The role of osteopontin in neurodegenerative diseases

Osteopontin (OPN) was shown to be involved in inflammatory and degenerative processes of the nervous system. In multiple sclerosis, the role of OPN has been studied in the inflammatory phase, where it was shown that the protein levels increase during disease relapses. Moreover, it was shown that subjects who carry a genotype associated with decreased protein levels tend to display a benign course. Taken altogether, these findings suggest that OPN may play a detrimental role in multiple sclerosis, at least in the inflammatory phase. In common neurodegenerative diseases, such as Parkinson's and Alzheimer's disease, OPN seems to act as a double-edged sword triggering neuronal toxicity and death in some contexts and functioning as a neuroprotectant in others. The involvement of OPN in several biological pathways and networks calls for more extensive research in order to unravel its role in the different disease phases and its potential as a therapeutic target.     

Treatment of multiple sclerosis with interferon beta 1b

Interferon beta 1b is now an established therapeutic option for relapsing remitting multiple sclerosis. More recently, it has also been shown to slow down disease progression in secondary progressive multiple sclerosis. Interferon beta 1b's clinical effect is reflected in MRI studies demonstrating a dramatic effect in reducing disease activity. The drug is generally well tolerated, but its efficacy can be compromised in some patients by the emergence of neutralizing antibodies. This chapter will focus on interferon beta 1b (Betaseron) treatment for multiple sclerosis, its clinical and MRI effects, and its putative mechanism of action.     

Glycosylation processing inhibition by castanospermine prevents experimental autoimmune encephalomyelitis by interference with IL-2 receptor signal transduction

In this study, we explored the therapeutic targets of the glycosylation processing inhibitor, castanospermine (CAST), in murine passive transfer experimental autoimmune encephalomyelitis (EAE), a model disease of multiple sclerosis. By using lymphocytic-endothelial adhesion and transmigration assays, FACScan and Western blotting, we defined the effects of CAST on expression, function and signal transduction of glycoproteins crucial in the pathophysiology of this disease. CAST prevented clinical signs of EAE and completely inhibited inflammatory CNS infiltrates associated with this disease. Here, we showed that CAST blocks antigen-induced lymphocytic activation and clonal expansion in a dose-dependent manner. Importantly, we observed that CAST strongly impairs IL-2-induced signal transduction of the IL-2 receptor. In contrast, neither expression nor binding ability of the IL-2 receptor was affected by this drug. In addition, we were able to exclude major effects of CAST on expression and function of different glycoproteins important in antigen presentation as well as lymphocytic-endothelial adhesion and transmigration. In conclusion, CAST strongly interferes in the signal transduction of the IL-2 receptor. This could explain both inhibitory effects of CAST in clonal T cell expansion and development of transfer EAE. This relatively selective pharmacological effect of CAST highlights its potential as a novel immunomodulatory approach in multiple sclerosis.     

Minocycline and neurodegenerative diseases

Minocycline is a semi-synthetic, second-generation tetracycline analog which is effectively crossing the blood-brain barrier, effective against gram-positive and -negative infections. In addition to its own antimicrobacterial properties, minocycline has been reported to exert neuroprotective effects over various experimental models such as cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, Parkinson's disease, kainic acid treatment, Huntington' disease and multiple sclerosis. Minocycline has been focused as a neuroprotective agent over neurodegenerative disease since it has been first reported that minocycline has neuroprotective effects in animal models of ischemic injury [Yrjanheikki J, Keinanen R, Pellikka M, Hokfelt T, Koisinaho J. Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia. Proc Natl Acad Sci USA 1998;95:15769-74; Yrjanheikki J, Tikka T, Keinanen R, Goldsteins G, Chan PH, Koistinaho J. A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. Proc Natl Acad Sci USA 1999;96:13496-500]. Recently, the effect of minocycline on Alzheimer's disease has been also reported. Although its precise primary target is not clear, the action mechanisms of minocycline for neuroprotection reported so far are; via; the inhibition of mitochondrial permeability-transition mediated cytochrome c release from mitochondria, the inhibition of caspase-1 and -3 expressions, and the suppression of microglial activation, involvement in some signaling pathways, metalloprotease activity inhibition. Because of the high tolerance and the excellent penetration into the brain, minocycline has been clinically tried for some neurodegenerative diseases such as stroke, multiple sclerosis, spinal cord injury, amyotropic lateral sclerosis, Hungtington's disease and Parkinson's disease. This review will briefly summarize the effects and action mechanisms of minocycline on neurodegenerative diseases.     

