Armando Sena

Therapeutic potential of lovastatin in multiple sclerosis

Sirs: In the last few years many studies have demonstrated that statins, in addition to their lipidlowering effects, have anti-inflammatory and immunomodulatory properties [1]. These properties of statins have suggested that they could have beneficial effects in immune mediated neurological disorders [2, 3]. In particular, lovastatin has been shown to inhibit the induction of inducible nitric oxide synthase and proinflammatory cytokines in rat astrocytes, microglia and macrophages [2] and to repress MHC-II mediated T-cell activation [3]. Moreover, lovastatin treatment decreased neuroinflammatory activity and clinical signs in experimental allergic encephalomyelitis, an animal model for multiple sclerosis (MS) [4]. On the basis of these findings we have begun to investigate whether lovastatin could be a treatment option for MS patients. We report the results observed on seven patients with the relapsing-remitting MS after 12 months of therapy with lovastatin. The study was designed as a one-center, open-label non placebo-controlled trial. All the subjects were recruited and treated on an outpatient basis, at the MS clinic of the Neurology Service of a general hospital. None of the patients was on any immunossuppressive or immunomodulating therapy and none received these agents during lovastatin treatment. The study was approved by the ethical committee of our Hospital and a written informed consent was provided from all patients. Our cohort consisted in women (age between 24 and 45 years) with a mean disease duration of 4.61 ± 2.16 years and clinical evidence of disease activity as measured by at least two relapses within the previous 2 years. Each subject was treated with 20 mg of lovastatin per day for one month and the dose was increased to 40 mg per day if no adverse effects were noted. A clinical examination and hematology and biochemical tests (including the plasma lipid profile and creatine kinase) were performed at baseline and every 3 months. Brain MRI was performed at baseline and every 6 months. During the follow-up, all clinical evaluations were done without knowledge of the neuroradiological results. No adverse events associated with therapy were observed. Our results (Table) show that the Kurtzke Expanded Disability Status Scale (EDSS) score was unchanged in 6 patients and improved one point in another patient after treatment. Three patients were free of relapses during therapy and for the whole group the mean annual relapse rate decreased during this period. In four patients there was a reduction of the inflammatory activity of the disease after treatment in comparison to baseline, as assessed by the number of gadolinium (Gd)-enhanced T1 lesions on MRI. One patient did not have active lesions at baseline and two enhanced lesions were seen at the end of the study. In five patients, the number of lesions on T2-weighted images increased after treatment. Lower post-treatment total cholesterol levels provide evidence of compliance with therapy. The results from this short pilot LETTER TO THE EDITORS

Lipid composition in liver and brain of genetically obese (ob/ob), heterozygote (ob/+) and normal (+/+) mice

Lipid composition was studied in liver and brain of normal (+/+), heterozygote (ob/+) and obese (ob/ob) mice. It was found that this genetic defect is expressed differently in the lipid composition of these organs. Cholesterol is increased in liver but strongly decreased in brain of obese animals. Phosphatide fatty acid composition is modified in liver and not in brain. In contrast, phospholipids and total ganglioside sialic acid are affected similarly in both organs. Although clinically normal, heterozygote (ob/+) mice already show an abnormal lipid composition in liver and brain. The potential importance of these results is presented.

Interferon β1a Therapy Changes Lipoprotein Metabolism in Patients with Multiple Sclerosis

Abstract To assess whether interferon β1a (IFNβ1a) therapy affects plasma lipoprotein metabolism, twelve patients with relapsing-remitting multiple sclerosis (MS) were studied during a two-year follow-up period. High density lipoprotein (Hdl2) cholesterol and the Hdl2/Hdl3 ratio were increased at year 2 and lipoprotein (a) was transitorily increased at year 1, in comparison to baseline levels. Apolipoprotein A-I was lower and apolipoprotein E higher at year 1, only in a subgroup of patients who experienced relapses and/or progressed during therapy. These findings suggest that IFNβ1a treatment is associated with changes in the lipoprotein metabolism. Alterations in this metabolism could be related to the immunomodulatory actions of the drug and the disease activity in multiple sclerosis patients.

