The cytokine network in the pathogenesis of major depressive disorder. Close to translation?

Petralia, Maria Cristina; Mazzon, Emanuela; Fagone, Paolo; Basile, Maria Sofia; Lenzo, Vittorio; Quattropani, Maria C.; Nuovo, Santo Di; Bendtzen, Klaus; Nicoletti, Ferdinando

doi:10.1016/j.autrev.2020.102504

Cited by 58 publications

(50 citation statements)

References 187 publications

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“…This data can be explained in light of the bioinformatic analysis, which showed different and sometimes, opposite, effects of imatinib and sorafenib on the modulation of the expression of known fibrogenetic genes. The use of whole-genome expression data has been largely used to identify pathogenic pathways and therapeutic targets [ 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ] for several disorders, including autoimmune diseases [ 42 , 43 ] and cancer [ 44 , 45 , 46 , 47 , 48 , 49 , 50 ].…”

Section: Discussionmentioning

confidence: 99%

Effects of Combined Admistration of Imatinib and Sorafenib in a Murine Model of Liver Fibrosis

Pesce

Bramanti

Iapichino³

et al. 2020

Molecules

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Liver fibrosis is defined as excessive extracellular matrix deposition in the hepatic parenchyma as a consequence of complex interactions among matrix-producing hepatic stellate cells (HSCs) and liver-resident and infiltrating cells. In addition to the liver, the process of fibrosis may represent end-stage disease of several diseases including kidneys, lungs, spleens, heart, muscles and at certain extent, the central nervous system and the peripheral nerves. To date, antifibrotic treatment of fibrosis represents an unconquered area for drug development. The aim of the present study was to test the efficacy of a new drug combination for the treatment of hepatic fibrosis in order to provide a proof-of-concept for the use of therapeutic agents in clinical practice. For this purpose, we have studied the effects of the PDGF inhibitor imatinib and the angiogenesis inhibitor sorafenib, administered alone or in combination, in reducing the progression of the fibrogenetic process in a pre-clinical model of liver damage induced in mice by repeated administration of Concanavalin A (ConA), resembling long-tern autoimmune hepatitis. Our results suggest that treatments with imatinib and sorafenib can modulate potently and, in a superimposable fashion, the fibrinogenic process when administered alone. However, and in agreement with the computational data presently generated, they only exert partial overlapping antifibrotic effects in modulating the main pathways involved in the process of liver fibrosis, without significant additive or synergist effects, when administered in combination.

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Section: Discussionmentioning

confidence: 99%

Effects of Combined Admistration of Imatinib and Sorafenib in a Murine Model of Liver Fibrosis

Pesce

Bramanti

Iapichino³

et al. 2020

Molecules

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“…Accumulating evidence has associated chronic inflammation to MDD and to chronic stress pathophysiology, but it is still a matter of debate how inflammation may contribute to the pathogenesis of these diseases (Kim and Won, 2017). As reported in the following paragraphs, alterations of immune cells, including lymphocytes, monocytes/macrophages and microglia, as well as soluble inflammatory mediators have been associated to several depressive states (Petralia et al, 2020) (Figures 1, 3).…”

Section: The Neuroinflammatory Theory In Mddmentioning

confidence: 95%

“…In 1991, Smith proposed the so-called cytokine theory of MDD, supported by clinical and pre-clinical studies (Dey and Giblin, 2018). According to this theory, MDD patients exhibit a chronic inflammatory status characterized by elevated serum levels of pro-inflammatory cytokines (Figures 1, 3), including tumor necrosis factor α (TNF-α), interleukin (IL-) 1β, IL-2, IL-6, IL-12, IL-13 interferon gamma (IFN-γ), and decreased level of anti-inflammatory cytokines, such as IL-10 and soluble receptor for IL-2 and IL-6, IL-1β receptor antagonist (IL-1ra), in respect to healthy controls (Petralia et al, 2020).…”

Section: The Cytokine Theory Of Mddmentioning

confidence: 99%

“…Moreover, elevated levels of TNF-α and IL-6 are predictive of a higher risk of suicide and more severe course of the disease (Janelidze et al, 2011;Haapakoski et al, 2015). Similarly, MDD patients with elevated plasmatic levels of IL-6, IL-8, IFN-γ, and TNF-α manifest slight responsiveness to sleep deprivation, a commonly approved approach to treat depressive symptoms in MDD (Petralia et al, 2020). Of note, all these studies have been limited to few cytokines such as TNF-α, IL-1β, IL-6, and IFN-γ.…”

Section: The Cytokine Theory Of Mddmentioning

confidence: 99%

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Inflammation-Associated Synaptic Alterations as Shared Threads in Depression and Multiple Sclerosis

Bruno

Dolcetti

Rizzo

et al. 2020

Front. Cell. Neurosci.

