The CNS‑penetrant soluble guanylate cyclase stimulator CYR119 attenuates markers of inflammation in the central nervous system

Journal of Neuroinflammation (2021)

Susana S. Correia, Guang Liu, Sarah Jacobson, Sylvie G. Bernier, Jenny V. Tobin, Chad D. Schwartzkopf, Emily Atwater, Elisabeth Lonie, Sam Rivers, Andrew Carvalho, Peter Germano, Kim Tang, Rajesh R. Iyengar, Mark G. Currie, John R. Hadcock, Christopher J. Winrow and Juli E. Jones

In preclinical research published in this paper, a small molecule soluble guanylate cyclase (sGC) stimulator was shown to cross the blood-brain barrier and resulted in the stimulation of cyclic guanosine monophosphate (cGMP) levels in cerebral spinal fluid, providing evidence of activation of the nitric oxide – sGC – cGMP pathway. Furthermore, pharmacological sGC stimulation resulted in a statistically significant decrease in biomarkers associated with neuroinflammation in multiple preclinical models. These data suggest that brain-penetrant sGC stimulators could provide therapeutic benefit to individuals living with CNS diseases associated with neuroinflammation.

Effects of CYR119 on markers of inflammation following QA administration - described below

Fig. 4 Effects of CYR119 on markers of inflammation following QA administration. Rats were administered 10 mg/kg CYR119 or vehicle for 7 days following QA administration into the dorsal striatum. Normalized gene expression was analyzed for A TNF and B CD40 or immunohistochemistry staining of C glial fibrillary acidic protein (GFAP), and D IBA1, represented as percent (%) area of Iba1 staining, and E pCREB, represented as intensity as a cumulative distribution and average intensity in the dorsal striatum. A representative image from each group is shown in F GFAP, G IBA1, and H pCREB. Data were analyzed by one-way ANOVA followed by Sidak’s multiple comparison test (*p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001). Data are expressed as mean ± SEM

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