CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 11, Issue 5, 2012

Multiple sclerosis (MS) is a common neurological disease mainly affecting young people. Around the world, over 2.5 million people suffer from this central nervous system (CNS) disorder. Although the exact disease mechanism is not completely clear, it is known that both environmental and genetic factors influence the development of MS. Here we aim to summarize a few major highlights of recent progress that have been made in clinical MS research. A genetic predisposition in combination with Epstein-Barr virus infection seems to be essential to get MS. Recently more than 50 susceptibility genetic loci for MS have been described. MS prevalence has a latitudinal gradient indicating that sunlight exposure and therefore vitamin D are important contributors to MS risk. Several studies found an inverse association between MS prevalence and serum vitamin D levels. In most cases, MS starts with an acute episode involving one or more sites of the CNS. The role of the recently revised McDonald Diagnostic Criteria for the diagnosis of MS, which sometimes allow the diagnosis after a first attack, is discussed. Most patients with MS suffer from exacerbations and remissions of neurological deficits: relapsing-and remitting MS. With time, the majority of these patients enter a disease phase characterized by continuous, irreversible neurological decline; this is called secondary progressive MS. In 10-20% of patients, the disease is progressive from onset. Life expectancy of patients after diagnosis with MS is around 35 years, and MS patients die 5-10 years earlier than the general population. A substantial percentage of MS patients have their first attack during childhood. Clinics of childhood-onset MS versus adult-onset are explained, as are diagnostics, differential diagnoses and therapeutic options for children with MS. Also another demyelinating disease of the CNS, neuromyelitis optica (NMO) is highlighted. Since NMO has been considered as a variant of MS and also has been misdiagnosed as MS, recent insights in the pathology of NMO are explained.

Pathological examination of the affected human tissue is key to understanding the possible mechanisms operating in the disease. In multiple sclerosis (MS), studies of central nervous system (CNS) tissues reveal the inflammatory nature of the disease associated with demyelination and axonal damage. Based on the concept of a pathogenic adaptive immune response, immunosuppressive therapies have been developed in an attempt to block or inhibit the potentially pathogenic T and B cells. More recently, re-examination of the neuropathology has led to a resurgence of interest in the neurodegenerative aspects of the disease, the involvement of cortical damage as well as the role of innate immunity in MS. These ideas have led to paradigm shifts from MS being the result of autoimmunity to myelin due to initial adaptive immune responses, to that of a neurodegenerative disease in which, besides T and B cells, innate immunity may play a major role in the disease process. The neuropathological studies have undoubtedly influenced pharmaceutical interest in development of neuroprotective approaches. Here we review the latest findings from pathological studies of MS tissues and discuss the relevance of these findings for future therapeutic approaches.

The pathophysiology of multiple sclerosis (MS) is typically characterised by inflammation and demyelination leading to neurodegeneration, which is associated with disability and the progressive stages of MS. The visual system is a valuable tool for studying neurodegeneration and potential neuroprotection in the central nervous system due to its ease of accessibility. Optical coherence tomography (OCT) is a non-invasive tool, which can be used to measure the thickness of the retinal nerve fibre layer (RNFL). The thickness of RNFL is reduced following the development of MS and optic neuritis and can therefore be used as a correlate of global axonal loss. OCT is currently being investigated as a structural outcome measure for neuroprotective clinical trials of MS. This review describes the relationship between MS and optic neuritis and the associated RNFL thinning, the technology and advancements of OCT, the role of OCT in clinical trials for new neuroprotective therapies in MS and the future role of OCT in MS research.

Multiple sclerosis (MS) is a heterogeneous disease that develops as an interplay between the immune system and environmental stimuli in genetically susceptible individuals. There is increasing evidence that viruses may play a role in MS pathogenesis acting as these environmental triggers. However, it is not known if any single virus is causal, or rather several viruses can act as triggers in disease development. Here, we review the association of different viruses to MS with an emphasis on two herpesviruses, Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV-6). These two agents have generated the most impact during recent years as possible co-factors in MS disease development. The strongest argument for association of EBV with MS comes from the link between symptomatic infectious mononucleosis and MS and from seroepidemiological studies. In contrast to EBV, HHV-6 has been found significantly more often in MS plaques than in MS normal appearing white matter or non-MS brains and HHV-6 re-activation has been reported during MS clinical relapses. In this review we also suggest new strategies, including the development of new infectious animal models of MS and antiviral MS clinical trials, to elucidate roles of different viruses in the pathogenesis of this disease. Furthermore, we introduce the idea of using unbiased sequence-independent pathogen discovery methodologies, such as next generation sequencing, to study MS brain tissue or body fluids for detection of known viral sequences or potential novel viral agents.

