Phosphodiesterase-4 enzyme as a therapeutic target in neurological disorders

Bhat, Abid; Ray, Bipul; Mahalakshmi, Arehally M.; Tuladhar, Sunanda; Nandakumar, DN; Srinivasan, Malathi; Essa, Musthafa Mohamed; Chidambaram, Saravana Babu; Guillemin, Gilles J.; Sakharkar, Meena Kishore

doi:10.1016/j.phrs.2020.105078

Cited by 68 publications

(38 citation statements)

References 271 publications

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“…Phosphodiesterases degrade cAMP and cGMP, two critical second messengers involved in many physiological processes, including learning, memory, and cognition. Interestingly, inhibition of phosphodiesterases in neurologic diseases has been the focus of many preclinical and clinical studies ( Wu et al, 2018 ; Bhat et al, 2020 ), with particular attention on PDE3 ( Yanai and Endo, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Serum Proteomics of Older Patients Undergoing Major Cardiac Surgery: Identification of Biomarkers Associated With Postoperative Delirium

Rhee

Кузнецов

McKay

et al. 2021

Front. Aging Neurosci.

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BackgroundPostoperative delirium (POD) is an acute altered mental state commonly encountered after cardiac surgery. The pathophysiological mechanisms underlying POD remain unclear. We aimed to identify circulating proteins significantly altered after major cardiac surgery with cardiopulmonary bypass (CPB). We also aimed to enable inferences on associations with POD.MethodsSerum and whole blood samples were collected before CPB (n = 16 patients; n = 8 with POD) and again from the same patients on postoperative day 1. All patients were clinically evaluated for POD on postoperative days 1–3. An aptamer-based proteomics platform (SOMAscan) was used to quantify serum protein abundance in patients with POD compared with non-POD controls. We also performed a lipopolysaccharide (LPS)-based in vitro functional analysis (TruCulture) on whole blood samples from patients with POD and non-POD controls to approximate surgical stress. Cytokine levels were determined using a Luminex immunoassay.ResultsCardiac surgery with CPB resulted in a significant (padj < 0.01) change in 48.8% (637 out of 1,305) of proteins detected by SOMAscan. Gene set enrichment showed that the most impacted biological processes involved myeloid cell activation. Specifically, activation and degranulation of neutrophils were the top five highest-scoring processes. Pathway analyses with the Kyoto Encyclopedia of Genes and Genomes (KEGG) showed that metabolic enzymes, particularly those of glycolysis, were elevated in serum concentration after surgery. Several proteins were significantly increased postoperatively in patients diagnosed with POD relative to the non-POD controls, with interleukin-6 (IL-6) showing the greatest fold-change. LPS stimulation of whole blood samples confirmed these findings. Linear regression analysis showed a highly significant correlation between Confusion Assessment Method (CAM) scores and CPB-mediated changes in cGMP-inhibited 3′,5′-cyclic phosphodiesterase A (PDE3A).Conclusionsardiac surgery with CPB resulted in inflammasome changes accompanied by unexpected increases in metabolic pathways. In exploratory analyses, we found that POD was associated with changes in the expression level of various proteins, most notably IL-6 and PDE3A. This study and ongoing protein biomarker studies will likely help quantify risk or confirm the diagnosis for POD and increase understanding of its pathophysiological mechanisms.

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Section: Discussionmentioning

confidence: 99%

Serum Proteomics of Older Patients Undergoing Major Cardiac Surgery: Identification of Biomarkers Associated With Postoperative Delirium

Rhee

Кузнецов

McKay

et al. 2021

Front. Aging Neurosci.

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“…Cromolyn sodium-treated mice showed a significant decrease in the levels of several proinflammatory mediators in both the spinal cord (CXCL1 and TNFα) and blood (IL2, IL6, and IL10) [91]. Besides, phosphodiesterase (PDE) activity inhibitors are another interesting anti-inflammatory strategy for ALS [92]. One of its inhibitors, ibudilast (an inhibitor of macrophage migration inhibitory factor and phosphodiesterases 3, 4, 10, and 11), is currently being assayed in ALS patients (NCT04057898, COMBAT-ALS).…”

Section: A Combination Therapy Strategy For Alsmentioning

confidence: 99%

NAD+ Precursors and Antioxidants for the Treatment of Amyotrophic Lateral Sclerosis

et al. 2021

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Charcot first described amyotrophic lateral sclerosis (ALS) between 1865 and 1874 as a sporadic adult disease resulting from the idiopathic progressive degeneration of the motor neuronal system, resulting in rapid, progressive, and generalized muscle weakness and atrophy. There is no cure for ALS and no proven therapy to prevent it or reverse its course. There are two drugs specifically approved for the treatment of ALS, riluzol and edaravone, and many others have already been tested or are following clinical trials. However, at the present moment, we still cannot glimpse a true breakthrough in the treatment of this devastating disease. Nevertheless, our understanding of the pathophysiology of ALS is constantly growing. Based on this background, we know that oxidative stress, alterations in the NAD+-dependent metabolism and redox status, and abnormal mitochondrial dynamics and function in the motor neurons are at the core of the problem. Thus, different antioxidant molecules or NAD+ generators have been proposed for the therapy of ALS. This review analyzes these options not only in light of their use as individual molecules, but with special emphasis on their potential association, and even as part of broader combined multi-therapies.

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“…Out of these, PDE4B and PDE4D are the most abundantly expressed PDE4 mRNAs in the periphery while in the brain PDE4B is the main present isoform [3,27]. Alterations of PDE4 activity are related to disorders of the neurological, immune and inflammatory system, particularly depression, Alzheimer´s disease, chronic obstructive pulmonary disease and asthma [27][28][29][30][31]. In vivo metabolism studies in rats revealed 30-46% and 93-95% of intact [ 18 F]4 at 30 min p.i.…”

Section: Pde4 Radioligandsmentioning

confidence: 99%

Challenges on Cyclic Nucleotide Phosphodiesterases Imaging with Positron Emission Tomography: Novel Radioligands and (Pre-)Clinical Insights since 2016

Schröder

Scheunemann

Wenzel

et al. 2021

IJMS

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Cyclic nucleotide phosphodiesterases (PDEs) represent one of the key targets in the research field of intracellular signaling related to the second messenger molecules cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP). Hence, non-invasive imaging of this enzyme class by positron emission tomography (PET) using appropriate isoform-selective PDE radioligands is gaining importance. This methodology enables the in vivo diagnosis and staging of numerous diseases associated with altered PDE density or activity in the periphery and the central nervous system as well as the translational evaluation of novel PDE inhibitors as therapeutics. In this follow-up review, we summarize the efforts in the development of novel PDE radioligands and highlight (pre-)clinical insights from PET studies using already known PDE radioligands since 2016.

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Phosphodiesterase-4 enzyme as a therapeutic target in neurological disorders

Cited by 68 publications

References 271 publications

Serum Proteomics of Older Patients Undergoing Major Cardiac Surgery: Identification of Biomarkers Associated With Postoperative Delirium

Serum Proteomics of Older Patients Undergoing Major Cardiac Surgery: Identification of Biomarkers Associated With Postoperative Delirium

NAD+ Precursors and Antioxidants for the Treatment of Amyotrophic Lateral Sclerosis

Challenges on Cyclic Nucleotide Phosphodiesterases Imaging with Positron Emission Tomography: Novel Radioligands and (Pre-)Clinical Insights since 2016

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