The Effect of Pexidartinib on Neuropathic Pain via Influences on Microglia and Neuroinflammation in Mice.

Background: Chronic pain is a debilitating medical condition that lacks effective treatments. Increasing evidence suggests that microglia and neuroinflammation underlie pain pathophysiology, which therefore supports a potential strategy for developing pain therapeutics. Here, our study is testing the hypothesis that the promise of pain amelioration can be achieved using the small-molecule pexidartinib (PLX-3397), a previously food and drug administration (FDA)-approved cancer medicine and a colony-stimulating factor-1 receptor (CSF-1R) inhibitor that display microglia-depleting properties.

Functional Characterization of an Arylsulfonamide-Based Small-Molecule Inhibitor of the NLRP3 Inflammasome.

Considerable evidence indicates that the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome plays key roles in human pathophysiology, suggesting it as a potential drug target. Currently, studies have yet to develop compounds that are promising therapeutics in the clinic by targeting the NLRP3 inflammasome. Herein, we aim to further biologically characterize a previously identified small-molecule inhibitor of the NLRP3 inflammasome from our group, YM-I-26, to confirm its functional activities.

Development of a New Positron Emission Tomography Imaging Radioligand Targeting RIPK1 in the Brain and Characterization in Alzheimer's Disease.

Targeting receptor-interacting protein kinase 1 (RIPK1) has emerged as a promising therapeutic stratagem for neurodegenerative disorders, particularly Alzheimer's disease (AD). A positron emission tomography (PET) probe enabling brain RIPK1 imaging can provide a powerful tool to unveil the neuropathology associated with RIPK1. Herein, the development of a new PET radioligand, [C]CNY-10 is reported, which may enable brain RIPK1 imaging.

Molecular Imaging of Alzheimer's Disease-Related Sigma-1 Receptor in the Brain a Novel Ru-Mediated Aromatic F-deoxyfluorination Probe.

Sigma-1 receptor (σR) is an intracellular protein implicated in a spectrum of neurodegenerative conditions, notably Alzheimer's disease (AD). Positron emission tomography (PET) imaging of brain σR could provide a powerful tool for better understanding the underlying pathomechanism of σR in AD. In this study, we successfully developed a F-labeled σR radiotracer [F]CNY-05 via an innovative ruthenium (Ru)-mediated F-deoxyfluorination method.

Sodium oligomannate alters gut microbiota, reduces cerebral amyloidosis and reactive microglia in a sex-specific manner.

It has recently become well-established that there is a connection between Alzheimer's disease pathology and gut microbiome dysbiosis. We have previously demonstrated that antibiotic-mediated gut microbiota perturbations lead to attenuation of Aβ deposition, phosphorylated tau accumulation, and disease-associated glial cell phenotypes in a sex-dependent manner. In this regard, we were intrigued by the finding that a marine-derived oligosaccharide, GV-971, was reported to alter gut microbiota and reduce Aβ amyloidosis in the 5XFAD mouse model that were treated at a point when Aβ burden was near plateau levels.

Early modulation of the gut microbiome by female sex hormones alters amyloid pathology and microglial function.

It is well-established that women are disproportionately affected by Alzheimer's disease. The mechanisms underlying this sex-specific disparity are not fully understood, but several factors that are often associated-including interactions of sex hormones, genetic factors, and the gut microbiome-likely contribute to the disease's etiology. Here, we have examined the role of sex hormones and the gut microbiome in mediating Aβ amyloidosis and neuroinflammation in APPPS1-21 mice.

Structure-Based Discovery of A Small Molecule Inhibitor of Histone Deacetylase 6 (HDAC6) that Significantly Reduces Alzheimer's Disease Neuropathology.

Histone deacetylase 6 (HDAC6) is one of the key histone deacetylases (HDACs) that regulates various cellular functions including clearance of misfolded protein and immunological responses. Considerable evidence suggests that HDAC6 is closely related to amyloid and tau pathology, the two primary hallmarks of Alzheimer's disease (AD). It is still unclear whether HDAC6 expression changes with amyloid deposition in AD during disease progression or HDAC6 may be regulating amyloid phagocytosis or neuroinflammation or other neuropathological changes in AD.

Design, synthesis, and anti-inflammatory activity characterization of novel brain-permeable HDAC6 inhibitors.

Targeting histone deacetylase 6 (HDAC6) has emerged as a promising therapeutic approach for anti-inflammation and related biological pathways, including inflammatory events associated with the brain. In this study, in order to develop brain-permeable HDAC6 inhibitors for anti-neuroinflammation, we report here the design, synthesis, and characterization of a number of N-heterobicyclic analogues that can inhibit HDAC6 with high specificity and strong potency. Among our analogues, PB131 exhibits potent binding affinity and selectivity against HDAC6, with an IC value of 1.

Development of a potential PET probe for HDAC6 imaging in Alzheimer's disease.

Although the epigenetic regulatory protein histone deacetylase 6 (HDAC6) has been recently implicated in the etiology of Alzheimer's disease (AD), little is known about the role of HDAC6 in the etiopathogenesis of AD and whether HDAC6 can be a potential therapeutic target for AD. Here, we performed positron emission tomography (PET) imaging in combination with histopathological analysis to better understand the underlying pathomechanisms of HDAC6 in AD. We first developed [F]PB118 which was demonstrated as a valid HDAC6 radioligand with excellent brain penetration and high specificity to HDAC6.