Natalizumab remains detectable in patients with multiple sclerosis long after treatment is stopped

Natalizumab is frequently used as a treatment for multiple sclerosis (MS). The occurrence of progressive multifocal leukoencephalopathy (PML) in natalizumab-treated patients indicates that its prominent beneficial effects need to be balanced against the risks. Also, cessation of the drug seems to be associated with recurrence of disease activity. Both the moment of rebound disease activity and the outcome of PML are related to clearance of the drug. Specific features of this IgG4 antibody (i.e. half-antibody exchange) may result in underestimated drug levels. Here, we demonstrate natalizumab levels in 10 patients with relapsing MS, using a recently developed sensitive assay. Remarkably, natalizumab was detectable up to 200 days after cessation of therapy.     

Cell-Based Therapy for Neural Disorders — Anticipating Challenges

Neurological syndromes, such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, Huntington’s disease, amyotrophic lateral sclerosis, and lysosomal storage disorders, such as Battens disease, are devastating because they result in increasing loss of cognitive and physical function. Sadly, no drugs are currently available to halt their progression. The relative paucity of curative approaches for these and other conditions of the nervous system have led to a widespread evaluation of alternative treatment modalities including cell-based interventions. Several cell types have been tested successfully in animal models where safety and efficacy have been demonstrated. Early clinical trials have also been initiated in humans, and some have shown a degree of success albeit on a more limited scale than in animal experiments. Recent demonstrations that pluripotent stem cells, such as embryonic stem cells and induced pluripotent stem cells, can differentiate into a variety of specific neural phenotypes has stimulated worldwide enthusiasm for developing cell-based intervention of neurological disease. Indeed, several groups are preparing investigational new drug applications to treat disorders as diverse as macular degeneration, lysosomal storage diseases, and Parkinson’s disease. It is noteworthy that cell replacement therapies for neurological conditions face key challenges, some of which are unique, because of the development and organization of the nervous system, its metabolism, and connectivity. Choice of the cell (or cells), the process of manufacturing them, defining the delivery pathway, developing and testing in an appropriate preclinical model, selecting a patient population, and visualizing and following or monitoring patients all pose specific issues as related to the central and peripheral nervous systems. In this review, we address a myriad of challenges that are solvable, but require careful planning and attention to the special demands of the human nervous system.     

Expert opinion: guidelines for the use of natalizumab in multiple sclerosis patients previously treated with immunomodulating therapies

Natalizumab (Tysabri) (anti-VLA4) is a novel agent for treatment of relapsing multiple sclerosis (MS) [Polman C.H., O'Connor P.W., Havrdova E. et al., 2006. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N. Engl. J. Med. 354, 899-910.]. Controlled trials have shown considerable efficacy in preventing relapses, in excess of that seen for other EMEA-approved disease modulating drugs. While well-tolerated and generally safe, three cases of progressive multifocal leukoencephalopathy (PML) occurred in the context of 3 clinical trials encompassing some 3300 patients using this drug in multiple sclerosis and Crohn's disease. Immune compromised patients, such as those receiving immunosuppressive medications, are at a higher risk of developing PML. Natalizumab was recently approved for the treatment of relapsing forms of MS. This includes patients who had an inadequate response to other therapies and some of these patients will have already received immunosuppressants. These agents have the potential to cause prolonged effects on the immune system, even after dosing has been discontinued. Determining that these patients are not immunocompromised will be an important safety issue to consider prior to the initiation of natalizumab therapy. This short report summarizes interdisciplinary practical recommendations from specialists in neuroimmunology, rheumatology, transplantation medicine and clinical immunology.     

Glucocorticoids in multiple sclerosis and experimental autoimmune encephalomyelitis

Glucocorticoids exert a variety of immunomodulatory activities. Since changes in glucocorticoid homeostasis impact on susceptibility to autoimmune diseases, and synthetic glucocorticoids are widely used in the treatment of multiple sclerosis, a detailed understanding of their mechanism of action is desirable. Experimental autoimmune encephalomyelitis is a common animal model that mirrors many hallmarks of multiple sclerosis, a chronic inflammatory disease of the CNS with presumed autoimmune origin. Experimental autoimmune encephalomyelitis has been instrumental for many years in studying multiple sclerosis, revealing the blood-brain barrier, the microglia and T-cell apoptosis as major targets of glucocorticoids in this disease. Despite the great advances in the field, the answers to many questions concerning the mechanism of glucocorticoids; for example, the contribution of nongenomic effects or the cell-type specificity of their action, remain elusive. This review will critically discuss what we have learned so far from the analysis of animal models of the molecular mode of therapeutic and endogenous glucocorticoid action in multiple sclerosis. With this knowledge in mind, we should be able to further improve the management of multiple sclerosis using this class of drugs.     

