Inhibition of Neutrophil Secretion Upon Adhesion as a Basis for the Anti-Inflammatory Effect of the Tricyclic Antidepressant Imipramine

Galkina, Svetlana I.; Golenkina, Ekaterina A.; Федорова, Н. В.; Ksenofontov, Alexander L.; Serebryakova, Marina V.; Arifulin, Eugene A.; Stadnichuk, Vladimir I.; Baratova, Ludmila A.; Sud’ina, Galina F.

doi:10.3389/fphar.2021.709719

Cited by 5 publications

(5 citation statements)

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“…Many pieces of evidence indicate that, similar to neurons, human neutrophils (PMNs) also express nNOS [ 30 ]. The infiltration of neutrophils in the CNS contributes to the development of numerous neurodegenerative disorders, including MDD [ 31 ]. Several clinical studies have shown that an alteration in the nNOS–NO pathway in the human brain is also reflected in circulating neutrophils [ 32 , 33 ].…”

Section: Introductionmentioning

confidence: 99%

Oxidative and Nitrosative Stress in Major Depressive Disorder: A Case Control Study

et al. 2022

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Introduction: The role of increased oxidative stress and alterations to the nitric oxide (NO) pathway have been implicated in major depressive disorder (MDD). The two pathways interact closely with each other but have not been studied simultaneously in MDD. This study aimed to assess and compare the levels of oxidative and nitrosative stress in the neutrophils (PMNs) of drug-naive MDD patients and their first-degree relatives. Methods: 29 drug-naive MDD patients and 27 healthy first-degree relatives and healthy controls aged 18–45 years were included in this study. An assessment of the levels of reactive oxygen species (ROS), nitrites, neuronal NO synthase (nNOS), and myeloperoxidase in PMNs, and cortisol in serum was carried out. Results: Compared to healthy controls, the generation of free radicals PMNs, myeloperoxidase activity, nNOS mRNA expression in PMNs, and cortisol level in serum were significantly higher in drug-naive depression patients. Indeed, increased levels of myeloperoxidase and serum cortisol were also noted in first-degree relatives. The total nitrite content in the PMNs and plasma however was significantly lower in both patients and first-degree relatives. Interestingly, a positive correlation was established in the ROS levels in the PMNs, plasma and neutrophil nitrite, and the serum cortisol level between MDD patients and their first-degree relatives. Conclusion: The results of this study contribute towards a better understanding of the familial association of depressive disorder, and demonstrate for the first time that neutrophil ROS/RNS, plasma nitrite, and serum cortisol levels are positively correlated between MDD patients and their first-degree relatives. However, further studies in larger, more diverse samples are needed to extend these pathways as potential biomarkers to identify persons at high risk for psychopathology at an early stage.

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Section: Introductionmentioning

confidence: 99%

Oxidative and Nitrosative Stress in Major Depressive Disorder: A Case Control Study

et al. 2022

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“…The source of LPS can be bacteria that have entered the body from the environment, or bacteria in the gastrointestinal tract. As previously published, the secretory protein profile of neutrophils that were attached to fibronectin in the presence of LPS contained the same proteins as control cells, and in addition: (i) MMP-9, a component of tertiary granules; (ii) cathepsin G and defensins, potent primary granule bactericides; and (iii) a number of cytosolic proteins such as actin, the glycolytic enzyme glucose-6-phosphate dehydrogenase, and S100 proteins [ 37 , 47 ]. When neutrophils were attached to fibronectin in the presence of LPS and 4-MU, neutrophil secretion was largely inhibited ( Figure 2 ).…”

Section: Resultsmentioning

confidence: 79%

“…Inhibition of neutrophil adhesion through the use of a non-adhesive substrate dramatically and selectively suppressed the release of hydroxylysine [ 24 ]. LH inhibitor minoxidil, the MMP inhibitor doxycycline, the PI3K/Akt pathway inhibitors wortmannin and the Akt1/2 inhibitor and actin depolymerizing microbial alkaloids [ 25 ], and imipramine [ 47 ] blocked the release of hydroxylysine. In all cases, inhibition of hydroxylysine occurred in a selective manner and was accompanied by blocking of cell adhesion and spreading.…”

Section: Resultsmentioning

confidence: 99%

“…4-MU selectively and significantly suppressed the release of hydroxylysine, but did not have a statistically significant effect on the release of other amino acids by neutrophils during adhesion ( Figure 3 A). Our previous data showed that LPS significantly stimulated the release of hydroxylysine by neutrophils upon adhesion to fibronectin, but did not alter the secretion of other free amino acids [ 47 ]. In the present work we demonstrate that 4-MU significantly inhibited the release of hydroxylysine by neutrophils that adhere to fibronectin in the presence of LPS, but did not cause statistically significant changes in the content of other amino acids ( Figure 3 B).…”

