Arachidonic acid (AA) has important physiological roles and is a key mediator of inflammation. Released from membrane glycerophospholipids by cyctosolic phospolipase-A2α (cPLA2α), AA may be further converted to prostaglandins, leukotrienes, lipoxins, and hydroxy-eicosatetraenoic acids by cyclooxygenases (COXs), lipoxygenases (LOs), and terminal enzymes.

It has already been established that cPLA2α plays an important role in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), but the downstream effectors have remained elusive. Collaborators from Tokyo, Kyushu and Osaka Universities have now conducted a targeted analysis of the AA cascade in the spinal cords of naïve and EAE mice using transcriptomics and lipidomics. The lipidomics study identified constitutive generation of eicosanoids in the spinal cords of naïve mice, predominantly via the cyclooxygenase (COX) pathway, with prostaglandin-D₂ (PGD₂) and metabolites favoured. In EAE lesions, however, levels of prostaglandin-E₂ (PGE₂) and metabolites were increased while PGD₂ decreased. The researchers then examined microsomal PGE synthase-1 (mPGES-1), a key enzyme involved in the production of PGE₂ in inflammation. Their findings suggest that PGE₂ levels in the spinal cords of EAE mice are dependent on mPGES-1 expressed in macrophages/microglia. In addition, the clinical course of EAE was less severe in mPGES-1^-/- mice.

Although there are currently no known, effective inhibitors of rodent mPGES-1, a potent and selective inhibitor of the human enzyme, MF63, was reported last year. In that study MF63 suppressed PGE₂ production, pyresis and inflammatory pain in a knock-in mouse expressing human mPGES-1.

The authors of the present study, published in PNAS, also examined autopsy brain tissues obtained from MS patients. In agreement with the data in murine EAE, immunohistochemistry on MS lesions revealed the overt expression of mPGES-1 protein in CD68⁺ macrophages. These data suggest that human MS pathology also appears to be influenced by the mPGES-1/PGE₂ axis of the AA cascade and that inhibition of mPGES-1 may have utility in the treatment of MS.

The neuropeptide galanin is widely distributed in the nervous system and levels are known to increase dramatically in response to injury. Galanin and galanin receptors have recently been shown to be overexpressed in some brain areas of people with Alzheimer’s disease and researchers at the University of Bristol have now shown that galanin is also upregulated in microglia from lesions and shadow plaques in multiple sclerosis sufferers as well as in oligodendrocytes from mice with EAE, an experimental form of the disease. To investigate whether the increased levels of galanin were modulating disease activity, the team monitored the development of EAE in wild type (WT) mice, galanin knockout (Gal-KO) mice, mice over-expressing galanin (Gal-OE) and mice expressing a mutated form of the galanin receptor-2 (GalR2-Mut). It was found that Gal-OE mice were completely resistant to the development of clinical symptoms whilst Gal-KO mice developed clinical disease earlier than WT mice and GalR2-Mut mice developed more severe disease than WT mice and at an earlier time point. The study clearly shows the importance of galanin in limiting disease severity in mice with EAE and suggests that GalR2 agonists, if these could be identified, may be of benefit to MS patients. The study is published in the August 26^th online edition of PNAS.

The renin-angiotensin system (RAS) was first studied for its role in regulation of the cardiovascular system and drugs that modulate the RAS are now widely used to treat high blood pressure, myocardial infarction and stroke. More recently, it has become apparent that components of the RAS also mediate inflammatory processes and two recently published studies have now expanded on the link between the RAS and multiple sclerosis (MS). A team led by researchers at Stanford University School of Medicine found that multiple sclerosis lesions from brains of MS patients had elevated levels of both the angiotensin I receptor (AT₁R) and angiotensin converting enzyme (ACE). The team then showed that treatment with the ACE inhibitor, lisinopril, or the AT₁R antagonist, candesartan, could prevent the development of experimental autoimmune encephalomyelitis (EAE) in mice and, perhaps more importantly, reverse the symptoms of established disease. Reduced activation of AT₁R was shown to increase the number of T_reg cells in the CNS and suppress TH1/TH17-mediated immune responses to autoantigens.

The study is published in the online early edition of PNAS.

The second study, by researchers in Germany and also published in the online early edition of PNAS, showed that renin, ACE and AT₁R were all up-regulated in the inflamed spinal cord and immune system, including antigen presenting cells (APC), of mice with EAE. Pretreatment with the renin inhibitor, aliskiren; the ACE inhibitor, enalapril; or the AT₁R antagonist, losartan, reduced the severity of EAE symptoms and losartan was also found to ameliorate the course of established disease. Blockade of AT₁R was found not to have a direct effect on T-cell responses but to significantly reduce APC in the spinal cord and immune organs, and to reduce cytokine-induced APC migration.