The promise of minocycline in neurology

The capacity of minocycline to alleviate disease for several neurological disorders in animals is increasingly being recognised. Indeed, that one drug alone can attenuate the severity of disease in stroke, multiple sclerosis, spinal-cord injury, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis is astounding. In this review, we describe the evidence for the efficacy of minocycline in several animal models of neurological disease, discuss the mechanisms by which minocycline affects a range of neurological diseases with diverse causes, and introduce the emerging investigation of minocycline in clinical neurology. The encouraging results of minocycline in experimental neurology bode well for its therapeutic use in human neurological diseases.     

Immune response to immunotherapy: the role of neutralising antibodies to interferon beta in the treatment of multiple sclerosis

Interferon beta was the first therapy to be approved for the treatment of relapsing-remitting multiple sclerosis (MS) more than 10 years ago. Interferon beta reduces relapse rates and disease burden and activity, and it may have beneficial effects on the progression of long-term disease disability. The occurrence of neutralising interferon-beta antibodies has been postulated as a possible cause of the failure of interferon beta in some patients with MS. Here we discuss the basic mechanisms that may account for the generation of an interferon-beta antibody response and its biological implications. We review the evidence for neutralising antibodies as a consequence of interferon-beta treatment, and discuss the implications for the treatment of MS. Strategies to assess and manage the long-term impact of neutralising antibodies will be outlined.     

The gap between effect of drugs and effectiveness of treatments

Despite profound effects on the immune system, drugs for multiple sclerosis (MS) therapy have shown only moderate treatment effectiveness. The approved drugs, interferon (IFN)-beta and glatiramer acetate, have a number of effects on the immune system that could interfere with the disease processes in MS but are only able to reduce the relapse rate by 30% and have little or no effect on disease progression. The new targeted immune therapies, campath-1H and natalizumab, have shown immense treatment effectiveness as for inflammation-related disease manifestations, i.e. relapses and MRI activity, but an effect on long-term disease progression has not yet been demonstrated. There are several explanations of the gap between drug effects and treatment effectiveness of which some are related to the properties of the immune system and some are related to the properties of drugs used for treatment of MS. To fill the gap we need to have drugs that both effectively and safely eliminate the inflammation and in addition have neuroprotective properties. However, this may not be obtained from a single drug but may require combinations of drugs with different actions on the disease processes.     

FTY720 (fingolimod) for relapsing multiple sclerosis

FTY720 (fingolimod) is a structural analogue of sphingosine, an endogenous lysophospholipid, which targets sphingosine-1-phosphate receptors after biotransformation to FTY720-phosphate. The immunomodulatory properties of this agent are mainly related to its ability to entrap lymphocytes in secondary lymphoid organs, reducing their availability for cell-mediated immune responses. Emerging evidence suggests that FTY720 also exerts direct actions on glial and precursor cells of the CNS which may be relevant for the process of tissue repair after injury. The therapeutic effects of the drug observed in animal models of human multiple sclerosis have provided the experimental basis for its clinical application. A recent Phase II study has demonstrated that oral FTY720 is effective in reducing disease activity in relapsing multiple sclerosis with a favorable adverse-effect profile. These results are awaiting confirmation in the three ongoing Phase III clinical trials evaluating FTY720 for relapsing-remitting multiple sclerosis.     

The forgotten effects of thyrotropin-releasing hormone: Metabolic functions and medical applications

Thyrotropin-releasing hormone (TRH) causes a variety of thyroidal and non-thyroidal effects, the best known being the feedback regulation of thyroid hormone levels. This was employed in the TRH stimulation test, which is currently little used. The role of TRH as a cancer biomarker is minor, but exaggerated responses to TSH and prolactin levels in breast cancer led to the hypothesis of a potential role for TRH in the pathogenesis of this disease. TRH is a rapidly degraded peptide with multiple targets, limiting its suitability as a biomarker and drug candidate. Although some studies reported efficacy in neural diseases (depression, spinal cord injury, amyotrophic lateral sclerosis, etc.), therapeutic use of TRH is presently restricted to spinocerebellar degenerative disease. Regulation of TRH production in the hypothalamus, patterns of expression of TRH and its receptor in the body, its role in energy metabolism and in prolactin secretion are addressed in this review.     