Section: Resultsmentioning

confidence: 99%

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Inhibitor of Hyaluronic Acid Synthesis 4-Methylumbelliferone Suppresses the Secretory Processes That Ensure the Invasion of Neutrophils into Tissues and Induce Inflammation

et al. 2022

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Integrin-dependent adhesion of neutrophils to tissue, accompanied by the development of neutrophil-induced inflammation, occurs both in the focus of infection and in the absence of infection in metabolic disorders such as reperfusion after ischemia, diabetes mellitus, or the development of pneumonia in patients with cystic fibrosis or viral diseases. Hyaluronic acid (HA) plays an important role in the recruitment of neutrophils to tissues. 4-methylumbilliferon (4-MU), an inhibitor of HA synthesis, is used to treat inflammation, but its mechanism of action is unknown. We studied the effect of 4-MU on neutrophil adhesion and concomitant secretion using adhesion to fibronectin as a model for integrin-dependent adhesion. 4-MU reduced the spreading of neutrophils on the substrate and the concomitant secretion of granule proteins, including pro-inflammatory components. 4-MU also selectively blocked adhesion-induced release of the free amino acid hydroxylysine, a product of lysyl hydroxylase, which can influence cell invasion by modifying the extracellular matrix. Finally, 4-MU inhibited the formation of cytonemes, the extracellular membrane secretory structures containing the pro-inflammatory bactericides of the primary granules. The anti-inflammatory effect of 4-MU may be associated with the suppression of secretory processes that ensure the neutrophil invasion and initiate inflammation. We suggest that HA, due to the peculiarities of its synthesis, can promote the release of secretory carriers from the cell and 4-MU can block this process.

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“…Another group of drugs strongly suppressed the release of hydroxylysine, but also caused a statistically significant increase in the release of phenylalanine. This group includes microbial alkaloids that depolymerize the actin cytoskeleton, such as cytochalasin D, as well as the AKT 1/2 inhibitor or imipramine [ 15 , 16 , 50 ]. Cytochalasin D and other components of this group stimulated the secretion of serine proteases, such as cathepsin G, and other components of primary granules, but not the components of tertiary granules [ 28 , 29 , 35 ].…”

Section: Resultsmentioning

confidence: 99%

Ivermectin Affects Neutrophil-Induced Inflammation through Inhibition of Hydroxylysine but Stimulation of Cathepsin G and Phenylalanine Secretion

et al. 2022

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The invasion and integrin-dependent adhesion of neutrophils to lung tissues and their secretion lead to the development of pneumonia in various pulmonary pathologies, including acute respiratory distress syndrome in coronavirus disease. We studied the effect of ivermectin, a possible therapeutic agent for inflammation and cancer, on integrin-dependent neutrophil adhesion to fibronectin and the concomitant secretion. Ivermectin did not affect the attachment of neutrophils to the substrate and the reactive oxygen species production but sharply inhibited the adhesion-induced release of hydroxylysine and stimulated the release of phenylalanine and cathepsin G. Hydroxylysine is a product of lysyl hydroxylase, which is overexpressed in tumor cells with an increased ability to invade and metastasize. The inhibition of hydroxylysine release by ivermectin, by analogy, may indicate the suppression of neutrophil invasion into tissue. The increase in the release of phenylalanine in our experiments coincided with the secretion of cathepsin G, which indicates the possible role of this enzyme in the cleavage of phenylalanine. What is the substrate in such a reaction is unknown. We demonstrated that exogenously added angiotensin II (1–8) can serve as a substrate for phenylalanine cleavage. Mass spectrometry revealed the formation of angiotensin II (1–7) in the secretion of neutrophils, which attached to fibronectin in the presence of ivermectin and exogenous angiotensin II (1–8), indicating a possible involvement of ivermectin in the inactivation of angiotensin II.

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Inhibition of Neutrophil Secretion Upon Adhesion as a Basis for the Anti-Inflammatory Effect of the Tricyclic Antidepressant Imipramine

Cited by 5 publications

References 77 publications

Oxidative and Nitrosative Stress in Major Depressive Disorder: A Case Control Study

Oxidative and Nitrosative Stress in Major Depressive Disorder: A Case Control Study

Inhibitor of Hyaluronic Acid Synthesis 4-Methylumbelliferone Suppresses the Secretory Processes That Ensure the Invasion of Neutrophils into Tissues and Induce Inflammation

Ivermectin Affects Neutrophil-Induced Inflammation through Inhibition of Hydroxylysine but Stimulation of Cathepsin G and Phenylalanine Secretion

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