Martin Rostami-Yazdi

Dimethylfumarate inhibits microglial and astrocytic inflammation by suppressing the synthesis of nitric oxide, IL-1β, TNF-α and IL-6 in an in-vitro model of brain inflammation

BackgroundBrain inflammation plays a central role in multiple sclerosis (MS). Dimethylfumarate (DMF), the main ingredient of an oral formulation of fumaric acid esters with proven therapeutic efficacy in psoriasis, has recently been found to ameliorate the course of relapsing-remitting MS. Glial cells are the effector cells of neuroinflammation; however, little is known of the effect of DMF on microglia and astrocytes. The purpose of this study was to use an established in vitro model of brain inflammation to determine if DMF modulates the release of neurotoxic molecules from microglia and astrocytes, thus inhibiting glial inflammation.MethodsPrimary microglial and astrocytic cell cultures were prepared from cerebral cortices of neonatal rats. The control cells were treated with LPS, an accepted inducer of pro-inflammatory properties in glial cells, and the experimental groups with LPS and DMF in different concentrations. After stimulation/incubation, the generation of nitric oxide (NO) in the cell culture supernatants was determined by measuring nitrite accumulation in the medium using Griess reagent. After 6 hours of treatment RT-PCR was used to determine transcription levels of iNOS, IL-1β, IL-6 and TNF-α mRNA in microglial and astrocytic cell cultures initially treated with DMF, followed after 30 min by LPS treatment. Moreover, we investigated possible involvement of the ERK and Nrf-2 transduction pathway in microglia using western blot analysis.ResultsPretreatment with DMF decreased synthesis of the proinflammatory mediators iNOS, TNF-α, IL-1β and IL-6 at the RNA level in activated microglia and astrocytes in vitro, associated with a decrease in ERK phosphorylation in microglia.ConclusionsCollectively, these results suggest that the neuroprotective effects of DMF may be in part functionally attributable to the compounds ability to inhibit expression of multiple neuroinflammatory mediators in brain of MS patients.

Oxidative stress in the pathogenesis of psoriasis

Psoriasis is a chronic immune-mediated hyperproliferative inflammatory skin disease in which a cytokine network concept is well established. Skin is a major target of oxidative stress mainly due to reactive oxygen species (ROS) originating from the environment and skin metabolism itself. Although endogenous antioxidants attenuate the harmful effects of ROS, increased or prolonged presence of free radicals can override ROS defense mechanisms and mediate numerous cellular responses that contribute to the development of a variety of skin disorders, including psoriasis. Regarding psoriasis, antioxidant strategies have proven to be beneficial therapeutics. The cellular signaling pathways such as mitogen-activated protein kinase/activator protein 1, nuclear factor kappaB, and Janus kinase-signal transducers and activators of transcription are known to be redox sensitive and proven to be involved in the progress of psoriasis. This review summarizes the current knowledge of the role of the redox system in regulating these signaling pathways related to the pathogenesis of psoriasis.

Adipokines and psoriasis

Abstract:  Adipose tissue is an active endocrine organ contributing to the regulation of multiple metabolic pathways via self‐produced bioactive products called adipokines. These adipokines are key players in the pathogenesis of metabolic syndrome and cardiovascular diseases. Co‐occurrence of obesity and psoriasis could lead to interactions of both diseases in which adipokines, at least in part, are involved and may contribute to associated comorbidities of psoriasis. Until today numerous adipokines have been identified of which the most important ones are discussed in the following within the context of obesity, chronic inflammation and their possible role in the pathogenesis of psoriasis. Adipokines could serve as a missing link in the causal relationship between psoriasis and comorbidities and may provide a biomarker for disease severity, risk of comorbidities and treatment success.