Direct leukocyte migration inhibition in multiple sclerosis--a possible assessment of activity.

Twenty-four patients with multiple sclerosis were evaluated and classified according to their clinical state. Specific migration inhibition studies were carried out on blood samples from each using myelin basic protein, an acid soluble protein fraction isolated from normal human CNS white matter, and multiple sclerosis myelin basic protein isolated from patients who had the disease, as the antigenic material. This test system employed selected media. Results were compared with those of normal controls and patients with other neurological disease states. Antigen concentration of 500 mu g/ml in serum free medium combined to produce the greatest inhibiting effect on leukocytes in patients with apparent multiple sclerosis and differentiated these patients from those in the other groups tested. Leukocytes in patients who had probable multiple sclerosis with partial impairment, signifying possible current activity of the disease, were especially inhibited as compared to the leukocytes from other groups tested against myelin antigen. Cerebrospinal fluid from affected patients when used as a media enhanced the test. This study suggests that migration inhibition of peripheral leukocytes using myelin protein may be useful in the diagnosis of patients with multiple sclerosis. There is additional evidence that the degree of leukocyte migration inhibition may reflect activity of the disease with its consequent implications on treatment and prognosis.     

Amantadine revisited: an open trial of amantadinesulfate treatment in chronically depressed patients with Borna disease virus infection.

Amantadinesulfate is a well known substance which has proven useful in the treatment and prophylaxis of viral infections, in treating symptoms of Parkinson's disease, cocaine dependence, and apathy in multiple sclerosis. It has also been reported as having mild antidepressive effects not sufficient to warrant its use as an antidepressant. Striking antidepressive effects in some patients have been attributed to its antiviral activity against human Borna disease virus (BDV) infection which is frequently seen in patients with depressive episodes. In this 8 to 12 week open study of oral amantadine in 30 depressed patients with various states of BDV infection we found a significant antidepressive response in 19 of 30. Peripheral BDV antigen indicating acute infection was cleared in both responders and non-responders, but only in responders peripheral infection was significantly reduced.     

Human polyomavirus JCV and expression of myelin genes

Myelin basic protein (MBP) is a major component of the myelin sheath of both the central and peripheral nervous systems. A number of neurological diseases in humans are associated with demyelination of the central and/or peripheral nervous systems, including multiple sclerosis and its variants such as acute disseminated encephalomyelitis (AD), acute hemorrhagic leukoencephalopathy, and idiopathic polyneuritis (Guilliame-Barre syndrome), as well as tropical spastic paraparesis (TSP), and progressive multifocal leukoencephalopathy (PML). Multiple sclerosis (MS) is perhaps the most common demyelinating disease and is one of great importance to the clinical neurologist. The underlying cause of the demyelination seen in multiple sclerosis patients is unknown. However, patients frequently have unusually high antibody titers to a number of common viruses, leading to speculation that viral infections may participate in the pathogenesis of MS. On the other hand, studies on maternal and paternal twins have suggested the involvement of genetic factors in the predisposition of an individual toward developing MS. PML, once a rare demyelinating disease of elderly patients with lymphoproliferative disorders, is now a much more common disease affecting patients of all ages due to the increasingly widespread use of immunosuppressive chemotherapy and the prevalence of AIDS. PML is the result of productive infection of oligodendrocytes, the myelin producing cells of the CNS, with the human polyomavirus, JCV. In this article, we have focused our attention on PML, and the role of JCV in disrupting myelin sheaths by affecting myelin basic gene expression, ultimately leading to demyelination.     

