Neuroinflammation drives anxiety and depression in relapsing-remitting multiple sclerosis

Rossi, Silvia; Studer, Valeria; Motta, Caterina; Polidoro, Serena; Perugini, Jacopo; Macchiarulo, Giulia; Giovannetti, Ambra Mara; Pareja-Gutierrez, Lorena; Calò, A; Colonna, Isabella; Furlan, Roberto; Martino, Gianvito; Centonze, Diego

doi:10.1212/wnl.0000000000004411

Cited by 128 publications

(88 citation statements)

References 38 publications

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“…On another hand, the expression of the anti-inflammatory cytokine IL-15 was unaltered. As neuroinflammation was shown to accompany pathological anxiety (Salim, 2017;Rossi et al, 2017) and since an increase in the synthesis of brain pro-inflammatory cytokines in mice can promote anxiogenic-like (Chen et al, 2013) and aggressive behaviors , present data implicate the reported here over-production of pro-inflammatory cytokines in the anxiogenic effects of ultrasound stress. We also demonstrated that in the ultrasound-exposed mice, elevated scores of anxietylike behaviors were associated with the over-expression of GSK-3β, that governs the production of pro-inflammatory cytokines , affects oxidative stress ) and regulates hippocampal cellular plasticity .…”

Section: Immunohistochemical Analysis Of Expression Of Internalizedsupporting

confidence: 65%

Understanding the molecular mechanisms of aggression in BALB/c and TPH2-deficient mice

Gorlova¹

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Section: Immunohistochemical Analysis Of Expression Of Internalizedsupporting

confidence: 65%

Understanding the molecular mechanisms of aggression in BALB/c and TPH2-deficient mice

Gorlova¹

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“…The association of neuroin ammation with depression has been widely acknowledged as increased circulatory cytokines level has been determined in patients with mood disorders [70][71][72][73]. Peripheral immune activation leads to the transportation of cytokines to the central nervous system (CNS), which stimulates glial cell activation and subsequently accelerates central cytokine production via a positive feedback mechanism [13,72].…”

Section: Discussionmentioning

confidence: 99%

Ibrutinib alleviated LPS-induced neuroinflammation and synaptic defects in a mouse model of depression

Ali

et al. 2020

Preprint

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Background Previous studies indicate a close association between the altered immune system and major depressive disorders. and inhibition of neuroinflammation may represent an alternative mechanism to treat depression. Recently, the anti-inflammatory activity of ibrutinib has been reported, however, the effect of ibrutinib on neuroinflammation allied depression and its underlying mechanism has not been comprehensively studied. Therefore, we aimed to elucidate the potential anti-depressive role and mechanism of ibrutinib against neuroinflammation induced depression as well as synaptic defects. Methods Adult C57BL/6J male mice weighing 25–30 g (age 7–8 weeks) were treated with LPS (2 mg/kg BW i.p) and 50 mg/kg BW ibrutinib, orally. Depressive-like behaviors were assessed by FST and SPT, cytokine levels were determined by ELISA, ROS, TBARs, and Nitric oxides were measured via biochemical assays, Iba-1 and GFAP expression were determined by immunofluorescence. Further, spine density was measured by Golgi staining, while NF-kB, Nrf2, SOD2, HO-1, NLRP3, P38, Caspase-1, BDNF, PSD95, and synaptophysin were measured by immunoblotting. Results Our results showed that ibrutinib treatment significantly reduced LPS induced depressive-like behaviors and neuroinflammation via inhibiting NF-kB activation, decreasing pro-inflammatory cytokines level, normalizing redox signaling and it’s a downstream component including Nrf2, HO-1, and SOD2 as well as glial cells activation markers such as Iba-1 and GFAP expression. Further, ibrutinib treatment inhibited LPS activated inflammasome activation by targeting NLRP3/P38/Caspase-1 signaling. Interestingly, LPS reduced dendritic spines numbers, expression of BDNF and synaptic related markers including PSD95, snap25, and synaptophysin were improved by ibrutinib treatment in the hippocampal area of the mice brain. Conclusion In conclusion, our finding suggested that ibrutinib could alleviate neuroinflammation and synaptic defects, rendering its antidepressant potential against LPS induced neuroinflammation and depression.