Detection of Metabolites of Fumaric Acid Esters in Human Urine: Implications for Their Mode of Action

Medvecz, Rachel Sajó, Réka Lepesi-Benk + o, Zsolt Tulassay, Mária Katona, Zsófia Hatvani, Antal Blazsek and Sarolta Kárpáti Semmelweis University, Department of Dermatology, Venerologie and Dermatooncology, Budapest, Hungary; Hungarian Academy of Sciences Semmelweis University Molecular Medicine Research Group, Budapest, Hungary and Szentágothai Regional Knowledge Centre, Semmelweis University, Budapest, Hungary E-mail: bona@bor.sote.hu

Leptin, adiponectin, visfatin and retinol‐binding protein‐4 – mediators of comorbidities in patients with psoriasis?

Abstract:  White adipose tissue is known to be involved in numerous physiological processes such as insulin‐mediated functions, lipid and glucose metabolism, vascular changes and coagulation. These processes are mainly mediated by adipokines that are secreted either from adipocytes or cells of the stromal‐vascular fraction of adipose tissue. In obesity, a shift in the production of adipokines can mediate the development of associated diseases, such as metabolic syndrome, and vascular complications, such as artherosclerosis, myocardial infarction or stroke, which are known comorbidities of psoriasis too. As obesity is a frequently seen comorbidity in psoriasis patients, adipokines could be involved in the pathogenesis of psoriasis and/or its comorbidities either dependently or independently from obesity. Therefore, this study investigates the levels of four major adipokines in psoriasis patients compared with a control group of healthy volunteers without chronic inflammatory diseases in relation to body composition. Leptin, adiponectin (high molecular weight (HMW) and total adiponectin), visfatin and retinol‐binding protein 4 (RBP4) have been analysed in 79 psoriasis patients and in 80 healthy volunteers. It was shown that HMW adiponectin (OR 1.3755; P = 0.0094) and visfatin (OR 1.1267; P = 0.0472) are independently increased, and RBP4 (OR 0.9884; P < 0.0001) is independently decreased in psoriasis. In conclusion, increased levels of HMW adiponectin and decreased levels of RBP4 could be a mechanism in a chronic inflammatory state that helps to protect against vascular and metabolic disorders, whereas the increase of the pro‐inflammatory adipokine visfatin could lead to atherosclerosis and vascular disorders found in psoriasis.

Triptolide in the treatment of psoriasis and other immune‐mediated inflammatory diseases

Apart from cancer chronic (auto)immune-mediated diseases are a major threat for patients and a challenge for physicians. These conditions include classic autoimmune diseases like systemic lupus erythematosus, systemic sclerosis and dermatomyositis and also immune-mediated inflammatory diseases such as rheumatoid arthritis and psoriasis. Traditional therapies for these conditions include unspecific immunosuppressants including steroids and cyclophosphamide, more specific compounds such as ciclosporin or other drugs which are thought to act as immunomodulators (fumarates and intravenous immunoglobulins). With increasing knowledge about the underlying pathomechanisms of the diseases, targeted biologic therapies mainly consisting of anti-cytokine or anti-cytokine receptor agents have been developed. The latter have led to a substantial improvement of the induction of long term remission but drug costs are high and are not affordable in all countries. In China an extract of the herb Tripterygium wilfordii Hook F. (TwHF) is frequently used to treat autoimmune and/or inflammatory diseases due to its favourable cost-benefit ratio. Triptolide has turned out to be the active substance of TwHF extracts and has been shown to exert potent anti-inflammatory and immunosuppressive effects in vitro and in vivo. There is increasing evidence for an immunomodulatory and partly immunosuppressive mechanism of action of triptolide. Thus, compounds such as triptolide or triptolide derivatives may have the potential to be developed as a new class of drugs for these diseases. In this review we summarize the published knowledge regarding clinical use, pharmacokinetics and the possible mode of action of triptolide in the treatment of inflammatory diseases with a particular focus on psoriasis.

