Is ß-catenin neutralization cross-involved in the mechanisms mediated by natalizumab action?

Aberrant activation of Wnt/ß-catenin signaling pathway is commonly associated to cancer development. However, molecular mechanisms controlling Wnt/ß-catenin signaling pathway have been clarified only in part. Here, we show that ß-catenin is differently modulated in patients with multiple sclerosis (MS), displaying that different pharmacological treatments used for clinical MS management cause different nuclear expression levels of ß-catenin. Proteins extracted by peripheral blood mononuclear cells were assessed to evaluate the western blot expression levels of ß-catenin. Analyzing our results, we realized that ß-catenin is totally inhibited by Natalizumab and could have a role in MS management. This could offer new promising studies focused on the possible therapeutic control of ß-catenin translocation.

4(α-L-RHAMNOSYLOXY)-BENZYL ISOTHIOCYANATE, A BIOACTIVE PHYTOCHEMICAL THAT DEFENDS CEREBRAL TISSUE AND PREVENTS SEVERE DAMAGE INDUCED BY FOCAL ISCHEMIA/REPERFUSION.

Natural compounds are a promising source to treat several pathologies. The present study shows the in vivo pharmacological beneficial effect of 4(α-L-rhamnosyloxy)-benzyl isothiocyanate (glucomoringin isothiocyanate; GMG-ITC) obtained from glucomoringin (GMG; 4(α;-L-rhamnosyloxy)- benzyl glucosinolate), purified from Moringa oleifera seeds and hydrolyzed by myrosinase enzyme (β-thioglucoside glucohydrolase; E.C. 3.2.1.147). Cerebral ischemia/reperfusion (CIR) was induced in rats according to a classic model of carotid artery occlusion for a time period of 1 h and the reperfusion time was prolonged for seven days. GMG-ITC (3.5 mg GMG/ml plus 30 µl enzyme/rat; one ml i.p./rat) was administered 15 min after the beginning of ischemia and daily. The results clearly show that GMG-ITC possesses the capability to counteract the CIR-induced damage reducing TNF-alpha release, IκB-alpha cytosolic degradation/NFκBp65 nuclear translocation, as well as several other direct or indirect markers of inflammation (phospho-ERK p42/44, p-selectin) and oxidative stress (inducible Nitric Oxide Synthase (iNOS), MMP-9). GMG-ITC was shown to exert neuroprotective properties in preventing CIR-induced damage and the related cascade of inflammatory and oxidative mediators that exacerbate the progression of this disease in an experimental rat model. Our results clearly show that the tested phytochemical GMG-ITC possesses the capability to counteract CIR-induced damage.

Purified Cannabidiol, the main non-psychotropic component of Cannabis sativa, alone, counteracts neuronal apoptosis in experimental multiple sclerosis.

OBJECTIVE: Multiple Sclerosis (MS) is a global concern disease leading to a progressive, chronic and demyelinating condition, affecting the central nervous system (CNS). The pathology has an inflammatory/autoimmune origin; nevertheless, neuronal cell death mechanisms are not to be underestimated. The present study was designed to test the effects of intraperitoneal administration of cannabidiol (CBD), the main non-psychotropic cannabinoid of Cannabis sativa (CS), in an experimental model of MS. The aim is to evaluate the capability of CBD administration to thwart the cascade of mediators involved in MS-induced apoptosis. MATERIALS AND METHODS: Experimental Autoimmune Encephalomyelitis (EAE) was induced by immunization with myelin oligodendroglial glycoprotein (MOG)35-55 peptide in mice. After immunization, mice were observed daily for signs of EAE and weight loss. Disease signs were evaluated using a standardized scoring system. RESULTS: Immunohistochemical and Western blot assessments of key apoptotic markers reveal that CBD treatment is able to avoid Fas pathway activation, phospho-ERK p42/44 and cleaved caspase-3 triggering as well as alterations in mitochondrial permeability due to Bax/Bcl-2 unbalance. Moreover, CBD interferes with p53-p21 axis activation. As results, the absence of tissue apobody formation in spinal cord tissues of EAE-mice treated with CBD was established. Most of therapeutic properties of CS are currently ascribed to the psychotropic effects of phenylterpenoid delta-9 tetrahydrocannabinol. CONCLUSIONS: We have demonstrated that, alone, purified CBD possesses an anti-apoptotic power against the neurodegenerative processes underlying MS development. This represents an interesting new profile of CBD that could lead to its introduction in the clinical management of MS.