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In the past years, several theories have been advanced to explain the pathogenesis of Major Depressive Disorder (MDD), a neuropsychiatric disease that causes disability in general population. Several theories have been proposed to define the MDD pathophysiology such as the classic “monoamine-theory” or the “glutamate hypothesis.” All these theories have been recently integrated by evidence highlighting inflammation as a pivotal player in developing depressive symptoms. Proinflammatory cytokines have been indeed claimed to contribute to stress-induced mood disturbances and to major depression, indicating a widespread role of classical mediators of inflammation in emotional control. Moreover, during systemic inflammatory diseases, peripherally released cytokines circulate in the blood, reach the brain and cause anxiety, anhedonia, social withdrawal, fatigue, and sleep disturbances. Accordingly, chronic inflammatory disorders, such as the inflammatory autoimmune disease multiple sclerosis (MS), have been associated to higher risk of MDD, in comparison with overall population. Importantly, in both MS patients and in its experimental mouse model, Experimental Autoimmune Encephalomyelitis (EAE), the notion that depressive symptoms are reactive epiphenomenon to the MS pathology has been recently challenged by the evidence of their early manifestation, even before the onset of the disease. Furthermore, in association to such mood disturbance, inflammatory-dependent synaptic dysfunctions in several areas of MS/EAE brain have been observed independently of brain lesions and demyelination. This evidence suggests that a fine interplay between the immune and nervous systems can have a huge impact on several neurological functions, including depressive symptoms, in different pathological conditions. The aim of the present review is to shed light on common traits between MDD and MS, by looking at inflammatory-dependent synaptic alterations associated with depression in both diseases.

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“…The pathogenesis of AD is not yet completely understood, with multiple factors all contributing to neuronal cell death to different extents [ 6 , 7 , 8 ]. Such factors may, for example, be lifestyle factors and conditions leading to upregulated production of proinflammatory cytokines [ 9 , 10 ]. Another factor is the accumulation of abnormal deposits of β-amyloid peptide (Aβ) and hyperphosphorylated tau protein in addition to widespread cell death and the loss of synapses, especially in the cholinergic system, which are considered to define the pathophysiology of AD [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Novel Acetylcholinesterase Inhibitors Based on Uracil Moiety for Possible Treatment of Alzheimer Disease

et al. 2020

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In this study, novel derivatives based on 6-methyluracil and condensed uracil were synthesized, namely, 2,4-quinazoline-2,4-dione with ω-(ortho-nitrilebenzylethylamino) alkyl chains at the N atoms of the pyrimidine ring. In this series of synthesized compounds, the polymethylene chains were varied from having tetra- to hexamethylene chains, and secondary NH, tertiary ethylamino, and quaternary ammonium groups were introduced into the chains. The molecular modeling of the compounds indicated that they could function as dual binding site acetylcholinesterase inhibitors, binding to both the peripheral anionic site and active site. The data from in vitro experiments show that the most active compounds exhibit affinity toward acetylcholinesterase within a nanomolar range, with selectivity for acetylcholinesterase over butyrylcholinesterase reaching four orders of magnitude. In vivo biological assays demonstrated the potency of these compounds in the treatment of memory impairment using an animal model of Alzheimer disease.

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The cytokine network in the pathogenesis of major depressive disorder. Close to translation?

Cited by 58 publications

References 187 publications

Effects of Combined Admistration of Imatinib and Sorafenib in a Murine Model of Liver Fibrosis

Effects of Combined Admistration of Imatinib and Sorafenib in a Murine Model of Liver Fibrosis

Inflammation-Associated Synaptic Alterations as Shared Threads in Depression and Multiple Sclerosis

Novel Acetylcholinesterase Inhibitors Based on Uracil Moiety for Possible Treatment of Alzheimer Disease

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