Anti-inflammatory effects of N-cyclooctyl-5-methylthiazol-2-amine hydrobromide on lipopolysaccharide-induced inflammatory response through attenuation of NLRP3 activation in microglial cells

Microglial activation is closely associated with neuroinflammatory pathologies. The nucleotide-binding and oligomerization domain-like receptor containing a pyrin domain 3 (NLRP3) inflammasomes are highly organized intracellular sensors of neuronal alarm signaling. NLRP3 inflammasomes activate nuclear factor kappa-B (NF-κB) and reactive oxygen species (ROS), which induce inflammatory responses. Moreover, NLRP3 dysfunction is a common feature of chronic inflammatory diseases. The present study investigated the effect of a novel thiazol derivative, N-cyclooctyl-5-methylthiazol-2-amine hydrobromide ({"type":"entrez-protein","attrs":{"text":"KHG26700","term_id":"728847257"}}KHG26700), on inflammatory responses in lipopolysaccharide (LPS)-treated BV-2 microglial cells. {"type":"entrez-protein","attrs":{"text":"KHG26700","term_id":"728847257"}}KHG26700 significantly attenuated the expression of several pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin-1β, and interleukin-6, in these cells, as well as the LPS-induced increases in NLRP3, NF-κB, and phospho-IkBα levels. {"type":"entrez-protein","attrs":{"text":"KHG26700","term_id":"728847257"}}KHG26700 also suppressed the LPS-induced increases in protein levels of autophagy protein 5 (ATG5), microtubule-associated protein 1 light chain 3 (LC3), and beclin-1, as well as downregulating the LPS-enhanced levels of ROS, lipid peroxidation, and nitric oxide. These results suggest that the anti-inflammatory effects of {"type":"entrez-protein","attrs":{"text":"KHG26700","term_id":"728847257"}}KHG26700 may be due, at least in part, to the regulation of the NLRP3-mediated signaling pathway during microglial activation.     

p65/RelA-Ser529 NF-??B Subunit Phosphorylation Induces Autophagic Astroglial Death (Clasmatodendrosis) Following Status Epilepticus

Clasmatodendrosis is an irreversible astroglial degenerative change, which includes extensive swelling and vacuolization of cell bodies and disintegrated and beaded processes. This study was designed to elucidate whether clasmatodendrosis may be one of the autophagy-related degeneration of astrocytes. In this study, clasmatodendritic astrocytes were observed only in the stratum radiatum in the CA1 region. Vacuoles in clasmatodendritic astrocytes showed LAMP-1 immunoreactivity. In addition, both LC3-II and Beclin-1 expression were detected in most of clasmatodendritic astrocytes as well as a few non-vacuolized astrocytes. Clasmatodendritic astrocytes also showed p65/RelA-Ser529 phosphorylation in the nuclei. The neutralization of TNF-α by sTNFp55R infusion reduced clasmatodendritic astrocytes with nuclear p65/RelA-Ser529 phosphorylation. Therefore, these findings suggest that clasmatodendrosis may be autophagic astroglial death in response to epileptic seizures through TNF-α-mediated p65/RelA-Ser529 phosphorylation.     

Dependency of Experimental Autoimmune Encephalomyelitis Induction on MOG<Subscript>35–55</Subscript> Properties Modulating Matrix Metalloproteinase-9 and Interleukin-6

Experimental autoimmune encephalomyelitis (EAE) is commonly induced with myelin oligodendrocyte glycoprotein (MOG)_35–55; occasionally, EAE is not well induced despite MOG_35–55 immunization. To confirm that EAE induction varies with difference in MOG_35–55 properties, we compared three MOG_35–55 from different commercial sources, which are MOG-A, MOG-B, and MOG-C. The peptides induced EAE disease with 100, 40, and 20 % incidence, respectively. Compared with others, MOG-A showed higher peptide purity (99.2 %) and content (92.2 %) and presented a sheet shape with additional sodium and chloride chemical elements. In MOG-A-treated group, MMP-9 activity and IL-6 levels were considerably higher than the other groups in CNS tissues, and significantly increased VCAM-1, IFN-γ, and decreased IL-4 were also shown compared to MOG-B- and/or MOG-C-treated group. In conclusion, the immunological and toxicological changes by the difference in MOG_35–55 properties modulate EAE induction, and MOG_35–55 which affects MMP-9 activity and IL-6 levels may be the most effective EAE-inducing antigen. This study can be potentially applied by researchers using MOG_35-55 peptide and manufacturers for MOG_35-55 synthesis.