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“…Comorbidity number showed a dose-dependent association with increased risk of newly positive depression-screen. Comorbidities have been associated with clinical outcomes in MS (Marrie and Horwitz, 2010), and while some are potentially due to common inflammatory antecedents (Rossi et al, 2017), others like depression could be attributable both to common pathophysiological processes, and to MS symptoms and other comorbidities. Thus, it is not surprising that comorbidity number was positively associated with depression, even after adjustment for disability and fatigue.…”

Section: Discussionmentioning

confidence: 99%

Associations of demographic and clinical factors with depression over 2.5-years in an international prospective cohort of people living with MS

Simpson

Taylor

Jelinek

et al. 2019

Multiple Sclerosis and Related Disorders

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A B S T R A C TBackground: Depression is highly prevalent among people with MS, and determinants thereof would be useful. Objectives: We examined the relationship of demographic and clinical factors with positive depression-screen and change in depression over 2.5 years in people with MS. Methods: Positive depression-screen assessed by Patient Health Questionnaire (PHQ)-2 and PHQ-9. Associations of demographic and clinical factors with depression-screen and change thereof assessed using multivariable regression models, adjusted for age, sex, disability, fatigue, antidepressant use, and baseline PHQ-2, as appropriate. Results: Overweight/obese BMI, comorbidity number, fatigue, and disability were associated with positive depression-screen, while married/partnered state, being employed, higher perceived socioeconomic status, and greater education were inversely associated with depression-screen. After adjustment, only marital status, socioeconomic status, antidepressant medication use, and fatigue were associated with risk of newly positive depression-screen. MS type, relapse number and immunomodulatory medication use were not associated with depression-screen after controlling for disability and fatigue. Conclusion: In a large prospective cohort study of depression in people with MS, we substantiated several potential determinants of a positive depression-screen and depression trajectory, particularly fatigue. Given that fatigue is the most common and most significant clinical symptom for people with MS, efforts to reduce fatigue may have follow-on benefits for reducing depression.T the frequency of positive depression-screen increased by 7.3% per year of follow-up over 2.3 years, strongly predicted by disability (Wood et al., 2012). The BEYOND clinical trial (n = 891 with depression data) examined depression using the Beck Depression Inventory-II, finding an average frequency of positive depression-screen of 25-30%, not greatly varying over three years of follow-up (Schippling et al., 2016). Koch and colleagues followed a subgroup of 94/228 patients with baseline depression data for ten years, finding the proportion with clinically significant depression as measured by the Center for Epidemiologic Studies Depression Scale increased from 47.9% to 52.1% (Koch et al., 2008).While there are many cross-sectional studies examining mood and depression in MS, there is a comparative lack of prospective studies of change in depression in large representative samples. We undertook a prospective cohort study among an international sample of people living with MS followed over 2.5 years, examining the demographic and clinical characteristics of positive depression-screen at 2.5-year review, and of change in depression-screen during follow-up. Of note, the lifestyle determinants of depression-screen during this same period are described in another article . S. Simpson, et al.

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Neuroinflammation drives anxiety and depression in relapsing-remitting multiple sclerosis

Abstract: Mood alterations are induced by intrathecal inflammation, even though not clinically apparent, and are able to predict inflammatory reactivations in RRMS. Inflammation is therefore a biological event, not less important than the traditional psychosocial factors, involved in mood disorders.

Cited by 128 publications

References 38 publications

Understanding the molecular mechanisms of aggression in BALB/c and TPH2-deficient mice

Understanding the molecular mechanisms of aggression in BALB/c and TPH2-deficient mice

Ibrutinib alleviated LPS-induced neuroinflammation and synaptic defects in a mouse model of depression

Associations of demographic and clinical factors with depression over 2.5-years in an international prospective cohort of people living with MS

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