Frontiers in Clinical Drug Research - CNS and Neurological Disorders

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.

Most of the 46.8 million people estimated in the year 2015 as living with dementia worldwide were attributed to have Alzheimer’s disease (AD), with projections set to be almost tripled by 2050. Current drugs to treat AD are focused on ameliorating symptoms instead of treating its underlying causes, becoming only palliative. Consequently, treatments to prevent, stop or reverse this overwhelming disease are desperately needful. This Chapter takes a tour through clinical and preclinical studies from different approaches, ranging from those based on small molecules to immunotherapy. But first it also addresses the role of biomarkers in early diagnosis, which is necessary not only to properly recruit patients but also for an accurate assessment of efficiency and safety in clinical trials. Among other approaches, Aβ- immunotherapy has emerged as a promising tool for the treatment of AD. Whereas active immunotherapy, namely administering fragments of the Aβ-peptide, is currently in Phase II, passive immunotherapy, specifically administering antibodies against the Aβ-peptide, reached Phase III. Some of these Phase III trials failed probably because they were performed in patients with mild-to-moderate AD, a too advanced stage of the disease. Currently, different cohorts have been recruited for clinical trials: asymptomatic and very-mildly symptomatic carriers of autosomal-dominant AD mutations as well as symptomatic elderly patients with amyloid positive PET. More studies are needed, but we are getting closer to find a disease-modifying drug to cure this devastating disease.

Alzheimer’s disease (AD) is a multi-faceted neurodegenerative disease. Clinically available treatments, such as cholinesterase inhibitors, are based mainly on the cholinergic hypothesis of AD. These treatments, as well as those targeting the NMDA type of glutamate receptors all provide only a limited therapeutic benefit. The field of AD research has also shifted focus to develop intervention strategies that prevent overt symptoms, such as amyloid plaque deposition and memory loss, in agreement with the more recent amyloid hypothesis of AD. However, to date, all amyloid-directed therapeutics for the treatment of AD have failed, suggesting that additional factors may be involved in the etiology of the disease and mobilizing the search for additional drug targets. By studying the early stages of AD, candidate drug targets (e.g. cytokines or neuronal network activity) have been identified and are now at advanced stages of preclinical development. Throughout this chapter we will focus on two aspects of AD that have garnered widespread attention with respect to future therapeutic intervention strategies. First, a common feature of both mouse models of AD and patients with the disease is hyperexcitability at the level of the synapse as well as neuronal networks. New research is starting to uncover the causes of this hyperexcitability and which cell types are vulnerable, thus, providing attractive therapeutic targets. Second, AD brains are affected by neuroinflammation-like alterations at early stages, which turn into overt neuroinflammation at the late stages. Reducing this activity by targeting the proinflammatory cytokine, tumor necrosis factor-α (TNFα), is thought to be a promising strategy to treat AD. Furthermore, given the cross-talk between the nervous system and the immune system, we hypothesize that the hyperexcitability and progressive induction of neuroinflammation may be related. Here, we summarize studies in both animal models of AD and AD patients related to hyperexcitability and neuroinflammation in the early stages of the disease. Finally, we propose that a combination treatment targeting these factors in addition to the amyloid burden would be a possible way to target more facets of AD.

Diabetic neuropathy (DN), characterized by nerve damage associated with diabetes mellitus, belongs among the earliest and most frequent chronic diabetic complications. It may occur in clinical form (as peripheral sensory/motor, autonomic, proximal, painful or focal) or in subclinical form detectable just by sensitive diagnostic methods. The etiology of DN is complex and not fully understood, untill now. Longterm hyperglycemia triggers a variety of interacting pathways such as production of advanced glycation end products (AGEs), products of oxidative stress and polyol pathway, protein kinase C activation, decrease activity of Na+K+ATP-ase, changed concentration of neural growth factor and production of proinflammatory cytokines. These pathomechanisms may target directly on nerve cells or on endothelial cells causing the microangiopathy of vasa nervorum.

According to multicentric studies, duration and poor compensation of diabetes are the principal risk factors associated with the development of chronic diabetic complications, so the basis for the management is to maintain adequate metabolic compensation. Intensified insulin regimen is the most effective in the treatment of patients with type 1 diabetes. In patients with type 2 diabetes, administration of selected peroral antidiabetics or insulin therapy is considered. Physical activity, lifestyle and dietary management also contribute to euglycemia. Currently used management of DN includes supportive (alpha-lipoic acid, vitamins, antioxidants) and symptomatic treatment (painkillers, beta blockers, magnetotherapy). Other therapeutic possibilities are experimental so far. These drugs interfere with the pathophysiological processes and few of them have been shown to be beneficial in clinical studies (inhibitors of aldose reductase, selective inhibitor of protein kinase C beta, C peptide substitution), however, the effect of other medicines seems to be controversial (vascular endothelial growth factor, erythropoietin). This chapter brings comprehensive review about current possibilities and future perspectives in the management of diabetic neuropathy.

The last few decades have witnessed a major progress in migraine treatment based on novel clinical findings as well as advanced pathophysiological understanding of the disease. Studies focusing on the activation of trigeminovascular system during migraine attacks complemented by identification of several genes related to migraine susceptibility have elaborated the role of dural neurogenic inflammation, nociceptive sensitization mechanisms and cortical spreading depression in migraine pathophysiology. Triptans and CGRP antagonists have emerged as novel migrainespecific agents for acute attack treatment although clinical use of CGRP antagonists is hampered by their side effects. Several unrelated classes of drugs ranging from betablockers to antiepileptics have been identified to be effective for migraine prophylaxis. A wide variety of novel targets including CGRP, glutamate receptors, nitric oxide synthase are in drug development pipeline for both acute as well as prophylactic treatment. Availability of a wide range of experimental and human models of migraine is promising in facilitating this progress. This chapter will focus on the current and future therapeutic agents for acute and prophylactic migraine treatment and their mechanisms of action.

The last decade has witnessed a number of major developments in the field of stroke. A major breakthrough in the treatment of ischemic stroke was attained by the demonstration of improved functional outcomes with intravenous tissue plasminogen activator therapy in the hyperacute period. Recent efforts of pre-hospital thrombolysis facilitated by the use of specialized stroke ambulance systems and newer generation thrombolytics provide promising results in terms of optimizing the benefit obtained from intravenous thrombolysis. These advances, together with successful results observed by endovascular recanalization, especially by the use of thrombectomy devices, unambiguously demonstrate that the penumbra concept (presence of a salvageable ischemic brain tissue) is valid. Despite these encouraging developments, other approaches like neuro-glial protection or restoration have not been so successful in patients with acute ischemic stroke. Nonetheless, there is still hope for these therapies, especially if clinical and radiological algorithms are developed for appropriate patient selection and the recanalization is supplemented by measures aiming neuroprotection and restoration of blood flow not only at the arterial but also microcirculatory level. As for secondary prophylaxis of ischemic stroke, the availability of new anti-platelet and anti-coagulant agents combined with the progress attained in risk factor control has led to an impressively significant reduction in stroke related mortality and morbidity over the last decades.