Frontiers in Clinical Drug Research - CNS and Neurological Disorders: Volume 4

Atta-ur-Rahman

• Publisher: Bentham Science Publishers
• Year: 2016
• ISBN:
  9781681082950
• Topic: Scienze fisiche
• Subtopic: Chimica clinica

Frontiers in Clinical Drug Research - CNS and Neurological Disorders is an eBook series that brings updated reviews to readers interested in advances in the development of pharmaceutical agents for the treatment of central nervous system (CNS) and other nerve disorders. The scope of the eBook series covers a range of topics including the medicinal chemistry, pharmacology, molecular biology and biochemistry of contemporary molecular targets involved in neurological and CNS disorders. Reviews presented in the series are mainly focused on clinical and therapeutic aspects of novel drugs intended for these targets. Frontiers in Clinical Drug Research - CNS and Neurological Disorders is a valuable resource for pharmaceutical scientists and postgraduate students seeking updated and critical information for developing clinical trials and devising research plans in the field of neurology. The fourth volume of this series features reviews that cover a variety of topics including:
-Multiple sclerosis drug therapy
-Treatment of diabetic neuropathy
-Migraine treatments
-Ischemic stroke treatments
-Alzheimer's disease biomarkers

Multiple Sclerosis Drug Therapy: From the Classical Pharmaceutical Down to Cellular and Molecular Approach

Roberta Rigolio^{1, 2, *}, Elisa Ballarini^{1, 2}, Maria Grimoldi¹, Margherita Gardinetti¹, Gabriele Di Sante³

¹ Experimental Neurology Unit, School of Medicine and Surgery, Università Milano-Bicocca, Via Cadore 48, 20900 Monza, Italy

² NeuroMI- Milan Center for Neuroscience, San Gerardo Hospital, Via Pergolesi, 33 - 20052, Monza, Italy

³ Institute of General Pathology, Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00168 Rome, Italy

Abstract

Multiple Sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) affecting over 2.000.000 individuals around the world. Although MS etiopathogenesis is still not completely defined environmental factor exposure and genetic background are relevant in disease development. Moreover, MS shows heterogeneous onset and course so that different disease forms can be described which are all characterized by motor and/or sensory and even cognitive impairment.

Two steps in the disease progression can be described. First MS lesions are originated by the activated immune system which recognizes CNS myelin as a foreign element thus leading to the formation of demyelinated plaques that evolve into axonal damage and subsequent neurodegeneration over the time.

Since the beginning MS therapy has been focused on counteracting immune system action. Nevertheless, besides the immunosuppressive/immunomodulating drugs such as Glatiramer acetate, Beta-interferons and steroids, the advance in the comprehension of the immune-mediated mechanisms has sustained the development and use of molecular

and cellular-focused approaches, e.g. monoclonal antibodies and stem cells.

At the same time very few weapons are specifically available for fighting MS neurodegenerative progression.

We report an overview on MS and both old and new therapeutic approaches to the disease.

Keywords: Alemtuzumab, Anti-Lingo-1 antibody, Daclizumab, Disease-modifying drugs, Ethiopathology, Helminthes, Histopathology, Immune system, Masinitib mesylate, Monoclonal antibodies, MOR103, Multiple Sclerosis, Ocrelizumab, Ofatumumab, Remyelination strategies, Rituximab, Secukinumab, Stem cells, Tabalumab, Tolerogenic vaccines, Vitamin D.

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^* Corresponding author Roberta Rigolio: Experimental Neurology Unit, School of Medicine and Surgery, Università Milano-Bicocca,Via Cadore 48, 20900 Monza, Italy; Tel: [phone]; Fax: [phone]; Email: [email protected]

MULTIPLE SCLEROSIS

Over the past 100 years the advances in immunology and neurobiology have led us to the current definition of Multiple Sclerosis (MS) as a chronic inflammatory disease of the central nervous system (CNS) primarily triggered by the activation of immune system elements against myelin sheath components, which is subsequently followed by irreversible damage to axons and neurons leading to permanent disability. Until now, no single etiopathogenetic factor has been identified and MS is generally considered to be a complex multifactorial autoimmune disease depending on genetic predisposition and environmental factors.

MS is characterized by a dissemination of CNS lesions in time and space with heterogeneous signs and symptoms that usually indicate more than one lesion and that can be due to injury to any part of the neuraxis. Moreover MS clinical presentation and course are highly variable. Several disease types can be recognized: relapsing-remitting MS (RRMS), primary-progressive (PPMS), secondary-progressive (SPMS).

Although our current pathogenetic concepts might be too simple to define such a multifaceted disease, our current knowledge of the MS-related immunological mechanisms has made possible the clinical viability of various effective immunomodulating/immunosuppressive strategies. These are mainly aimed at limiting/modifying the inflammation-related component of the disease so that the main part of the research activity and treatments has been focused on the RRMS form, while the MS symptoms are mainly managed by means of non-specific symptomatic therapies.

Epidemiology, Environmental Agents and Genetics

MS is the most frequently diagnosed neurological disease leading to non-traumatic disability among young adults, affecting more than 2 million individuals worldwide [1]. As with many other autoimmune diseases, the prevalence of MS is 2-3 times as high in women as in men and this ratio seems to have increased slightly over time, mainly in the polar latitude countries [2]. The incidence of MS has increased in various countries due both to the improvement in diagnostic tools and to the lengthening of patients’ lives together with the improvement in hygiene conditions over the last century [3].

MS can affect individuals at any age with the first clinical signs occurring most frequently between 20 and 40 years of age although the disease can occur even in individuals over 50 years of age; pediatric MS has also been recognized and diagnostic criteria have recently been redefined [4, 5]. The prevalence of the disease has been shown to increase from the equator to the pole with important exceptions such as the Sardinian and the Inuit populations in the Mediterranean and Canada respectively. Moreover, the migration studies which have shown changes in the risk of MS susceptibility in individuals moving to different MS-risk areas before pubescence [6] and the fluctuations in the rates of MS patients in some areas such as the North Atlantic islands have suggested a strong interaction between genetically-based and environmental factors, i.e. viruses, vitamin D deficiency and other factors [1, 7].

Thanks to these epidemiological studies, a hygiene hypothesis has been put forward suggesting that the higher incidence of MS in industrialized countries is due to certain infections or inappropriate responses to certain substances [8]. This notion is supported by analogies of the geographical distribution of certain infections [9], and by the fact that, in developed countries, certain typical childhood diseases, such as measles or mononucleosis, are contracted at later ages, and also by a recent study that noted an amelioration of the clinical course of MS in the presence of parasitic infestations [10].

Some scientists have associated MS with the seasons and, consequently, with seasonal infections, such as arbovirus and epidemic influenza, or with zoonoses, such as visna from sheep and the canine distemper virus from dogs. MS and infectious agents, particularly viruses, and more recently the human microbiome have been widely studied in order to investigate the manner in which they interact with each other and with the human genome to influence the risk of MS; however, until now there has been an absence of conclusive data [11].

Furthermore, the different pathological lesions described and classified in MS probably derive from multiple mechanisms of pathogenesis, and this accounts for the fact that there could be multiple causes and mechanisms involved in its etiology.

In particular, viruses have been widely detected in MS patients due to their ability to induce demyelination and axonal loss through many different mechanisms, directly and indirectly [12].

Recent reports have focused on herpesviruses, i.e. HHV6 [13], and Chlamydia pneuomoniae [14], all ubiquitous and essentially asymptomatic infections occurring especially in childhood, while Epstein-Barr virus (EBV) anti...