The protective effects of bioactive (RS)-glucoraphanin on the permeability of the mice blood-brain barrier following experimental autoimmune encephalomyelitis.

OBJECTIVES: Alterations in blood-brain barrier (BBB) permeability are due to the disruption of the Tight Junctions (TJs), large multiprotein complexes important for the maintenance of structural integrity and for permeability of the barrier. In this experimental study we evaluated the neuroprotective role of (RS)-glucoraphanin, a glucosinolate present in Brassicaceae, notably in Tuscan black kale, and bioactivated with myrosinase enzyme (bioactive RS-GRA) (10 mg/kg/d intraperitoneally), to prevent the dysfunction of BBB, in an experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). MATERIALS AND METHODS: EAE was induced by immunization with myelin oligodendroglial glycoprotein peptide (MOG)35-55 in mice. By western blot analysis of brain tissues, we evaluated expression and distribution of the TJ-associated proteins, claudin-1, -3, -5 and ZO-1. Additionally, in order to gain a better insight into the mechanisms of action of bioactive RS-GRA, we investigated Foxp3, ERK1/2 and caspase 3 expression associated both to inflammatory response as well as to apoptotic pathway. RESULTS: Our results demonstrated that treatment with bioactive RS-GRA counteracts the alteration of all these parameters and preserves TJ integrity through an antinflammatory and antiapoptotic activity during MS. CONCLUSIONS: Bioactive RS-GRA, could be a therapeutic perspective helpful in preventing dysfunction of the BBB.

Severe septal panniculitis in a multiple sclerosis patient treated with interferon-beta.

We report a memorable case of severe septal panniculitis in an MS patient following the subcutaneous administration of interferon beta-1b, manifesting as a painful, indurated, erythematous lesion of the thigh, which appeared at the injection site.

Pharmacogenomic update on multiple sclerosis: a focus on actual and new therapeutic strategies.

Multiple sclerosis (MS) is an inflammatory and demyelinating disease of central nervous system comprising several subtypes. Pharmacological treatment involves only few drugs. Among these, interferon beta (IFN-ß) and glatiramer acetate were the most used. Although evidence supports the efficacy of these agents in treating MS symptoms, actual studies allowed to introduce new innovative drugs in clinical practice. Applying pharmacogenetic approach to MS, IFN-ß and several other immune pathways were abundantly investigated. Numerous reports identified some promising therapy markers but only few markers have emerged as clinically useful. This may be partially due to differences in clinical and methodological criteria in the studies. Indeed, responder and non-responder definitions lack standardized clinical definition. The goal of this review is to treat advances in research on the pharmacogenetic markers of MS drugs and to highlight possible correlations between type of responses and genetic profile, with regard to clinical and methodological discrepancies in the studies.

Role of resveratrol and its analogues in the treatment of neurodegenerative diseases: focus on recent discoveries.

Neurodegenerative diseases are a group of chronic, progressive disorders characterized by the gradual loss of neurons in several areas of the central nervous system (CNS). Substantial evidence has documented a common inflammatory mechanism in neurodegeneration. It is known that classical anti-inflammatory agents, steroids and nonsteroidal anti-inflammatory drugs, have not played a major role in the management of CNS inflammatory conditions. This may be partly due to the natural compartmentation of the brain by the blood-brain barrier. Thus, there is much interest in developing novel anti-inflammatory drugs that may help to prevent or ameliorate CNS inflammation. Resveratrol (RSV) has received considerable attention over the last several decades. Experimental studies have revealed its benefits in several human disease models, including cardio- and neuro-protection, immune regulation and cancer chemoprevention. The broad action spectrum of RSV is explained by the involvement of numerous signaling networks and cellular effector mechanisms. Among them, apoptotic and antioxidant targets have been implicated. Recently, also anti-neuroinflammatory activity has been observed. A number of studies demonstrated that RSV mediates the downregulation of various inflammatory biomarkers such as tumor necrosis factor, cyclooxygenase 2, inducible nitric oxide synthase and interleukins. This activity seems to depend on some structural features of RSV such as the number and the position of hydroxyl groups. In this review, a comprehensive account of multiple intracellular RSV targets involved in neuroinflammation and its analogues design will be treated, pointing to structure/activity relationships.