Multiple sclerosis (MS) is a highly debilitating immune mediated disorder of the central nervous system and represents a substantial burden to the developed world. Despite the recent advances in MS research, which risk factors are implicated and how they contribute to MS pathogenesis is largely unknown. However, in line with older studies investigating the genetic and geographical epidemiology of this complex disease, more recent studies have highlighted how MS arises from a combination of genetic susceptibility and environmental exposures acting from gestation to early adulthood. Vitamin D deficiency, season of birth, Epstein Barr virus infection, and smoking behaviour are strongly implicated and able to influence genetic predisposition to MS. Furthermore, these factors appear to act synergistically and the risk of MS in individuals exposed to more than one factor combines multiplicatively. Current evidence suggests that a large part of MS could be prevented and understanding how and when during life risk factors act will ultimately aid the development of prevention strategies.

Both immune-mediated and neurodegenerative processes play a role in the pathogenesis of multiple sclerosis (MS). There is still considerable debate, however, on how to link these two seemingly unrelated elements in disease. It has also remained unclear how the immune system can be involved without harboring any obvious myelin-directed abnormality in MS patients. Here, we propose that the unique properties of a small heat shock protein, HSPB5, can help reconcile the role of the immune system with the neurodegenerative element in MS, and explain the absence of any peripheral immune abnormality in patients. By being selectively induced as a protective stress protein in oligodendrocytes, and subsequently triggering activation of nearby microglia, HSPB5 accumulation translates neurodegenerative signals into a local innate immune response. The immune-regulatory profile of HSPB5-activated microglia, as well as animal model data, indicate that the HSPB5-induced innate response is neuroprotective. However, the presence of pro-inflammatory HSPB5-reactive memory T cells in the human immune repertoire, a unique feature among mammals, can subvert this response. Recruited by the innate response, such T cells respond to the accumulation of HSPB5 by an adaptive immune response, dominated by IFN-γ production, that ultimately overwhelms the originally protective microglial response, and culminates in tissue damage. Thus, HSPB5 accumulation caused by neurodegeneration can provoke a destructive local adaptive response of an otherwise normal immune system. This scenario is fully consistent with known causative factors and the pathology of MS, and with the effects of various therapies. It also helps explain why MS develops only in humans.

Multiple sclerosis (MS) is widely considered to be the result of an aggressive autoreactive T cell attack on myelin. How these autoimmune responses arise in MS is unclear, but they could result from virus infections. Thus, viral and autoimmune diseases in animals have been used to investigate the possible pathogenic mechanisms operating in MS. The autoimmune model, experimental autoimmune encephalomyelitis, is the most widely-used animal model and has greatly influenced therapeutic approaches targeting autoimmune responses. To investigate demyelination and remyelination in the absence of the adaptive immune response, toxin-induced demyelination models are used. These include using cuprizone, ethidium bromide and lysolecithin to induce myelin damage, which rapidly lead to remyelination when the toxins are withdrawn. The virus models include natural and experimental infections such as canine distemper, visna infection of sheep, and infection of non-human primates. The most commonly used viral models in rodents are Semliki Forest virus and Theiler's murine encephalomyelitis virus. The viral and experimental autoimmune encephalomyelitis models have been instrumental in the understanding of how viruses trigger inflammation, demyelination and neurodegeneration in the central nervous system. However, due to complexity of the animal models, pathological mechanisms are also examined in central nervous system cell culture systems including co-cultures, aggregate cultures and brain slice cultures. Here we critically review in vitro and in vivo models used to investigate MS. Since knowledge gained from these models forms the basis for the development of new therapeutic approaches for MS, we address the applicability of the models. Finally, we provide guidance for using and reporting animal studies with the aim of improving translational studies to the clinic.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). Mechanisms of disease progression in MS are poorly understood but are thought to relate to both focal pathology as well as diffuse inflammation in the white and grey matter. Evidence points to neurodegeneration combined with a loss of cellular function in the remaining tissue as an important factor to the progression of MS. Mitochondria are implicated to play a role in the pathogenesis of MS with evidence of loss of mitochondrial respiratory chain activity, down regulation of both nuclear DNA and mitochondrial DNA (mtDNA) encoded transcripts as well as oxidative damage to, and deletions of, the mitochondrial DNA (mtDNA). The double stranded circle of mtDNA (16.6 kb) encompasses genes encoding key subunits within the mitochondrial respiratory chain required for the production of ATP as well as transfer RNA and ribosomal RNA molecules within the cell. The stability of mtDNA is essential for a healthy CNS as highlighted by the patients with primary mitochondrial disease. In this review, we focus on the potential role of mtDNA mutations, in particular somatic mtDNA deletions, in the pathogenesis of the progressive stage of MS. We propose clonal expansion of somatic mtDNA deletions as a potential molecular link between early inflammatory events and a delayed cellular energy failure, dysfunction and degeneration. The high level of somatic mtDNA deletions within single cells in MS is likely to cause cellular dysfunction as well as increase the susceptibility of the CNS tissue to additional stress.

