Results of a randomized, double blind, placebo controlled, crossover trial of melatonin for treatment of Nocturia in adults with multiple sclerosis (MeNiMS)

© 2018 The Author(s). Background: Nocturia is a common urinary symptom of multiple sclerosis (MS) which can affect quality of life (QoL) adversely. Melatonin is a hormone known to regulate circadian rhythm and reduce smooth muscle activity such as in the bladder. There is limited evidence supporting use of melatonin to alleviate urinary frequency at night in the treatment of nocturia. The aim of this study was to evaluate the effect of melatonin on the mean number of nocturia episodes per night in patients with MS. Methods: A randomized, double blind, placebo controlled crossover trial was conducted. 34 patients with nocturia secondary to multiple sclerosis underwent a 4-day pre-treatment monitoring phase. The patients were randomized to receive either 2 mg per night (taken at bedtime) of capsulated sustained-release melatonin (Circadin®) or 1 placebo capsule for 6 weeks followed by a crossover to the other regimen for an additional 6 weeks after a 1-month washout period. Results: From the 26 patients who completed the study, there was no significant difference observed in the signs or symptoms of nocturia when taking 2 mg melatonin compared to placebo. The primary outcome measure, mean number of nocturia episodes on bladder diaries, was 1.8/night at baseline, and 1.4/night on melatonin, compared with 1.6 for placebo (Medians 1.70, 1.50, and 1.30 respectively, p = 0.85). There was also no significant difference seen in LUTS, QoL and sleep quality when taking melatonin. No significant safety concerns arose. Conclusions: This small study suggests that a low dose of melatonin taken at bedtime may be ineffective therapy for nocturia in MS. Trial registration: (EudraCT reference) 2012-00418321 registered: 25/01/13. ISRCTN Registry: ISRCTN38687869

The Expression of VEGF-A Is Down Regulated in Peripheral Blood Mononuclear Cells of Patients with Secondary Progressive Multiple Sclerosis

BACKGROUND: Most patients with relapsing-remitting multiple sclerosis (RRMS) eventually enter a secondary progressive (SPMS) phase, characterized by increasing neurological disability. The mechanisms underlying transition to SPMS are unknown and effective treatments and biomarkers are lacking. Vascular endothelial growth factor-A (VEGF-A) is an angiogenic factor with neuroprotective effects that has been associated with neurodegenerative diseases. SPMS has a prominent neurodegenerative facet and we investigated a possible role for VEGF-A during transition from RRMS to SPMS. METHODOLOGY/PRINCIPAL FINDINGS: VEGF-A mRNA expression in peripheral blood mononuclear (PBMC) and cerebrospinal fluid (CSF) cells from RRMS (n = 128), SPMS (n = 55) and controls (n = 116) were analyzed using real time PCR. We demonstrate reduced expression of VEGF-A mRNA in MS CSF cells compared to controls (p<0.001) irrespective of disease course and expression levels are restored by natalizumab treatment(p<0.001). VEGF-A was primarily expressed in monocytes and our CSF findings in part may be explained by effects on relative monocyte proportions. However, VEGF-A mRNA expression was also down regulated in the peripheral compartment of SPMS (p<0.001), despite unchanged monocyte counts, demonstrating a particular phenotype differentiating SPMS from RRMS and controls. A possible association of allelic variability in the VEGF-A gene to risk of MS was also studied by genotyping for six single nucleotide polymorphisms (SNPs) in MS (n = 1114) and controls (n = 1234), which, however, did not demonstrate any significant association between VEGF-A alleles and risk of MS. CONCLUSIONS/SIGNIFICANCE: Expression of VEGF-A in CSF cells is reduced in MS patients compared to controls irrespective of disease course. In addition, SPMS patients display reduced VEGF-A mRNA expression in PBMC, which distinguish them from RRMS and controls. This indicates a possible role for VEGF-A in the mechanisms regulating transition to SPMS. Decreased levels of PBMC VEGF-A mRNA expression should be further evaluated as a biomarker for SPMS

Autoimmune encephalomyelitis in NOD mice is not initially a progressive multiple sclerosis model.

OBJECTIVE: Despite progress in treating relapsing multiple sclerosis (MS), effective inhibition of nonrelapsing progressive MS is an urgent, unmet, clinical need. Animal models of MS, such as experimental autoimmune encephalomyelitis (EAE), provide valuable tools to examine the mechanisms contributing to disease and may be important for developing rational therapeutic approaches for treatment of progressive MS. It has been suggested that myelin oligodendrocyte glycoprotein (MOG) peptide residues 35-55 (MOG35-55 )-induced EAE in nonobese diabetic (NOD) mice resembles secondary progressive MS. The objective was to determine whether the published data merits such claims. METHODS: Induction and monitoring of EAE in NOD mice and literature review. RESULTS: It is evident that the NOD mouse model lacks validity as a progressive MS model as the individual course seems to be an asynchronous, relapsing-remitting neurodegenerative disease, characterized by increasingly poor recovery from relapse. The seemingly progressive course seen in group means of clinical score is an artifact of data handling and interpretation. INTERPRETATION: Although MOG35-55 -induced EAE in NOD mice may provide some clues about approaches to block neurodegeneration associated with the inflammatory penumbra as lesions form, it should not be used to justify trials in people with nonactive, progressive MS. This adds further support to the view that drug studies in animals should universally adopt transparent raw data deposition as part of the publication process, such that claims can adequately be interrogated. This transparency is important if animal-based science is to remain a credible part of translational research in MS.Stichting MS ResearchWellcome TrustMedical Research CouncilNational Multiple Sclerosis Society. Grant Number: RG4132A5/

Detecting oxysterols in the human circulation

Oxysterols are oxygenated metabolites of cholesterol. On the basis of in vitro experiments, oxysterols have been ascribed many regulatory roles in connection with inflammation, neurodegeneration and atherosclerosis. They are present in trace amounts in biological systems, and their analysis represents a challenging analytical problem