MRI and the diagnosis of multiple sclerosis: expanding the concept of "no better explanation"

Although the diagnosis of multiple sclerosis relies on the demonstration of disease dissemination in space and time, the exclusion of other neurological disorders is also essential. The limited specificity of abnormalities disclosed by MRI may increase the likelihood of diagnosis of multiple sclerosis in patients affected by other disorders. The available criteria for diagnosis of multiple sclerosis have not taken advantage of the potential of MRI to detect features "not suggestive" of multiple sclerosis. Recognition of such features in the work-up of patients suspected of having multiple sclerosis may reduce the likelihood of a false positive diagnosis of the disorder in some, while suggesting the correct alternative diagnosis in other patients. On the basis of this, a workshop of the European MAGNIMS (Magnetic Resonance Network in Multiple Sclerosis) was held to define a series of MRI red flags in the setting of clinically suspected multiple sclerosis that is derived from evidence-based findings and educated guesses. The presence of such red flags should alert clinicians to reconsider the differential diagnosis more extensively. In this review we will report on the conclusions of this international consensus, which should represent a first step beyond the concept of "no better explanation", and inform future diagnostic criteria for multiple sclerosis.     

Magnetic resonance in the diagnosis and treatment of multiple sclerosis

Although the diagnosis of multiple sclerosis is still based on clinical criteria, confirmation by magnetic resonance imaging (MRI) is considered to be essential, thank to its high sensitivity in demonstrating the spatial dissemination of the demyelinating plaques in the brain and spinal cord. Additionally, MRI can establish an approximation of the pathological substrate of the multiple sclerosis plaques and it has proven useful for studying the natural history of the disease and monitoring the effects of new treatments. This capacity of MRI is based on its ability to estimate the degree of demyelination, gliosis, edema, inflammation and axonal damage and to detect diffuse involvement of the normal appearing white matter. The selective identification of the lesions that contribute most to the patient's disability and clinical progression, such as severe demyelination and axonal damage, improves the MRI correlation with the neurological impairment scales. However, a correct application of MRI in the study of multiple sclerosis requires standardization of the techniques and sequences used in the different clinical forms of the disease and of the systems for measuring the lesion load. In this way multiple sclerosis can serve as a true biological marker of the severity of the disease.     

KNS-760704 [(6R)-4,5,6,7-tetrahydro-N6-propyl-2, 6-benzothiazole-diamine dihydrochloride monohydrate] for the treatment of amyotrophic lateral sclerosis

Developing effective treatments for chronic neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) has proven extremely difficult. ALS is universally fatal, characterized by progressive weakness due to the degeneration of upper and lower motor neurons, and leads eventually to respiratory failure which is the usual cause of death. Only a single treatment has been approved, the modestly effective nonspecific neuroprotectant Rilutek (riluzole; 2-amino-6-(trifluoromethoxy)benzothiazole). KNS-760704 [(6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine dihydrochloride, RPPX], a synthetic amino-benzothiazole with demonstrated activity in maintaining mitochondrial function, is being developed as a treatment for ALS. It has proven to be effective in multiple in vitro and in vivo assays of neuroprotection, including the G93A-SOD1 mutant mouse model; however, its specific mechanism of action remains unknown. The potential of KNS-760604 as a treatment for ALS was first suggested by studies showing that its optical enantiomer, Mirapex[(6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine; pramipexole dihydrochloride; PPX], a high-affinity agonist at dopamine D2, D3, and D4 receptors, exhibits important neuroprotective properties independent of its dopamine receptor agonism. In cell-based assays, both RPPX and PPX reduce the production of reactive oxygen species (ROS), attenuate the activation of apoptotic pathways, and increase cell survival in response to a variety of neurotoxins. However, PPX has limited utility as a clinical neuroprotective agent because the drug concentrations required for neuroprotection would likely produce unacceptable dopaminergic side effects. RPPX, on the other hand, while possessing the same neuroprotective potential as PPX, is a much lower-affinity dopamine receptor agonist and may therefore be more useful in the treatment of ALS. This review will examine the data supporting the hypothesis that the RPPX may have therapeutic potential for the treatment of neurodegenerative disorders including ALS. In addition, we will briefly review recent preclinical data in support of RPPX, and discuss the current status of its clinical development.     

Novel roles for Nogo receptor in inflammation and disease

The Nogo receptor (NgR), which was identified as a common receptor for three axon growth inhibitors associated with myelin, has been extensively characterized for its role in triggering growth cone collapse and arresting neurite/axon growth. Recent studies indicate that NgR is also expressed in nonneuronal cells and modulates macrophage responses during inflammation after peripheral nerve injury. In this article, we discuss the possibility that NgR might have wider effects on inflammation in a variety of neurological conditions ranging from central nervous system trauma to diseases such as multiple sclerosis or Alzheimer's disease.