The Role of NO/cGMP Signaling on Neuroinflammation: A New Therapeutic Opportunity

Peixoto, Christina A.; Nunes, Ana Karolina Santana; Rapôso, Catarina

doi:10.5772/intechopen.68990

Cited by 10 publications

(12 citation statements)

References 202 publications

(255 reference statements)

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“…Cyclic nucleotide phosphodiesterase (PDE) inhibitors had shown their remarkable outcomes in different inflammation associated disorders (Peixoto et al, 2017;Li et al, 2018). The PDE superfamily comprises 11 members (PDE1-11), the common N-terminus to C-terminus structure is profoundly known for their catalytic action on cAMP and cGMP.…”

Section: Introductionmentioning

confidence: 99%

PDE9 Inhibitor PF-04447943 Attenuates DSS-Induced Colitis by Suppressing Oxidative Stress, Inflammation, and Regulating T-Cell Polarization

Rana

Xue

et al. 2021

Front. Pharmacol.

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Ulcerative colitis (UC) is a form of inflammatory bowel disease, which manifests as irritation or swelling and sores in the large intestine in a relapsing and remitting manner. In a dextran sulfate sodium sulfate (DSS)-induced UC model in female mice, we found that the levels of cyclic guanosine monophosphate (cGMP) are reduced, while the expression of phosphodiesterase 9A (PDE9A) is highest among all phosphodiesterase (PDEs). Since PDE9 has the highest affinity toward cGMP, we evaluated the selective PDE9 inhibitor PF-04447943 (PF) as a potential candidate for UC treatment. PF has been extensively studies in cognitive function and in sickle cell disease, but not in models for inflammatory bowel disease (IBD). Therefore, we used female C57BL/6 mice treated with 3% DSS alone or co-treated with PF or sulfasalazine (SASP) to study the body weight, colon length, histopathology, and measure superoxide dismutase (SOD), malondialdehyde (MDA), and cGMP level, as well as cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-17 (IL-17), interleukin-12/23 (IL-12/23), interleukin-10 (IL-10), and pathways including nuclear factor kappa B (NF-κB), signal transducer and activator of transcription 3 (STAT3), and inflammasome activation. In addition, the number of dendritic cells (DC) and regulatory T cells (Treg cell) was assessed in the spleen, lymph node, and colon using flow cytometry. DSS reduced the number of goblet cells, decreased colon lengths and body weights, all of them were attenuated by PF treatment. It also suppressed the elevated level of inflammatory cytokines and increased level the anti-inflammatory cytokine, IL-10. PF treatment also reduced the DSS-induced inflammation by suppressing oxidative stress, NF-κB, STAT3, and inflammasome activation, by upregulating nuclear factor erythroid 2-related factor 2 (Nrf-2) and its downstream proteins via extracellular signal-regulated kinase (ERK) phosphorylation. Importantly, PF reversed imbalance in Treg/T helper 17 cells (Th17) cells ratio, possibly by regulating dendritic cells and Treg developmental process. In summary, this study shows the protective effect of a PDE9A inhibitor in ulcerative colitis by suppressing oxidative stress and inflammation as well as reversing the Treg/Th17 cells imbalance.

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Section: Introductionmentioning

confidence: 99%

PDE9 Inhibitor PF-04447943 Attenuates DSS-Induced Colitis by Suppressing Oxidative Stress, Inflammation, and Regulating T-Cell Polarization

Rana

Xue

et al. 2021

Front. Pharmacol.

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“…Experiments in the mouse model of noise-induced SNHL demonstrated that Pde5 inhibition protected against NIHL [102]. Pde5 inhibition has also been clinically beneficial in reversing deficits in stroke patients [103].…”

Section: Resultsmentioning

confidence: 99%

Evidence Supporting the Hypothesis That Inflammation-Induced Vasospasm Is Involved in the Pathogenesis of Acquired Sensorineural Hearing Loss

