[Treatment options in painful diabetic polyneuropathy]. / Therapieoptionen der schmerzhaften diabetischen Polyneuropathie.

Distal symmetrical polyneuropathy is the most frequent manifestation of diabetic neuropathy and crucially contributes to the development of diabetic foot and subsequent amputation in 70 to 80% of all cases. In 10 to 15% of affected patients considerable pain is present, in particular in early diabetic polyneuropathy. This review summarizes evidence based data on prevention, neuroregenerative, and symptomatic treatment of painful diabetic polyneuropathy. The most important clinical trials on treatment and prevention are presented. Conclusions from these clinical studies in particular detailed treatment recommendations including dosage and side effects are given. Combined treatments and escalating therapies for severe pain syndromes are discussed.

IVIG therapy in neurological disorders of childhood.

There is growing evidence that intravenous immunoglobulins (IVIG) are effective in some neuroimmunological disorders of childhood. This short review summarizes the evidence-based indications and recommendations of IVIG therapy in these disorders. Despite considerable efforts to define the role and mechanisms of IVIG, more clinical studies are needed to further explore the therapeutic potential of IVIG in childhood diseases of the nervous system and muscle.

Multiple sclerosis: Mitoxantrone promotes differential effects on immunocompetent cells in vitro.

Mitoxantrone is an anti-neoplastic anthracenedione derivative that, based on its immunosuppressive properties, is approved for the treatment of severe forms of relapsing-remitting or secondary progressive multiple sclerosis (MS). Whether the beneficial clinical effects of mitoxantrone in MS are due to a broad immunosuppression, or whether there is a specific mechanism of action remains unknown. Peripheral blood mononuclear cells (PBMCs) from untreated or interferon-beta-treated patients with MS or from healthy donors were stimulated in the presence or absence of mitoxantrone. Irrespective of the source of the cells and the cellular phenotype, mitoxantrone inhibited proliferation of activated PBMCs, B lymphocytes, or antigen-specific T-cell lines (TCLs) stimulated on antigen-presenting cells (APCs) in a dose-dependent manner. For functional analysis, TCLs or APCs were incubated separately with mitoxantrone. Pre-incubation of APC more effectively impaired TCL proliferation than pre-incubation of TCLs. Production of cytokines, expression of activation markers, matrix metalloproteinases, and chemokine receptors were not influenced substantially by mitoxantrone. In contrast, in dendritic cells (DCs), mitoxantrone interfered with the antigen-presenting capabilities. For evaluation of apoptotic cell death of target cells, annexin-V-conjugates and a DNA fragmentation assay were applied. Mitoxantrone induced apoptosis of PBMCs, monocytes and DCs at low concentrations, whereas higher doses caused cell lysis. Our observations suggest that the beneficial effects of mitoxantrone in MS result (i) from its immunosuppressive action based on nonspecific cytotoxic effects on lymphocytes, (ii) by inducing programmed cell death of professional APCs, such as DCs.

Putative mechanisms of action of statins in multiple sclerosis--comparison to interferon-beta and glatiramer acetate.

Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase and are widely prescribed as cholesterol-lowering agents. They are promising candidates for future treatment in multiple sclerosis (MS) as they have been shown to exhibit immunomodulatory effects. Recent reports have demonstrated that statins are effective in preventing and reversing chronic and relapsing experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Furthermore, in vitro experiments with human immune cells have documented an immunomodulatory mode of action of statins comparable to that of interferon (IFN)-beta. An open label clinical trial assessing simvastatin in MS revealed a significant decrease in the number and volume of new MRI lesions and a favourable safety profile. This article reviews data thus far present on the putative mechanisms of action of statins in the immunopathogenesis of MS. Furthermore, the role of statins as potential pharmacotherapy for MS is discussed in the context of the mechanisms of approved immunotherapies in MS, namely IFN-beta and glatiramer acetate (GA).

Different effects of simvastatin and interferon beta on the proteolytic activity of matrix metalloproteinases.

