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In the recent decade, the effect of phosphodiesterase inhibitors (PDEi) in neurological diseases has been extensively investigated. In previous studies, the beneficial effects of PDEi on multiple sclerosis (MS) and oligodendroglial health have been indicated. However, as phosphodiesterase affects many different cellular and molecular pathways on both neurons and glial cells, knowledge about most PDEi is still missing. Roflumilast, a PDE4 inhibitor, is a potent anti-inflammatory drug currently used to treat chronic obstructive pulmonary disease. Recent studies have demonstrated the neuroprotective effects of roflumilast in neurological and immune diseases. Therefore, in this study, we aimed to investigate the effect of roflumilast on the experimental autoimmune encephalitis (EAE)-induced MS model in mice. The effects of roflumilast on the levels of immune semaphorins Sema3A and Sema4D, and proinflammatory cytokines, also motor behavior function and myelin integrity were examined. EAE model was created with myelin oligodendrocyte glycoprotein35-55 (MOG35-55) immunization. Animals were treated with roflumilast and FTY720 (Fingolimod hydrochloride) (as positive control) for 28 days and observed for motor impairments. Brain tissue levels of tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), semaphorin 3A (sema3A), semaphorin 4D (sema4D) were determined by enzyme-linked immunosorbent assay (ELISA). Myelin integrity was assessed with luxol fast blue staining. As a result, roflumilast prevented EAE-induced motor impairment and prevented the loss of myelin in the corpus callosum. Additionally, roflumilast suppressed EAE-induced increase in TNF-α, IL-1β, IL-6, and sema3A, sema4D levels in the brain tissue. Our results demonstrated that roflumilast exerts a neuroprotective effect and prevents EAE-induced myelin loss, possibly via decreasing inflammatory cytokines in the brain. [ABSTRACT FROM AUTHOR]

Since the early 1980s, phosphodiesterase 4 (PDE4) has been an attractive target for the treatment of inflammation-based diseases. Several scientific advancements, by both academia and pharmaceutical companies, have enabled the identification of many synthetic ligands for this target, along with the acquisition of precise information on biological requirements and linked therapeutic opportunities. The transition from pre-clinical to clinical phase was not easy for the majority of these compounds, mainly due to their significant side effects, and it took almost thirty years for a PDE4 inhibitor to become a drug i.e., Roflumilast, used in the clinics for the treatment of chronic obstructive pulmonary disease. Since then, three additional compounds have reached the market a few years later: Crisaborole for atopic dermatitis, Apremilast for psoriatic arthritis and Ibudilast for Krabbe disease. The aim of this review is to provide an overview of the compounds that have reached clinical trials in the last ten years, with a focus on those most recently developed for respiratory, skin and neurological disorders. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a neuroinflammatory and neurodegenerative disease with unknown etiology that can be characterized by the presence of demyelinated lesions. Prevailing treatment protocols in MS rely on the modulation of the inflammatory process but do not impact disease progression. Remyelination is an essential factor for both axonal survival and functional neurological recovery but is often insufficient. The extracellular matrix protein fibronectin contributes to the inhibitory environment created in MS lesions and likely plays a causative role in remyelination failure. The presence of the blood–brain barrier (BBB) hinders the delivery of remyelination therapeutics to lesions. Therefore, therapeutic interventions to normalize the pathogenic MS lesion environment need to be able to cross the BBB. In this review, we outline the multifaceted roles of fibronectin in MS pathogenesis and discuss promising therapeutic targets and agents to overcome fibronectin-mediated inhibition of remyelination. In addition, to pave the way for clinical use, we reflect on opportunities to deliver MS therapeutics to lesions through the utilization of nanomedicine and discuss strategies to deliver fibronectin-directed therapeutics across the BBB. The use of well-designed nanocarriers with appropriate surface functionalization to cross the BBB and target the lesion sites is recommended. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS), a chronic autoimmune disorder, affects the central nervous system of many young adults. More than half of MS patients develop cognition problems. Although several genomic and transcriptomic studies are currently reported in MS cognitive impairment, a comprehensive repository dealing with all the experimental data is still underdeveloped. In this study, we combined text mining, gene regulation, pathway analysis, and genome-wide association studies (GWAS) to identify miRNA biomarkers to explore the cognitive dysfunction in MS, and to understand the genomic etiology of the disease. We first identified the dysregulated miRNAs associated with MS and cognitive dysfunction using PubTator (text mining), HMDD (experimental associations), miR2Disease, and PhenomiR database (differentially expressed miRNAs). Our results suggest that miRNAs such as hsa-mir-148b-3p, hsa-mir-7b-5p, and hsa-mir-7a-5p are commonly associated with MS and cognitive dysfunction. Next, we retrieved GWAS signals from GWAS Catalog, and analyzed the enrichment analysis of association signals in genes/miRNAs and their association networks. Then, we identified susceptible genetic loci, rs17119 (chromosome 6; p = 1 × 10−10), rs1843938 (chromosome 7; p = 1 × 10−10), and rs11637611 (chromosome 15; p = 1.00 × 10−15), associated with significant genetic risk. Lastly, we conducted a pathway analysis for the susceptible genetic variants and identified novel risk pathways. The ECM receptor signaling pathway (p = 3.98 × 10−8) and PI3K/Akt signaling pathway (p = 5.98 × 10−5) were found to be associated with differentially expressed miRNA biomarkers. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease (AD) represents the most common cause of dementia in the elderly. AD is a neurodegenerative disorder characterized by progressive memory loss and cognitive decline. Although the aetiology of AD is not clear, both environmental factors and heritable predisposition may contribute to disease occurrence. In addition, inflammation and immune system alterations have been linked to AD. The prevailing hypothesis as cause of AD is the deposition in the brain of amyloid beta peptides (Aβ). Although Aβ have a role in defending the brain against infections, their accumulation promotes an inflammatory response mediated by microglia and astrocytes. The production of proinflammatory cytokines and other inflammatory mediators such as prostaglandins and complement factors favours the recruitment of peripheral immune cells further promoting neuroinflammation. Age-related inflammation and chronic infection with herpes virus such as cytomegalovirus may also contribute to inflammation in AD patients. Natural killer (NK) cells are innate lymphoid cells involved in host defence against viral infections and tumours. Once activated NK cells secrete cytokines such as IFN-γ and TNF-α and chemokines and exert cytotoxic activity against target cells. In the elderly, changes in NK cell compartment have been described which may contribute to the lower capacity of elderly individuals to respond to pathogens and tumours. Recently, the role of NK cells in the immunopathogenesis of AD is discussed. Although in AD patients the frequency of NK cells is not affected, a high NK cell response to cytokines has been described together with NK cell dysregulation of signalling pathways which is in part involved in this altered behaviour. [ABSTRACT FROM AUTHOR]

Axonal damage is widely accepted as a major cause of permanent functional disability in Multiple Sclerosis (MS). In relapsing-remitting MS, there is a possibility of remyelination by myelin producing cells and restoration of neurological function. The purpose of this study was to delineate the pathophysiological mechanisms underpinning axonal injury through hitherto unknown factors present in cerebrospinal fluid (CSF) that may regulate axonal damage, remyelinate the axon and make functional recovery possible. We employed primary cultures of rat unmyelinated cerebellar granule neurons and treated them with CSF obtained from MS and Neuromyelitis optica (NMO) patients. We performed microarray gene expression profiling to study changes in gene expression in treated neurons as compared to controls. Additionally, we determined the influence of gene-gene interaction upon the whole metabolic network in our experimental conditions using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) program. Our findings revealed the downregulated expression of genes involved in glucose metabolism in MS-derived CSF-treated neurons and upregulated expression of genes in NMO-derived CSF-treated neurons. We conclude that factors in the CSF of these patients caused a perturbation in metabolic gene(s) expression and suggest that MS appears to be linked with metabolic deformity. [ABSTRACT FROM AUTHOR]

