The soluble guanylate cyclase stimulator IWP-550 decreased markers of neuroinflammation in vitro and in obese mice Susana S. Correiaa, Juli E. Jonesa, Guang Liua, Chad D. Schwartzkopfa, Andrew Carvalhoa, Peter Germanoa, Kim Tanga, Rajesh R. Iyengara, Christopher Winrowa, Daniel P. Zimmera, Mark G. Curriea and John R. Hadcocka aIronwood Pharmaceuticals Inc., 301 Binney Street, Cambridge, MA 02142
Soluble guanylate cyclase (sGC) is an enzyme expressed in many cell types throughout the body, including the central nervous system (CNS). sGC is activated by nitric oxide (NO), leading to the conversion of guanosine-5′-triphosphate (GTP) to the secondary messenger cyclic guanosine-3′,5′-monophosphate (cGMP). sGC stimulators are small molecules that potentiate the NO-sGC-cGMP signaling pathway by synergizing with endogenous NO or by directly stimulating sGC in an NO-independent manner, resulting in increased cGMP production. The NO-sGC-cGMP signaling pathway modulates broad physiological mechanisms such as vasodilation, fibrosis, inflammation, and metabolism. However, understanding the role of sGC in the CNS has been hampered by the lack of available CNS-penetrant sGC stimulators. We evaluated the effects of IWP-550, a brain-penetrant sGC stimulator, on markers of neuroinflammation in rat brain 3D microtissues (MT, InSpheroTM) and in brain regions from diet-induced obese (DIO) mice. In brain MT, which contain a mix of neurons, astrocytes, microglia, and oligodendrocytes, IWP-550 stimulated cGMP formation and phosphorylation of CREB. Moreover, brain MT treated with IWP-550 (1 and 10 µM) in the presence of DETA-NO (an NO donor) showed lower LPS-induced elevation of IL-6, IFNγ, TNFα, IL-1β, IL-13 and CXCL1, as compared to vehicle treated MT. Oral dosing of IWP-550 (10 mg/kg) in C57BL/6J mice led to cGMP elevation in the brain. In a DIO mouse model that displays neuroinflammation, IWP-550 did not change body weight or food intake, but showed lower expression of inflammatory genes (ICAM-1 and GFAP) and other genes (NOX2, TRKB, Map1lc3a and ApoE) in select brain regions, as compared to vehicle treated DIO mice. These results show that IWP-550 suppressed markers of neuroinflammation in vitro in rat brain microtissues as well as in vivo in obese mice, suggesting that sGC stimulation may provide potential neuroprotective effects by reducing neuroinflammation.
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