BACKGROUND: Interferon beta and statins are known to exert immunomodulatory actions by inhibiting gene transcription and translation of various proinflammatory molecules. Although interferon beta represents a mainstay in therapy for multiple sclerosis (MS), statins are considered a potential new approach in treating MS. OBJECTIVE: To investigate the effect of interferon beta and statins on the posttranslational activity of matrix metalloproteinases (MMPs) released from mononuclear cells in vitro that were obtained from patients with MS and healthy donors. DESIGN: Blood samples from 10 patients with a relapsing-remitting course of MS and 5 matched healthy individuals were studied. Peripheral blood mononuclear cells were isolated and stimulated with an antibody to CD3, phytohemagglutinin, or medium alone as a negative control. Proteolytic activity was investigated in the supernatants by means of sodium dodecyl sulfate-polyacrylamide gel electrophoresis zymography in which gels were incubated with interferon beta or simvastatin during development. Zones of gelatin digestion were visualized and quantified. RESULTS: Incubation with interferon beta resulted in an inhibition of the gelatinolytic activity of MMP-9 and MMP-2. In contrast, simvastatin enhanced the proteolytic capacity of MMP-2 and MMP-9, with a statistically significant increase of MMP-2 activity when compared with findings in controls. There were no differences in the enzymatic response between patients with MS and healthy individuals. CONCLUSIONS: Interferon beta exhibits inhibitory effects at the posttranslational level of MMP activity, whereas simvastatin augments the proteolytic activity of MMP-2 and MMP-9, suggesting that statins exert anti-inflammatory and proinflammatory effects. This dual mechanism of action should be considered, given the recent interest in developing these drugs for treatment of MS.

Tau protein and 14-3-3 are elevated in the cerebrospinal fluid of patients with multiple sclerosis and correlate with intrathecal synthesis of IgG.

Recently it has been shown that axonal damage occurs in all stages of multiple sclerosis (MS) and can be detected very early in the course of the disease. Axonal pathology has been related to the inflammatory demyelinating environment, but its dependence on inflammation is still unknown. We measured tau protein and 14-3-3, two intracellular proteins expressed in neurons and glial cells, in the cerebrospinal fluid (CSF) of 114 patients with MS, in 79 patients with other inflammatory neurological diseases (IND) and in the CSF of 60 patients with non-inflammatory neurological diseases (NIND) as controls. Concentrations of tau protein and 14-3-3 were measured by enzymelinked immunoassay and were correlated to the following immune parameters in the CSF: leukocyte cell count, total protein, albumin CSF/serum ratio as a marker of disruption of the blood-brain barrier, immunoglobulin (IgG concentrations and IgG index as an indicator for intrathecal synthesis of IgG in the CSF). Both in MS and IND tau protein levels were significantly higher than in NIND (p<0.05). In MS patients levels of tau protein were positively correlated with the IgG index (p<0.05) and this association was present in both relapsing remitting MS (RRMS) (p<0.05) and progressive MS (p<0.05). Tau and 14-3-3 were also correlated with the IgG index in patients with IND (p<0.05). These findings strengthen the hypothesis that inflammation may be at least in part responsible for the axonal damage observed in MS patients.

Comparative proteomics of the Mycobacterium leprae binding protein myelin P0: its implication in leprosy and other neurodegenerative diseases.

Mycobacterium leprae, the causative agent of leprosy invades Schwann cells of the peripheral nerves leading to nerve damage and disfigurement, which is the hallmark of the disease. Wet experiments have shown that M. leprae binds to a major peripheral nerve protein, the myelin P zero (P0). This protein is specific to peripheral nerve and may be important in the initial step of M. leprae binding and invasion of Schwann cells which is the feature of leprosy. Though the receptors on Schawann cells, cytokines, chemokines and antibodies to M. leprae have been identified the molecular mechanism of nerve damage and neurodegeneration is not clearly defined. Recently pathogen and host protein/nucleotide sequence similarities (molecular mimicry) have been implicated in neurodegenerative diseases. The approach of the present study is to utilise bioinformatic tools to understand leprosy nerve damage by carrying out sequence and structural similarity searches of myelin P0 with leproma and other genomic database. Since myelin P0 is unique to peripheral nerve, its sequence and structural similarities in other neuropathogens have also been noted. Comparison of myelin P0 with the M. leprae proteins revealed two characterised proteins, Ferrodoxin NADP reductase and a conserved membrane protein, which showed similarity to the query sequence. Comparison with the entire genomic database (www.ncbi.nlm.nih.gov) by basic local alignment search tool for proteins (BLASTP) and fold classification of structure-structure alignment of proteins (FSSP) searches revealed that myelin P0 had sequence/structural similarities to the poliovirus receptor, coxsackie-adenovirus receptor, anthrax protective antigen, diphtheria toxin, herpes simplex virus, HIV gag-1 peptide, and gp120 among others. These proteins are known to be associated directly or indirectly with neruodegeneration. Sequence and structural similarities to the immunoglobin regions of myelin P0 could have implications in host-pathogen interactions, as it has homophilic adhesive properties. Although these observed similarities are not highly significant in their percentage identity, they could be functionally important in molecular mimicry, receptor binding and cell signaling events involved in neurodegeneration.

