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Concomitant Use of Neuroprotective Drugs in Neuro Rehabilitation of Multiple Sclerosis.

ABSTRACT: We provide an overview of rehabilitation in neurological diseases. A large amount of literature available on neurorehabilitation is based from the rehabilitative work on stroke and spinal cord injuries. After a brief description of rehabilitation, the potential application of neurorehabilitation in neurodegenerative diseases specifically multiple sclerosis (MS) is summarized. Since MS causes a wide variety of symptoms, the rehabilitation in MS patients may benefit from an interdisciplinary approach that encloses physiotherapy, cognitive rehabilitation, psychological therapy, occupational therapy, and other methods to improve fatigue. Neurorehabilitation helps patients to reach and maintain their optimal physical, psychological and intellectual, levels but it does not reverse long-term disabilities that arise from neurological disorders. This calls for the need of better neuroregenerative and neuroprotective treatment strategies in addition to neurorehabilitation. We discuss neuroprotective drugs aimed at preventing axonal, neuronal, myelin and oligodendrocyte damage and cell death that are approved and others that are currently in clinical trials, with an emphasis on human derived natural antibodies with remyleination potential. Our investigative group developed recombinant natural human IgM antibodies against oligodendrocytes and neurons with a potential for CNS repair and remyleination. One such recombinant antibody, rHIgM22 completed a phase 1 clinical trial with no toxicity and with an objective of promoting remyleination in multiple sclerosis. Inclusion of these drugs as a multifaceted approach may further enhance the efficacy of neurorehabilitation in neuroinflammatory and neurodegenerative disorders.

SUBMITTER: Dasari H

PROVIDER: S-EPMC5006625 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Concomitant Use of Neuroprotective Drugs in Neuro Rehabilitation of Multiple Sclerosis.

Dasari Harika H Wootla Bharath B Warrington Arthur E AE Rodriguez Moses M

International journal of physical medicine & rehabilitation 20160623 4

We provide an overview of rehabilitation in neurological diseases. A large amount of literature available on neurorehabilitation is based from the rehabilitative work on stroke and spinal cord injuries. After a brief description of rehabilitation, the potential application of neurorehabilitation in neurodegenerative diseases specifically multiple sclerosis (MS) is summarized. Since MS causes a wide variety of symptoms, the rehabilitation in MS patients may benefit from an interdisciplinary appro ...[more]

PMID: 27595123

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Project description:BackgroundDue to limited access to brain tissue, the precise mechanisms underlying neuro-axonal dysfunction in neurological disorders such as multiple sclerosis (MS) are largely unknown. In that context, profiling DNA methylation, which is a stable and cell type-specific regulatory epigenetic mark of genome activity, offers a unique opportunity to characterize the molecular mechanisms underpinning brain pathology in situ. We examined DNA methylation patterns of neuronal nuclei isolated from post-mortem brain tissue to infer processes that occur in neurons of MS patients.ResultsWe isolated subcortical neuronal nuclei from post-mortem white matter tissue of MS patients and non-neurological controls using flow cytometry. We examined bulk DNA methylation changes (total n = 29) and further disentangled true DNA methylation (5mC) from neuron-specific DNA hydroxymethylation (5hmC) (n = 17), using Illumina Infinium 450K arrays. We performed neuronal sub-type deconvolution using glutamate and GABA methylation profiles to further reduce neuronal sample heterogeneity. In total, we identified 2811 and 1534 significant (genome-wide adjusted P value < 0.05) differentially methylated and hydroxymethylated positions between MS patients and controls. We found striking hypo-5mC and hyper-5hmC changes occurring mainly within gene bodies, which correlated with reduced transcriptional activity, assessed using published RNAseq data from bulk brain tissue of MS patients and controls. Pathway analyses of the two cohorts implicated dysregulation of genes involved in axonal guidance and synaptic plasticity, with meta-analysis confirming CREB signalling as the most highly enriched pathway underlying these processes. We functionally investigated DNA methylation changes of CREB signalling-related genes by immunohistofluoresence of phosphorylated CREB in neurons from brain sections of a subcohort of MS patients and controls (n = 15). Notably, DNA methylation changes associated with a reduction of CREB activity in white matter neurons of MS patients compared to controls.ConclusionsOur data demonstrate that investigating 5mC and 5hmC modifications separately allows the discovery of a substantial fraction of changes occurring in neurons, which can escape traditional bisulfite-based DNA methylation analysis. Collectively, our findings indicate that neurons of MS patients acquire sustained hypo-5mC and hyper-5hmC, which may impair CREB-mediated neuro-axonal integrity, in turn relating to clinical symptoms.