Since drugs that modulate the RAS have been used in millions of people around the world and have few side effects, the researchers hope that clinical trials to test their effectiveness in MS patients should be straightforward to carry out.

Multiple sclerosis (MS), an autoimmune disease that results in damage to oligodendrocytes which maintain insulating myelin sheaths around nerve fibres in the central nervous system, is the most common disabling neurological disorder affecting young adults. The inflammatory process in MS is initiated by T-cells which recognise myelin as ‘foreign’ and attack it as if it were an invading virus. Disease-modifying agents are now available to treat MS but these are not effective for all patients and advanced forms of MS remain difficult to treat. Analysis of tissue samples from MS patients has revealed that two pathways more usually associated with blood pressure regulation – the renin-angiotensin system and the kallikrein-kinin system – are altered compared with samples from normal subjects.

A team led by researchers in Berlin have now shown that the bradykinin B1 receptor specifically controls infiltration of immune cells into the CNS. In the mouse EAE model of MS, activating the B1 receptor resulted in reduced disease severity whereas blocking the receptor led to more rapid disease onset. The protective effect of the B1 receptor was found to be mediated by its expression on T-cells. In an in vitro model of CNS penetration, a B1 receptor agonist, R838, considerably reduced the number of migrated T-cells and additional application of a B1 antagonist, R715, restored migration. Analysis of immune cells from the CNS of mice with EAE revealed that, in mice lacking the B1 receptor, the proportion of infiltrating CD4⁺ T-cells was increased and, significantly, the proportion of T_H17 cells – believed to be crucial for autoimmune neuroinflammation – was also greater. The study suggests that the B1 receptor acts as an endogenous modulator of recruitment of pathogenic lymphocytes into the CNS and limits harmful immune responses. The authors hope that selective B1 receptor agonists could one day play a role in the management of chronic inflammatory diseases such as MS.

The study is published in the journal Nature Medicine.

The axons of nerve cells are sheathed by an insulating layer of myelin which is made up of about 80% lipid and 20% protein. Demyelination, leading to impaired or lost conduction of signals along the nerve, is a hallmark of multiple sclerosis (MS). In relapsing-remitting MS myelin can be replaced but, after repeated attacks, the repair system becomes less efficient. Researchers at the University of Medicine and Dentistry of New Jersey have now identified a key pathway which regulates the production of new oligodendrocytes – the myelin-producing cells of the CNS – and the production of myelin. They found that activation of the mammalian target of rapamycin (mTOR) is essential for oligodendrocyte differentiation at the late progenitor to immature oligodendrocyte transition. The effects were found to be mediated via two distinct signalling complexes, mTORC1 and mTORC2. mTORC2 was found to control myelin gene expression at the mRNA level whereas mTORC1 influenced expression of myelin basic protein via an alternative mechanism.

Although it remains to be determined whether stimulation of the mTOR pathway or removal of some inhibitory mechanism would be most appropriate, allowing the pathway to function normally could provide new treatments for MS and other demyelinating diseases.

The study is published in the May 13th online edition of the Journal of Neuroscience.

Approved in 1995, glatiramer acetate (Copaxone®, copolymer-1) is a disease-modifying drug that has been demonstrated to reduce the relapse rate and progression of disability in relapsing-remitting multiple sclerosis (RRMS) patients. The compound is a mixture of synthetic peptides (50-90 amino acids) composed of alanine, glutamic acid, lysine and tyrosine. Originally developed to mimic myelin basic protein, a major component of the neuronal myelin sheath, it was intended for use as an inducer of experimental autoimmune encephalitis (EAE). The unexpected inhibition of EAE that was observed with glatiramer acetate led to clinical trials and subsequent approval for RRMS.

The efficacy of glatiramer acetate has been ascribed to an effect on the adaptive immune response, shifting towards a Th2 polarisation of myelin-specific T-cells. Further studies have demonstrated an immunomodulatory effect on monocytes, macrophages and dendritic cells. However, the full mechanistic picture is still unclear.

Collaborating scientists from the University of Geneva, Technische Universität München and University of California, San Francisco, have now demonstrated an effect of glatiramer acetate on the IL-1 system. Their research has shown that treatment with the polymer increases blood levels of secreted IL-1 receptor antagonist (sIL-1Ra), a natural inhibitor of IL-1β, both in RRMS patients and in EAE mice. In the same subjects, levels of IL-1β were undetectable. Additional in vitro experiments with T-cell contact-activated monocytes, a model relevant to chronic inflammation, showed that glatiramer acetate strongly reduced expression of IL-1β, whilst enhancing expression of sIL-1Ra. This is in contrast to effects in monocytes subjected to acute inflammatory conditions (stimulation with LPS), where glatiramer acetate increased production of both sIL-1Ra and IL-1β. The authors conclude that the effects on the IL-1 system in chronic inflammatory conditions contribute to the therapeutic effects of glatiramer acetate in RRMS.