Plasma Lipoproteins in Brain Inflammatory and Neurodegenerative Diseases

Functions of the central nervous system (CNS) are mainly performed by neurons and glial cells (astrocytes, oligodendrocytes and microglia). Microglia or microcytes have macrophage-like immune related functions; oligodendrocytes are the myelinating cells in the CNS; and astrocytes have diverse roles in synaptogenesis, neurotransmission, myelination and reactive mechanisms to injury. CNS tissue is separated from blood circulation by specialized cell barriers, the most extensive being the endothelium of the socalled blood-brain barrier (BBB).

Natalizumab Treatment Modulates Peroxisome Proliferator-Activated Receptors Expression in Women with Multiple Sclerosis

Peroxisome Proliferator-Activated Receptors (PPAR) are transcription factors suggested to be involved in inflammatory lesions of autoimmune encephalomyelitis and multiple sclerosis (MS). Our objective was to assess whether Natalizumab (NTZ) therapy is associated with alterations of PPAR expression in MS patients. We analyzed gene expression of PPAR in peripheral blood mononuclear cells (PBMC) as well as blood inflammatory markers in women with MS previously medicated with first-line immunomodulators (baseline) and after NTZ therapy. No differences in PPARα, PPARβ/δ, PPARγ, and CD36 mRNA expression were found in PBMC between patients under baseline and healthy controls. At three months, NTZ increased PPARβ/δ mRNA (p = 0.009) in comparison to baseline, while mRNA expression of PPARγ and CD36 (a well-known PPAR target gene) was lower in comparison to healthy controls (p = 0.026 and p = 0.028, resp.). Although these trends of alterations remain after six months of therapy, the results were not statistically significant. Osteopontin levels were elevated in patients (p = 0.002) and did not change during the follow-up period of NTZ treatment. These results suggest that PPAR-mediated processes may contribute to the mechanisms of action of NTZ therapy.

Metabolic Dysfunction and Peroxisome Proliferator-Activated Receptors (PPAR) in Multiple Sclerosis

Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system (CNS) probably caused, in most cases, by the interaction of genetic and environmental factors. This review first summarizes some clinical, epidemiological and pathological characteristics of MS. Then, the involvement of biochemical pathways is discussed in the development and repair of the CNS lesions and the immune dysfunction in the disease. Finally, the potential roles of peroxisome proliferator-activated receptors (PPAR) in MS are discussed. It is suggested that metabolic mechanisms modulated by PPAR provide a window to integrate the systemic and neurological events underlying the pathogenesis of the disease. In conclusion, the reviewed data highlight molecular avenues of understanding MS that may open new targets for improved therapies and preventive strategies for the disease.

No association of multiple sclerosis activity and progression with EBV or tobacco use in BENEFITAuthor Response

We read with interest the article by Munger et al.1 The authors were incorrect that “(only) one study among patients with multiple sclerosis (MS) has found no association between smoking and progression, …”1 In a study of 205 women with MS of 5-year mean duration, we also found no association between smoking and progression.2 Nevertheless, this work suggested that APOE …

Contribution to the Study of the Lipid Constitution in Liver and Brain Homogenates of Mice Genetically Obese

Lipid composition was compared in liver and brain from genetically obese (ob/ob), heterozygote (ob/+) and normal (+/+) mice. In liver, but not in brain, a constitution favoring a “rigidification” of the membranes was found in (ob/ob) mice. In both organs a decrease of the total ganglioside sfalic acid concentration was observed. These results could be related to the reduced number of insulin receptors in (ob/ob) mice hepatocytes and to a different behaviour of their brain receptors. In addition, they suggest that an abnormal complex carbohydrate metabolism involving gangliosides may exist in this syndrome.