Marc ; Rech, Jason ; Amhaoul, Halima ; Ali, Idrish ; Lord, Brian ; Szewczyk, Krystyna ; Mola, Marco

BACKGROUNDThe available pharmacotherapy for patients with epilepsy primarily address the symptoms and are ineffective in about 40% of patients. Brain inflammation gained support as potential target for developing new therapies, especially the P2X7 receptor (P2X7R), involved in processing of IL-1β, might be an interesting candidate. This study was designed to investigate the effect of a novel P2X7R antagonist on the severity and on the number of chronic spontaneous recurrent seizures (SRS), which was unexplored until now.METHODSAfter one-week of vehicle treatment (20% HP-β-cyclodextrin), JNJ-42253432 was administered subcutaneously for another week under continuous video-electroencephalography monitoring (n = 17) in Sprague Dawley rats 3 months after kainic acid-induced status epilepticus. The proportion of different seizure classes, as well as the number of SRS/day were calculated for the vehicle and treatment period. In addition, post-mortem microglial activation and astrogliosis were assessed.RESULTSA significant decrease of the proportion of type 4-5 SRS (p < 0.05), while an increase of type 1-3 was demonstrated (p < 0.05) from the vehicle to the treatment period. There was no effect of the P2X7R antagonist on the number of SRS/day or the glial markers.CONCLUSIONSThe P2X7R antagonist gave rise to a less severe profile of the chronic seizure burden without suppressing the SRS frequency. More studies are needed to unravel the underlying mechanisms of the beneficial effect on seizure severity and whether the administration of the compound during early epileptogenesis could induce long-term disease-modifying effects.

2014-12-01·Journal of Pharmacology and Experimental Therapeutics3区 · 医学

Pharmacology of a Novel Central Nervous System–Penetrant P2X7 Antagonist JNJ-42253432

3区 · 医学

Article

作者: Bonaventure, Pascal ; Varlinskaya, Elena I ; Drinkenburg, Wilhelmus ; Letavic, Michael A ; Carruthers, Nicholas ; Neff, Robert A ; Deak, Terrence ; Ceusters, Marc ; Lovenberg, Timothy W ; Lord, Brian ; Bhattacharya, Anindya ; Shoblock, James R ; Aluisio, Leah

In the central nervous system, the ATP-gated Purinergic receptor P2X ligand-gated ion channel 7 (P2X7) is expressed in glial cells and modulates neurophysiology via release of gliotransmitters, including the proinflammatory cytokine interleukin (IL)-1β. In this study, we characterized JNJ-42253432 [2-methyl-N-([1-(4-phenylpiperazin-1-yl)cyclohexyl]methyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide] as a centrally permeable (brain-to-plasma ratio of 1), high-affinity P2X7 antagonist with desirable pharmacokinetic and pharmacodynamic properties for in vivo testing in rodents. JNJ-42253432 is a high-affinity antagonist for the rat (pKi 9.1 ± 0.07) and human (pKi 7.9 ± 0.08) P2X7 channel. The compound blocked the ATP-induced current and Bz-ATP [2'(3')-O-(4-benzoylbenzoyl)adenosine-5'-triphosphate tri(triethylammonium)]-induced release of IL-1β in a concentration-dependent manner. When dosed in rats, JNJ-42253432 occupied the brain P2X7 channel with an ED50 of 0.3 mg/kg, corresponding to a mean plasma concentration of 42 ng/ml. The compound blocked the release of IL-1β induced by Bz-ATP in freely moving rat brain. At higher doses/exposure, JNJ-42253432 also increased serotonin levels in the rat brain, which is due to antagonism of the serotonin transporter (SERT) resulting in an ED50 of 10 mg/kg for SERT occupancy. JNJ-42253432 reduced electroencephalography spectral power in the α-1 band in a dose-dependent manner; the compound also attenuated amphetamine-induced hyperactivity. JNJ-42253432 significantly increased both overall social interaction and social preference, an effect that was independent of stress induced by foot-shock. Surprisingly, there was no effect of the compound on either neuropathic pain or inflammatory pain behaviors. In summary, in this study, we characterize JNJ-42253432 as a novel brain-penetrant P2X7 antagonist with high affinity and selectivity for the P2X7 channel.

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