Project description:BackgroundNeurodegeneration is the pathological substrate that causes major disability in secondary progressive multiple sclerosis. A synthesis of preclinical and clinical research identified three neuroprotective drugs acting on different axonal pathobiologies. We aimed to test the efficacy of these drugs in an efficient manner with respect to time, cost, and patient resource.MethodsWe did a phase 2b, multiarm, parallel group, double-blind, randomised placebo-controlled trial at 13 clinical neuroscience centres in the UK. We recruited patients (aged 25-65 years) with secondary progressive multiple sclerosis who were not on disease-modifying treatment and who had an Expanded Disability Status Scale (EDSS) score of 4·0-6·5. Participants were randomly assigned (1:1:1:1) at baseline, by a research nurse using a centralised web-based service, to receive twice-daily oral treatment of either amiloride 5 mg, fluoxetine 20 mg, riluzole 50 mg, or placebo for 96 weeks. The randomisation procedure included minimisation based on sex, age, EDSS score at randomisation, and trial site. Capsules were identical in appearance to achieve masking. Patients, investigators, and MRI readers were unaware of treatment allocation. The primary outcome measure was volumetric MRI percentage brain volume change (PBVC) from baseline to 96 weeks, analysed using multiple regression, adjusting for baseline normalised brain volume and minimisation criteria. The primary analysis was a complete-case analysis based on the intention-to-treat population (all patients with data at week 96). This trial is registered with ClinicalTrials.gov, NCT01910259.FindingsBetween Jan 29, 2015, and June 22, 2016, 445 patients were randomly allocated amiloride (n=111), fluoxetine (n=111), riluzole (n=111), or placebo (n=112). The primary analysis included 393 patients who were allocated amiloride (n=99), fluoxetine (n=96), riluzole (n=99), and placebo (n=99). No difference was noted between any active treatment and placebo in PBVC (amiloride vs placebo, 0·0% [95% CI -0·4 to 0·5; p=0·99]; fluoxetine vs placebo -0·1% [-0·5 to 0·3; p=0·86]; riluzole vs placebo -0·1% [-0·6 to 0·3; p=0·77]). No emergent safety issues were reported. The incidence of serious adverse events was low and similar across study groups (ten [9%] patients in the amiloride group, seven [6%] in the fluoxetine group, 12 [11%] in the riluzole group, and 13 [12%] in the placebo group). The most common serious adverse events were infections and infestations. Three patients died during the study, from causes judged unrelated to active treatment; one patient assigned amiloride died from metastatic lung cancer, one patient assigned riluzole died from ischaemic heart disease and coronary artery thrombosis, and one patient assigned fluoxetine had a sudden death (primary cause) with multiple sclerosis and obesity listed as secondary causes.InterpretationThe absence of evidence for neuroprotection in this adequately powered trial indicates that exclusively targeting these aspects of axonal pathobiology in patients with secondary progressive multiple sclerosis is insufficient to mitigate neuroaxonal loss. These findings argue for investigation of different mechanistic targets and future consideration of combination treatment trials. This trial provides a template for future simultaneous testing of multiple disease-modifying medicines in neurological medicine.FundingEfficacy and Mechanism Evaluation (EME) Programme, an MRC and NIHR partnership, UK Multiple Sclerosis Society, and US National Multiple Sclerosis Society.

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Concomitant Use of Neuroprotective Drugs in Neuro Rehabilitation of Multiple Sclerosis.

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Concomitant Use of Neuroprotective Drugs in Neuro Rehabilitation of Multiple Sclerosis.

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