In multiple sclerosis, conduction block in demyelinated axons underlies early neurological symptoms, whereas axonal transection is believed to be responsible for more permanent later deficits. Approved treatments for the disease are immunoregulatory and reduce the rate of lesion formation and clinical exacerbation, but are only partially effective in preventing the onset of disability. Remyelination is a term for the re-generation of the nerve's myelin sheath and is a subject of active medical research. Remyelination capacity varies from patient to patient or even from lesion to lesion in one and the same patient. Efforts to understand the causes for remyelination failure have prompted research into the biology of remyelination and the complex molecular factors that regulate remyelination. In the current review article we address challenges of remyelination research with a special focus on histo-pathological studies using brain biopsy and autopsy material. We summarize our current knowledge about extent of remyelination in multiple sclerosis patients and its relation to disease duration, lesion type, inflammation, affected brain region and gender. Furthermore we will address which step(s) of the oligodendrocyte maturation program is impaired and, thus, could be a feasible target for therapeutic interventions. Specifically mentioned will be the distribution of oligodendrocyte progenitor cells in demyelinated multiple sclerosis plaques and therapeutic approaches which aim to boost intrinsic properties of progenitor cells or to supply progenitors by cell transplantation approaches. This comprehensive overview is complemented by recent findings suggesting that U.S. Food and Drug Administration-approved treatment options, such as FTY720 (Gilenya®) or glatiramer acetate (Copaxone®) might boost myelin repair.

The term “disease modifying drugs” (DMD) is taken from rheumatologists who coined it after the use of immunosuppressive drugs and, more recently, the association of “biological drugs” that changed the degenerative course of rheumatic disease. In the treatment of multiple sclerosis (MS), the advent of interferon (IFN)-β, which caused a reduction in the number of relapses and possibly improvement in disability outcomes, was the first strategy to prevent inflammatory damage in the central nervous system (CNS). Soon after, glatiramer acetate showed similar results. It would be more than a decade before natalizumab was licensed, showing a much better efficiency in relapse reduction than was seen after first-line therapies failed. The pipeline is now much larger with several drugs on the horizon. Overall, the anti-inflammatory strategy has been mostly successful but drugs that have protection and repair mechanisms are still missing.

For many years, multiple sclerosis (MS) patients have been self-medicating with illegal street cannabis to alleviate symptoms associated with MS. Data from animal models of MS and clinical studies have supported the anecdotal data that cannabis can improve symptoms such as limb spasticity, which are commonly associated with progressive MS, by the modulation of excessive neuronal signalling. This has lead to cannabis-based medicines being approved for the treatment of pain and spasticity in MS for the first time. Experimental studies into the biology of the endocannabinoid system have revealed that cannabinoids have activity, not only in symptom relief but also potentially in neuroprotective strategies which may slow disease progression and thus delay the onset of symptoms such as spasticity. This review appraises the current knowledge of cannabinoid biology particularly as it pertains to MS and outlines potential future therapeutic strategies for the treatment of disease progression in MS.