Comparative proteomics of the Mycobacterium leprae binding protein myelin P0: its implication in leprosy and other neurodegenerative diseases

Mycobacterium leprae, the causative agent of leprosy invades Schwann cells of the peripheral nerves leading to nerve damage and disfigurement, which is the hallmark of the disease. Wet experiments have shown that M. leprae binds to a major peripheral nerve protein, the myelin P zero (P0). This protein is specific to peripheral nerve and may be important in the initial step of M. leprae binding and invasion of Schwann cells which is the feature of leprosy. Though the receptors on Schawann cells, cytokines, chemokines and antibodies to M. leprae have been identified the molecular mechanism of nerve damage and neurodegeneration is not clearly defined. Recently pathogen and host protein/nucleotide sequence similarities (molecular mimicry) have been implicated in neurodegenerative diseases. The approach of the present study is to utilise bioinformatic tools to understand leprosy nerve damage by carrying out sequence and structural similarity searches of myelin P0 with leproma and other genomic database. Since myelin P0 is unique to peripheral nerve, its sequence and structural similarities in other neuropathogens have also been noted. Comparison of myelin P0 with the M. leprae proteins revealed two characterised proteins, Ferrodoxin NADP reductase and a conserved membrane protein, which showed similarity to the query sequence. Comparison with the entire genomic database (www.ncbi.nlm.nih.gov) by basic local alignment search tool for proteins (BLASTP) and fold classification of structure-structure alignment of proteins (FSSP) searches revealed that myelin P0 had sequence/structural similarities to the poliovirus receptor, coxsackie-adenovirus receptor, anthrax protective antigen, diphtheria toxin, herpes simplex virus, HIV gag-1 peptide, and gp120 among others. These proteins are known to be associated directly or indirectly with neruodegeneration. Sequence and structural similarities to the immunoglobin regions of myelin P0 could have implications in host-pathogen interactions, as it has homophilic adhesive properties. Although these observed similarities are not highly significant in their percentage identity, they could be functionally important in molecular mimicry, receptor binding and cell signaling events involved in neurodegeneration.

Mycobacterium leprae binds to a major human peripheral nerve glycoprotein myelin P zero (P0).

We have previously shown that a major phosphorylated 25-kDa glycoprotein of the human peripheral nerve binds to Mycobacterium leprae. In the present study, we confirm that the 25-kDa glycoprotein of the human peripheral nerve is myelin P zero (P0) by immunoprecipitation and Western blot experiments using monoclonal antibodies to myelin P0. Immunohistochemical studies on human nerve using these antibodies to myelin P0 exhibited a strong immunoreactivity to the myelin and Schwann cells. Myelin P0 is a peripheral nerve specific protein; therefore it could likely be one of the key target molecules for M. leprae binding/internalization or even contact-dependent demyelination. This finding of M. leprae binding to myelin P0 adds to the present understanding on neural predilection of M. leprae.

Prevalence of autoimmune thyroiditis and non-immune thyroid disease in multiple sclerosis.

Since multiple sclerosis (MS) and autoimmune thyroiditis (AIT) are presumed to be of autoimmune origin the correlation of these two diseases is of special interest. The aim of this study was to determine whether there are differences in the prevalence of thyroid disease with special emphasis on AIT compared with MS and normal subjects and whether the presence of thyroid disease correlates with disability, disease course, age, and disease duration. 353 consecutive patients with clinically definite MS, without interferon-beta treatment and 308 patients with low back pain or headache were extensively examined for the presence of non-immune or autoimmune thyroid disease. We found a significantly higher prevalence of AIT in male MS patients (9.4 %) than in male controls (1.9 %; p = 0.03). The prevalence of AIT in female MS patients (8.7 %) did not differ from female controls (9.2 %). Hypothyroidism, caused by AIT in almost all cases, showed a tendency to be more severe and more often present in patients with MS. There was no association between relapsing-remitting and secondary progressive disease course of MS and the prevalence of AIT. MS patients with AIT were significantly older but did not differ in disease duration and expanded disability status scale (EDSS). Further studies are warranted, to see if there is a difference in sex-hormone levels between MS patients with and without AIT and healthy controls. Longitudinal studies comparing MS patients with or without AIT could show whether there is an influence of AIT on the disease course or progression.

Immunomodulation in multiple sclerosis: from immunosuppression to neuroprotection.

Multiple sclerosis (MS) is the most common disabling neurological disease of young adulthood. Following advances in the understanding of the immunological mechanisms that underlie the pathogenesis of MS, a growing arsenal of immunomodulatory agents is available. Two classes of immunomodulators are approved for long-term treatment of MS, the efficacy of several promising new concepts is being tested in clinical trials and classical immunosuppressive agents used in MS treatment have been shown to exert specific, immunomodulatory effects. Furthermore, two recent observations have changed our basic understanding of the pathogenesis of MS. First, immune cells in MS lesions have neuroprotective activity, which indicates a beneficial role of neuroinflammation. Second, there is evidence that axonal loss, rather than demyelination, underlies the progression of MS and, hence, constitutes a therapeutic target.