Discovery of NP3-253, a Potent Brain Penetrant Inhibitor of the NLRP3 Inflammasome.

Activation of the NLRP3 inflammasome in response to danger signals is a key innate immune mechanism and results in the production of the pro-inflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18) as well as pyroptotic cell death. Aberrant NLRP3 activation has been linked to many acute and chronic conditions ranging from atherosclerosis to Alzheimer's disease and cancer, and based on the clinical success of IL-1-targeting therapies, NLRP3 has emerged as an attractive therapeutic target. Herein we describe our discovery, characterization, and structure-based optimization of a pyridazine-based series of NLRP3 inhibitors initiating from an high-throughput screening campaign.

Evaluation of protein kinase D auto-phosphorylation as biomarker for NLRP3 inflammasome activation.

Background: The NLRP3 inflammasome is a critical component of sterile inflammation, which is involved in many diseases. However, there is currently no known proximal biomarker for measuring NLRP3 activation in pathological conditions. Protein kinase D (PKD) has emerged as an important NLRP3 kinase that catalyzes the release of a phosphorylated NLRP3 species that is competent for inflammasome complex assembly.

Alertness fluctuations when performing a task modulate cortical evoked responses to transcranial magnetic stimulation.

Transcranial magnetic stimulation (TMS) has been widely used in human cognitive neuroscience to examine the causal role of distinct cortical areas in perceptual, cognitive and motor functions. However, it is widely acknowledged that the effects of focal cortical stimulation can vary substantially between participants and even from trial to trial within individuals. Recent work from resting state functional magnetic resonance imaging (fMRI) studies has suggested that spontaneous fluctuations in alertness over a testing session can modulate the neural dynamics of cortical processing, even when participants remain awake and responsive to the task at hand.

Stimulus-Driven Cortical Hyperexcitability in Individuals with Charles Bonnet Hallucinations.

Throughout the lifespan, the cerebral cortex adapts its structure and function in response to changing sensory input [1, 2]. Whilst such changes are typically adaptive, they can be maladaptive when they follow damage to the peripheral nervous system, including phantom limb pain and tinnitus [3, 4]. An intriguing example occurs in individuals with acquired ocular pathologies-most commonly age-related macular degeneration (MD) [5]-who lose their foveal vision but retain intact acuity in the peripheral visual field.

Corticospinal Plasticity in Bilateral Primary Motor Cortices Induced by Paired Associative Stimulation to the Dominant Hemisphere Does Not Differ between Young and Older Adults.

Older adults have been shown to exhibit a reduction in the lateralization of neural activity. Although neuroplasticity induced by noninvasive brain stimulation has been reported to be attenuated in the targeted motor cortex of older adults, it remains possible that the plasticity effects may instead manifest in a more distributed (bilateral) network. Furthermore, attention, which modulates neuroplasticity in young adults, may influence these effects.