The study is published in the online early edition of the journal PNAS.

Multiple sclerosis (MS) is an auto-immune disease in which the myelin sheaths surrounding nerve fibres are destroyed. The disease affects millions of people worldwide and can lead to loss of sight and mobility as well as depression, fatigue and problems with cognition. There is currently no cure, and few truly effective treatments.

A study published in the New England Journal of Medicine describes the results of a randomized, blinded, phase II clinical trial examining the effects of alemtuzumab in patients with previously untreated, early, relapsing-remitting multiple sclerosis. Alemtuzumab is a humanized monoclonal antibody that targets the CD52 receptor on lymphocytes and monocytes and is prescribed for the treatment of chronic lymphocytic leukemia and T-cell lymphoma. Patients with scores of 3.0 or less on the Expanded Disability Status Scale and disease duration of 3 years or less were assigned to receive either subcutaneous interferon β-1a, (44 µg) three times per week, or annual intravenous cycles of alemtuzumab (either 12 mg or 24 mg per day) for 36 months. Interferon β-1a is one of the most effective licensed therapies for similar cases of MS. Alemtuzumab therapy was suspended in September 2005 after immune thrombocytopenic purpura developed in three patients, one of whom died. Treatment with interferon β-1a continued for the full duration of the study.

Alemtuzumab treatment was found to significantly reduce the rate of sustained accumulation of disability by 71% and the annualized rate of relapse by 74% compared with interferon β-1a treatment. Importantly, the mean disability score on a 10-point scale improved by 0.39 point in the alemtuzumab group and worsened by 0.38 point in the interferon β-1a group. The lesion burden was also reduced in the alemtuzumab group compared with the interferon β-1a group and, from month 12 to month 36, brain volume increased in the alemtuzumab group but decreased in the interferon β-1a group.

The incidence of side effects was somewhat higher in the alemtuzumab group compared with the interferon β-1a group. Adverse events included thyroid disorders (23% vs 3%), immune thrombocytopenic purpura (3% vs 1%) and infections (66% vs 47%). There were no significant differences in outcomes between the 12-mg dose and the 24-mg dose of alemtuzumab.

Multiple sclerosis (MS) is a disorder of the central nervous system with initial inflammation of the protective myelin sheath encasing nerve fibres. Symptoms vary widely and often occur initially as discrete episodes interspersed with relatively symptom-free periods (relapsing MS).

A drug currently being tested for its effectiveness in treating relapsing forms of MS is now to be tested to see whether it can prevent the disease from developing. The drug, cladribine, will be given orally to patients who have a first clinical event suggestive of MS. Patients will be treated for two years, or up to the time when they experience a second attack leading to a definite clinical diagnosis of MS. Treatment will be given in two or four cycles in the first year, with a single daily dose of cladribine tablets being given on four to five consecutive days in each cycle. This means that patients in the study will take cladribine for only 8 – 20 days in the first year. In the second year, two treatment cycles will be given to all patients.

Cladribine is also used as an intravenous infusion to treat hairy cell leukemia, chronic lymphocytic leukemia, and non-Hodgkin’s lymphomas.

A drug that is being developed to treat multiple sclerosis (MS) by damping down the immune system may also have the potential to treat viral infections. A study published in the journal, Nature, showed that mice treated with the drug FTY-720 (fingolimod) were able to clear a viral meningitis infection that persisted in untreated mice.

It is, at first sight, surprising that a drug developed to suppress the immune response in MS patients can help to fight a viral infection.

FTY720-P is an agonist of the sphingosine-1-phosphate receptor and causes lymphopenia by preventing egress of lymphocytes from the lymph nodes. The new finding builds on the observation that more easily cleared strains of the virus also cause lymphocytes to become sequestered in lymph nodes. The reason why trapping circulating lymphocytes allows a more robust response to infection is not clear, but may be linked to the fact the lymph nodes are where the immune response is primed. Clearance of the virus does not occur when CD4 T cells are absent at the time of treatment, indicating that the drug is not exerting direct antiviral effects. Some viruses, including HIV, replicate at high levels in lymph nodes and the team plan to test the effect of FTY720 on infection with other viruses.

FTY720 is currently in Phase III clinical trials to test its safety and efficacy as a disease modifying therapy for relapsing-remitting MS.