Eisenhut

2019

International Journal of Otolaryngology

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Sensorineural hearing loss is mainly acquired and affects an estimated 1.3 billion humans worldwide. It is related to aging, noise, infection, ototoxic drugs, and genetic defects. It is essential to identify reversible and preventable causes to be able to reduce the burden of this disease. Inflammation is involved in most causes and leads to tissue injury through vasospasm-associated ischemia. Vasospasm is reversible. This review summarized evidence linking inflammation-induced vasospasm to several forms of acquired sensorineural hearing loss. The link between vasospasm and sensorineural hearing loss is directly evident in subarachnoid haemorrhage, which involves the release of vasoconstriction-inducing cytokines like interleukin-1, endothelin-1, and tumour necrosis factor. These proinflammatory cytokines can also be released in response to infection, autoimmune disease, and acute or chronically increased inflammation in the ageing organism as in presbyacusis or in noise-induced cochlear injury. Evidence of vasospasm and hearing loss has also been discovered in bacterial meningitis and brain injury. Resolution of inflammation-induced vasospasm has been associated with improvement of hearing in autoimmune diseases involving overproduction of interleukin-1 from inflammasomes. There is mainly indirect evidence for vasospasm-associated sensorineural hearing loss in most forms of systemic or injury- or infection-induced local vascular inflammation. This opens up avenues in prevention and treatment of vascular and systemic inflammation as well as vasospasm itself as a way to prevent and treat most forms of acquired sensorineural hearing loss. Future research needs to investigate interventions antagonising vasospasm and vasospasm-inducing proinflammatory cytokines and their production in randomised controlled trials of prevention and treatment of acquired sensorineural hearing loss. Prime candidates for interventions are hereby inflammasome inhibitors and vasospasm-reducing drugs like nitric oxide donors, rho-kinase inhibitors, and magnesium which have the potential to reduce sensorineural hearing loss in meningitis, exposure to noise, brain injury, arteriosclerosis, and advanced age-related and autoimmune disease-related inflammation.

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“…3), with all of them having interactions. It has been reported that GUCY1A1 (guanylate cyclases), which was involved in NO/cGMP/PKG mediated neuroprotection, is activated by nitric oxide and plays a key role in inhibiting neuroinflammation 42 . From this perspective, we infer that the combination of nitrergic and dopaminergic neurons contributes to the regulation of smooth muscle contraction.…”

Section: Discussionmentioning

confidence: 99%

Comparative Transcriptomics Reveal Highly Conserved Regional Programs Between Porcine and Human Colonic Enteric Nervous System

Morselli

et al. 2022

Preprint

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The porcine gut is increasingly regarded as a useful translational model. The enteric nerve system (ENS) in the colon coordinates diverse functions. However, knowledge of the molecular profiling of porcine ENS and its similarity to that of human is limited. We identified the distinct transcriptional programs associated with functional characteristics between inner submucosal and myenteric ganglia (ISG, MG) in porcine proximal and distal colon (p-pC, p-dC) using bulk RNA sequencing (RNA-seq) and single-cell RNA-seq. Comparative transcriptomics of MG in corresponding colonic regions of porcine and human revealed highly conserved programs existing in p-pC and p-dC, which explained >90% of their transcriptomic responses to vagal nerve stimulation (VNS), suggesting that p-pC and p-dC could serve as predictors in translational studies. The conserved programs specific for inflammatory modulation were displayed in porcine with VNS. This study provides a valuable transcriptomic resource for understanding of human colonic functions and neuromodulation using porcine model.

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The Role of NO/cGMP Signaling on Neuroinflammation: A New Therapeutic Opportunity

Cited by 10 publications

References 202 publications

PDE9 Inhibitor PF-04447943 Attenuates DSS-Induced Colitis by Suppressing Oxidative Stress, Inflammation, and Regulating T-Cell Polarization

PDE9 Inhibitor PF-04447943 Attenuates DSS-Induced Colitis by Suppressing Oxidative Stress, Inflammation, and Regulating T-Cell Polarization

Evidence Supporting the Hypothesis That Inflammation-Induced Vasospasm Is Involved in the Pathogenesis of Acquired Sensorineural Hearing Loss

Comparative Transcriptomics Reveal Highly Conserved Regional Programs Between Porcine and Human Colonic Enteric Nervous System

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