Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) in which T lymphocytes, macrophages, and antibodies are believed to be involved in disease pathogenesis1-2
. Although the cause of MS is unknown, there is general agreement that MS results from an acquired immune-dysregulation and aberrant activation leading to T cell driven inflammatory processes in the CNS that result in demyelination and axonal damage. About 85% of patients begin with a relapsing-remitting clinical course in which there are relapses or attacks of MS lasting days to weeks followed by improvement and stability lasting months to years. About 50% of patients with relapsing-remitting MS (RRMS) develop secondary progressive MS in which there is progressive worsening of the disease. Although there are heterogeneous mechanisms to disease pathology, active inflammatory processes in the CNS are more highly associated with RRMS than with the progressive types of MS3
Current pharmacological therapies for MS include: interferon beta, glatiramer acetate, natalizumab, and mitoxantrone. These are immunomodulatory therapies and act by altering the T cell driven inflammatory processes in the CNS4-7
. In large randomized, double-blind, placebo-controlled trials, these therapies decrease the frequency and severity of relapses and have a modest effect on lengthening time to disability4-9
. Although the availability of these therapies has improved the disease course in MS, they all require injection rather than an oral route of administration and there are significant side effects which include, injection site reactions, flu-like symptoms, and muscle aches10
. A subset of MS patients produce anti-interferon-beta neutralizing antibodies in response to interferon beta (IFN-beta) therapy which decreases the effectiveness of this therapy and can increase the risk of subsequent relapses in these patients11
. The high cost of MS immunomodulatory therapies, which can cost $25,000 or more per year, may prohibit their use in some patients. Considering the limitations of current MS immunomodulatory therapies, identifying a cost effective oral therapy that has the potential to alter the MS disease course with minimal side effects is warranted.
The immunomodulatory effects of omega-3 fatty acids have been well documented. Numerous studies have reported a decrease in protein levels of inflammatory cytokines including, tumor necrosis factor- α (TNF-α), interferon- γ (IFN-γ), interleukin-1 (IL-1), interleukin-2 (IL-2), and vascular cell adhesion molecule-1 (VCAM-1)12
. Omega-3 fatty acids (omega-3 FA) have been evaluated in a number of inflammatory diseases such as rheumatoid arthritis and multiple sclerosis with proven benefit13, 14
. In an open-label study (n=20 MS and 15 healthy participants), Gallai et al. found a significant decrease from baseline, in the levels of interleukin-1β (p<0.03), TNF-α (p<0.02), IL-2 (p<0.002), and IFN-γ (p<0.01) produced from unstimulated and stimulated peripheral blood mononuclear cells (PBMC) after 3-months of omega-3 FA supplementation containing 3.0 grams/day of eicosapentaenoic acid (EPA) and 1.8 grams/day docosahexaenoic acid (DHA)15
. Weinstock-Guttman et al. conducted a double-blind, placebo-controlled study in RRMS patients (n=31) and found a significant improvement in quality of life (physical and mental health components) favoring participants receiving a low saturated fat diet and omega-3 FA supplementation at six months. This study also examined changes in plasma inflammatory cytokine levels and found no difference between groups16
. The difference in outcomes on inflammatory cytokine levels between these two studies may reflect differences in the concentrations of EPA and DHA evaluated (Weistock-Guttman et al. evaluated a lower concentration than Gallai et al.) and differences in cytokine measures (plasma versus immune cell secreted). Despite these differences, both studies reported positive effects of omega-3 FA supplementation in MS.
In addition to the omega-3 FA effect on decreasing proinflammatory cytokines levels, there is evidence supporting an omega-3 FA effect in decreasing matrix metalloproteinase (MMP) levels. There are a number of published in vitro studies that report a significant omega-3 FA effect in decreasing genetic expression, protein levels, and activity of MMP-2, -3, -9, -1317-19
. One in vitro study reports a significant and dose-dependent decrease in MMP-9 protein levels secreted from LPS activated microglial cells that were incubated with either fish oil or an omega-3 FA mixture (53% EPA and 27% DHA)20
In MS, MMP-9 is thought to have a significant role in the transmigration of inflammatory cells into the CNS by aiding in the disruption of the blood brain barrier21
. Several studies have reported higher MMP-9 levels in MS subjects when compared to control subjects22-24
. RRMS patients are reported to have an increase in immune cell expression of MMP-9 (measured by messenger ribonucleic acid (mRNA) levels), compared to healthy controls25
. Interferon beta has the ability to inhibit MMP-9 levels produced from T-lymphocytes and CD4+ T cells26-28
which is thought to be one mechanism by which this therapy acts to alter the disease course23
. To date the immunomodulatory effects of omega-3 FA on MMP-9 levels in MS patients have not been evaluated.
The primary objective of the present study was to evaluate the ability of omega-3 FA supplementation in decreasing MMP-9 protein levels secreted from peripheral blood mononuclear cells (PBMC) and from serum in RRMS.