Neuropsychopharmacology of JNJ-55308942: evaluation of a clinical candidate targeting P2X7 ion channels in animal models of neuroinflammation and anhedonia

Abstract

Emerging data continues to point towards a relationship between neuroinflammation and neuropsychiatric disorders. ATP-induced activation of P2X7 results in IL-1β release causing neuroinflammation and microglial activation. This study describes the in-vitro and in-vivo neuropharmacology of a novel brain-penetrant P2X7 antagonist, JNJ-55308942, currently in clinical development. JNJ-55308942 is a high-affinity, selective, brain-penetrant (brain/plasma of 1) P2X7 functional antagonist. In human blood and in mouse blood and microglia, JNJ-55308942 attenuated IL-1β release in a potent and concentration-dependent manner. After oral dosing, the compound exhibited both dose and concentration-dependent occupancy of rat brain P2X7 with an ED of 0.07 mg/kg. The P2X7 antagonist (3 mg/kg, oral) blocked Bz-ATP-induced brain IL-1β release in conscious rats, demonstrating functional effects of target engagement in the brain. JNJ-55308942 (30 mg/kg, oral) attenuated LPS-induced microglial activation in mice, assessed at day 2 after a single systemic LPS injection (0.8 mg/kg, i.p.), suggesting a role for P2X7 in microglial activation. In a model of BCG-induced depression, JNJ-55308942 dosed orally (30 mg/kg), reversed the BCG-induced deficits of sucrose preference and social interaction, indicating for the first time a role of P2X7 in the BCG model of depression, probably due to the neuroinflammatory component induced by BCG inoculation. Finally, in a rat model of chronic stress induced sucrose intake deficit, JNJ-55308942 reversed the deficit with concurrent high P2X7 brain occupancy as measured by autoradiography. This body of data demonstrates that JNJ-55308942 is a potent P2X7 antagonist, engages the target in brain, modulates IL-1β release and microglial activation leading to efficacy in two models of anhedonia in rodents.

Clemastine Alleviates Depressive-Like Behavior Through Reversing the Imbalance of Microglia-Related Pro-inflammatory State in Mouse Hippocampus

“…In our study, the expressions of P2X7R were augmented in hippocampus and mPFC, which was partly consistent with previous findings (Pan et al, 2014 ). In several very recently published articles, researchers showed that P2X7 receptor antagonists including JNJ-55308942 and brilliant blue G (BBG) could modulate neuroinflammation and anhedonia in rodent models (Bhattacharya et al, 2018 ; Farooq et al, 2018 ). Concerned that Apolloni et al ( 2016b ) demonstrated that clemastine inhibited the increase of P2X7R expression in SOD1 G93A mice in lumbar spinal cord compared to vehicle group, we applied clemastine, a safe and effective clinical drug, as a potential P2X7 inhibitor.…”

The P2X7 Receptor: Central Hub of Brain Diseases

“…P2X7 receptor activation induces K + efflux, which is needed for efficient NLRP3 inflammasome activation (Gustin et al, 2015). NLRP3 inflammasome trigger the activation of caspase-1, which causes the maturation of IL-1β and IL-18 and, consequently, increasing proinflammatory cytokine release (Bernier, 2012;Jo et al, 2016;He et al, 2017;Bhattacharya et al, 2018). This signaling appears to be in functional in microglia and not astrocytes (Gustin et al, 2015).…”

“…Similarly to the LPS-induced effects, P2X7 receptor overexpression was sufficient to trigger microglial activation in primary microglia derived from hippocampus ( Monif et al, 2009 ). Interestingly, a recent study evidenced that the selective P2X7 receptor antagonist, JNJ-55308942, inhibited neuroinflammation development induced in different rodent models by LPS, BCG or chronic stress ( Bhattacharya et al, 2018 ). Recently, efforts were made to detect in vivo neuroinflammation.…”

Purinergic Receptors of the Central Nervous System: Biology, PET Ligands, and Their Applications

“…These are the brain penetrant benzamides GSK1482160, 196 JNJ-42253432, 197 JNJ-47965567, 198 triazoles JNJ-54232334 and JNJ-54140515, 199 JNJ-54166060, 200 JNJ-54173717, 201 JNJ-54175446, 202 and JNJ-55308942. 203 These molecules have demonstrated P2X 7 receptor antagonist activities in rodent and human. Three of these molecules, GSK1482160, JNJ-54175446, and JNJ-55308942, have already moved into clinical trials for evaluation of the disorders of CNS.…”