The CNS-penetrant soluble guanylate cyclase stimulator CYR119 attenuates markers of inflammation in the central nervous system
| Autor: | Sylvie G. Bernier, Peter Germano, Christopher J. Winrow, Chad D. Schwartzkopf, Susana S. Correia, Kim Tang, Juli E. Jones, Sam Rivers, Elisabeth Lonie, Guang Liu, Sarah Jacobson, Andrew Carvalho, Jenny Tobin, John R. Hadcock, Emily Atwater, Rajesh R. Iyengar, Mark G. Currie |
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| Rok vydání: | 2021 |
| Předmět: |
Central Nervous System
Male sGC Immunology Anti-Inflammatory Agents Pharmacology Neuroprotection Rats Sprague-Dawley Mice Cellular and Molecular Neuroscience chemistry.chemical_compound Soluble Guanylyl Cyclase Neuroinflammation medicine Animals Humans Soluble guanylate cyclase Quinolinic acid RC346-429 Cyclic GMP Cells Cultured Neurons Dose-Response Relationship Drug Glial fibrillary acidic protein biology Microglia CREB Research General Neuroscience HEK 293 cells Nitric oxide Rats Mice Inbred C57BL cGMP High-fat diet HEK293 Cells medicine.anatomical_structure Neurology chemistry biology.protein Tumor necrosis factor alpha Neurology. Diseases of the nervous system Inflammation Mediators cGMP-dependent protein kinase Biomarkers |
| Zdroj: | Journal of Neuroinflammation, Vol 18, Iss 1, Pp 1-13 (2021) Journal of Neuroinflammation |
| ISSN: | 1742-2094 |
| Popis: | Background Inflammation in the central nervous system (CNS) is observed in many neurological disorders. Nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate (NO–sGC–cGMP) signaling plays an essential role in modulating neuroinflammation. CYR119 is a CNS-penetrant sGC stimulator that amplifies endogenous NO–sGC–cGMP signaling. We evaluated target engagement and the effects of CYR119 on markers of neuroinflammation in vitro in mouse microglial cells and in vivo in quinolinic acid (QA)-induced and high-fat diet-induced rodent neuroinflammation models. Methods Target engagement was verified in human embryonic kidney (HEK) cells, rat primary neurons, mouse SIM-A9 cells, and in rats by measuring changes in cGMP and downstream targets of sGC signaling [phosphorylated vasodilator-stimulated phosphoprotein (pVASP), phosphorylated cAMP-response element binding (pCREB)]. In SIM-A9 cells stimulated with lipopolysaccharides (LPS), markers of inflammation were measured when cells were treated with or without CYR119. In rats, microinjections of QA and vehicle were administered into the right and left hemispheres of striatum, respectively, and then rats were dosed daily with either CYR119 (10 mg/kg) or vehicle for 7 days. The activation of microglia [ionized calcium binding adaptor molecule 1 (Iba1)] and astrocytes [glial fibrillary acidic protein (GFAP)] was measured by immunohistochemistry. Diet-induced obese (DIO) mice were treated daily with CYR119 (10 mg/kg) for 6 weeks, after which inflammatory genetic markers were analyzed in the prefrontal cortex. Results In vitro, CYR119 synergized with exogenous NO to increase the production of cGMP in HEK cells and in primary rat neuronal cell cultures. In primary neurons, CYR119 stimulated sGC, resulting in accumulation of cGMP and phosphorylation of CREB, likely through the activation of protein kinase G (PKG). CYR119 attenuated LPS-induced elevation of interleukin 6 (IL-6) and tumor necrosis factor (TNF) in mouse microglial cells. Following oral dosing in rats, CYR119 crossed the blood–brain barrier (BBB) and stimulated an increase in cGMP levels in the cerebral spinal fluid (CSF). In addition, levels of proinflammatory markers associated with QA administration or high-fat diet feeding were lower in rodents treated with CYR119 than in those treated with vehicle. Conclusions These data suggest that sGC stimulation could provide neuroprotective effects by attenuating inflammatory responses in nonclinical models of neuroinflammation. |
| Databáze: | OpenAIRE |
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