Detection of fumarate–glutathione adducts in the portal vein blood of rats: evidence for rapid dimethylfumarate metabolism

Dimethylfumarate (DMF), the essential ingredient of the drug product Fumaderm®, is used to treat psoriasis with a recognized favorable long-term safety profile. Interestingly, the mode of action and the pharmacokinetics of DMF in psoriasis or multiple sclerosis are not fully explored. It is known that DMF as an α,β-unsaturated carboxylic acid ester forms an adduct with the antioxidant glutathione in vitro via a Michael-type addition within a very short period of time. In addition, it was shown that this reaction also takes place in vivo since the mercapturic acid of DMF was detected in urine of psoriasis patients after oral intake of Fumaderm®. To verify the hypothesis that DMF reacts with GSH already in or even before entering the portal vein blood an in vivo study in rats was initiated and portal vein blood was analyzed for the presence of DMF, MMF, GS-DMS and break down products, after DMF was given directly into the small intestine. The results show that no free DMF could be detected in the rat portal vein blood at any time point. MMF was the dominant metabolite and GS-DMS was also detectable in portal vein blood. In the rat mucosa the glutathione adducts of DMF and MMF were present. The data obtained provide evidence that the modulation of immune-mediated inflammatory pathways responsible for development of psoriasis and MS are targeted by DMF regulating redox-sensitive pathways for which the reaction with glutathione by DMF plays a crucial role.

15 Jahre Fumaderm®: Fumarsäureester für die systemische Behandlung der mittelschweren und schweren Psoriasis vulgaris

1.1 Allgemeine Merkmale der Psoriasis Die Psoriasis ist eine der häufigsten chronisch entzündlichen Hauterkrankungen. In westlichen Industriestaaten sind ca. 2–3 % der Bevölkerung an einer Psoriasis erkrankt, Männer und Frauen sind gleichermaßen betroffen. Somit leiden allein in Deutschland etwa 2 Millionen Menschen an Psoriasis. Jährlich lassen sich 1 Million Menschen aufgrund einer Psoriasis in dermatologischen oder hausärztlichen Praxen behandeln. Eine Psoriasis mit familiärer Häufung kommt in etwa 60 % der Fälle vor, es findet sich zudem eine Assoziation zu Merkmalen des HLA-Systems (HLACw6 und -DR7), der Erkrankungsbeginn liegt in der zweiten bis dritten Lebensdekade (Typ-1-Psoriasis). Bei der Typ-2-Psoriasis ohne familiäre Häufung und HLA-Assoziation, liegt der Gipfel der Erstmanifestation in der fünften bis sechsten Lebensdekade [1]. In der Hälfte der Fälle liegt die Erstmanifestation der Psoriasis (Typ 1 und Typ 2) vor dem 22. Lebensjahr. Dies bedeutet für die Patienten viele Jahrzehnte Leben mit Psoriasis und insbesondere bei den mittelschweren und schwereren, chronischen Formen eine lebenslange Therapie. Bei der Mehrzahl der Erkrankten (90 %) liegt eine Psoriasis vulgaris vor, die in Anlehnung an die angloamerikanische Nomenklatur nun häufig auch als chronischer Plaque-Typ bezeichnet wird. Eine mittelschwer oder schwer ausgeprägte Psoriasis wird bei der Hälfte der Betroffenen diagnostiziert [2].

[New insights into fumaric acid esters (Fumaderm ®):results of the 2nd Expert Workshops].

Ulrich Mrowietz, Peter Altmeyer, Matthias Augustin, Wolf-Henning Boehncke, Bernd Bonnekoh, Yvonne Frambach, Thilo Gambichler, Kamran Ghoreschi, Michael Hertl, Anna-Carina Hund, Arnd Jacobi, Annegret Kuhn, Ralf J Ludwig, Thomas Luger, Stefan F Martin, Hans Merk, Johannes Norgauer, Kristian Reich, Martin Rostami-Yazdi, Robert Sabat, Knut Schäkel, Karin Scharffetter-Kochanek, Michael Peter Schön, Nina Scola, Michael Sticherling, Diamant Thaci, Dagmar Wilsmann-Theis, Antje Viehweg, Gottfried Wozel, Christos C. Zouboulis, Marcus Neureither