Evidence map›Paper›PMID 34537066›Full record

ArticleJournal of neuroinflammation2021

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

Susana S Correia, Guang Liu, Sarah Jacobson, Sylvie G Bernier, Jenny V Tobin, Chad D Schwartzkopf, Emily Atwater, Elisabeth Lonie, Sam Rivers, Andrew Carvalho and 7 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal of neuroinflammation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.

0numbers the graph read from it
0cells of the map it votes in
16citing papers in PubMed
2.1field-weighted citation impact, top 12% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

16 citing papers in PubMed, 32 citations in OpenAlex.

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  16. The Interplay between cGMP and Calcium Signaling in Alzheimer's Disease.International journal of molecular sciences · 2022
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

17 authors at 2 institutions in 1 country.

Susana S CorreiaCyclerion Therapeutics, 245 First St., Riverview II, 18th Floor, Cambridge, MA, 02142, USA.
Guang LiuCyclerion Therapeutics, 245 First St., Riverview II, 18th Floor, Cambridge, MA, 02142, USA.
Sarah JacobsonCyclerion Therapeutics, 245 First St., Riverview II, 18th Floor, Cambridge, MA, 02142, USA.
Sylvie G BernierCyclerion Therapeutics, 245 First St., Riverview II, 18th Floor, Cambridge, MA, 02142, USA.
Jenny V TobinCyclerion Therapeutics, 245 First St., Riverview II, 18th Floor, Cambridge, MA, 02142, USA.
Chad D SchwartzkopfCyclerion Therapeutics, 245 First St., Riverview II, 18th Floor, Cambridge, MA, 02142, USA.
Emily AtwaterCyclerion Therapeutics, 245 First St., Riverview II, 18th Floor, Cambridge, MA, 02142, USA.
Elisabeth LonieIronwood Pharmaceuticals, Cambridge, MA, 02142, USA.
Sam RiversCyclerion Therapeutics, 245 First St., Riverview II, 18th Floor, Cambridge, MA, 02142, USA.
Andrew CarvalhoCyclerion Therapeutics, 245 First St., Riverview II, 18th Floor, Cambridge, MA, 02142, USA.
Peter GermanoCyclerion Therapeutics, 245 First St., Riverview II, 18th Floor, Cambridge, MA, 02142, USA.
Kim TangIronwood Pharmaceuticals, Cambridge, MA, 02142, USA.
Rajesh R IyengarCyclerion Therapeutics, 245 First St., Riverview II, 18th Floor, Cambridge, MA, 02142, USA.
Mark G CurrieCyclerion Therapeutics, 245 First St., Riverview II, 18th Floor, Cambridge, MA, 02142, USA.
John R HadcockCyclerion Therapeutics, 245 First St., Riverview II, 18th Floor, Cambridge, MA, 02142, USA.
Christopher J WinrowCyclerion Therapeutics, 245 First St., Riverview II, 18th Floor, Cambridge, MA, 02142, USA.
Juli E JonesCyclerion Therapeutics, 245 First St., Riverview II, 18th Floor, Cambridge, MA, 02142, USA. jjones@cyclerion.com.ORCID http://orcid.org/0000-0002-3870-1705
Cyclerion (United States) · USIronwood Pharmaceuticals (United States) · US

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundInflammation 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.

methodsTarget 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.

resultsIn 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.

conclusionsThese data suggest that sGC stimulation could provide neuroprotective effects by attenuating inflammatory responses in nonclinical models of neuroinflammation.

Indexed as

AnimalsAnti-Inflammatory AgentsBiomarkersCells, CulturedCentral Nervous SystemCyclic GMPDose-Response Relationship, DrugHEK293 CellsHumansInflammation MediatorsMaleMiceMice, Inbred C57BLNeuronsRatsRats, Sprague-DawleyAnti-Inflammatory AgentsBiomarkersCyclic GMPInflammation MediatorsSoluble Guanylyl CyclasecGMPCREBHigh-fat dietMicrogliaNeuroinflammationNitric oxideQuinolinic acidsGCSoluble guanylate cyclase

Identifiers

PMID34537066
PMCPMC8449877
OpenAlexW3199368172

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.