In relapsing-remitting multiple sclerosis (RRMS) subtype, the patient's brain itself is capable of repairing the damage, remyelinating the axon and recovering the neurological function. Cerebrospinal fluid (CSF) is in close proximity with brain parenchyma and contains a host of proteins and other molecules, which influence the cellular physiology, that may balance damage and repair of neurons and glial cells. The purpose of this study was to determine the pathophysiological mechanisms underpinning myelin repair in distinct clinical forms of MS and neuromyelitis optica (NMO) patients by studying the effect of diseased CSF on glucose metabolism and ATP synthesis. A cellular model with primary cultures of oligodendrocyte progenitor cells (OPCs) from rat cerebrum was employed, and cells were treated with CSF from distinct clinical forms of MS, NMO patients and neurological controls. Prior to comprehending mechanisms underlying myelin repair, we determine the best stably expressed reference genes in our experimental condition to accurately normalize our target mRNA transcripts. The GeNorm and NormFinder algorithms showed that mitochondrial ribosomal protein (Mrpl19), hypoxanthine guanine phosphoribosyl transferase (Hprt), microglobulin b2 (B2m), and transferrin receptor (Tfrc) were identified as the best reference genes in OPCs treated with MS subjects and were used for normalizing gene transcripts. The main findings on microarray gene expression profiling analysis on CSF treated OPCs cells revealed a disturbed carbohydrate metabolism and ATP synthesis in MS and NMO derived CSF treated OPCs. In addition, using STRING program, we investigate whether gene-gene interaction affected the whole network in our experimental conditions. Our findings revealed downregulated expression of genes involved in carbohydrate metabolism, and that glucose metabolism impairment and reduced ATP availability for cellular damage repair clearly differentiate more benign forms from the most aggressive forms and worst prognosis in MS patients. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is an inflammatory, demyelinating and neurodegenerative disease triggered by infiltration of activated T cells into the central nervous system. Interferon (IFN)-β is an established, safe and effective treatment for patients with relapsing-remitting MS (RRMS). The cytokine can inhibit leucocyte infiltration into the central nervous system; however, little is known about the precise molecular mechanisms. Previously, in vitro application of IFN-β1b was shown to reduce CXCL12/CXCR4-mediated monocyte migration. Here, we analysed the effects of IFN-β1b on CXCR4-dependent T cell function. In vitro exposure to IFN-β1b (1000 U/ml) for 20 h reduced CXCR4-dependent chemotaxis of primary human T cells from healthy individuals and patients with RRMS. Investigating the IFN-β1b/CXCR4 signalling pathways, we found no difference in phosphorylation of ZAP70, ERK1/2 and AKT despite an early induction of the negative regulator of G-protein signalling, RGS1 by IFN-β1b. However, CXCR4 surface expression was reduced. Quantitative real time-PCR revealed a similar reduction in CXCR4-mRNA, and the requirement of several hours' exposure to IFN-β1b supports a transcriptional regulation. Interestingly, T cells from MS patients showed a lower CXCR4 expression than T cells from healthy controls, which was not reduced further in patients under IFN-β1b therapy. Furthermore, we observed no change in CXCL12-dependent chemotaxis in RRMS patients. Our results demonstrate clearly that IFN-β1b can impair the functional response to CXCR4 by down-regulating its expression, but also points to the complex in vivo effects of IFN-β1b therapy. [ABSTRACT FROM AUTHOR]

The predictors for the development of cardiovascular diseases and peripheral arterial diseases in patients with systemic sclerosis (SSc) were not clearly established, and there is no specific study conducted to investigate the mean platelet volume (MPV) levels in SSc patients. Therefore, this study evaluates the MPV levels in SSc and possible relationship between SSc, its clinical features and activity/severity scores, and MPV. In total, 76 SSc patients (67 women and 9 men, mean age 50.44 ± 13.21 years) diagnosed according to the classification criteria of the American College of Rheumatology and 45 healthy volunteers were enrolled into study. Data relating to anamnesis, physical examination, MPV, erythrocyte sedimentation rate, C-reactive protein levels, electrocardiography, echocardiography, high-resolution computerized tomography findings, complaints, and treatment processes were recorded into the database. Of the total cases, 17 had (22.3 %) cardiac involvement, 45 had gastrointestinal involvement (59.2 %), 47 had (61.8 %) lung involvement, 31 (32 %) had finger flexion deformity, and 27 (35.5 %) had digital ulcers at the fingertips. The mean MPV levels of SSc patients were significantly higher than those of the control group ( p = 0.008). The mean MPV levels of SSc patients with cardiac involvement, digital ulcers, and gangrene presence were significantly high, and lower in Ilomedin-receiving patients than in the Ilomedin naives ( p < 0.05). A negative relationship was discovered between the mean MPV levels, Valentini score, and Disease Severity Index of the patients with systemic sclerosis ( p = 0.006, r = −0.310; p = 0.047, r = −0.229). MPV levels were significantly elevated in SSc patients and they were negatively correlated with disease activity scores. Increased MPV levels would be a predictive marker in the diagnosis of macrovascular and microvascular disease involvement in SSc patients. [ABSTRACT FROM AUTHOR]