Objectives
The objective of the research proposal is to identify components of flax, specifically alpha linolenic acid (ALA), that may be beneficial in preventing myelin sheath damage.
Project Description
Multiple sclerosis (MS) is a chronic, debilitating neurodegenerative condition. Canada, and in particular Saskatchewan, has one of the highest rates of MS in the world. Neurological deficits associated with MS result from the loss of myelin, the fatty sheath surrounding axons of the central nervous system (CNS). In the CNS, this myelin sheath is made by oligodendrocytes (OLs). Disease progression in MS typically involves repeated rounds of demyelinating insults followed by remyelination; remyelination is often incomplete. This leads to impaired neurotransmission, and ultimately neurodegeneration. There are three components of Flax that have potential neuro-protective properties: alpha linolenic acid (ALA), vitamin E and secoisolariciresinol (SECO). Based on literature supporting a role for polyunsaturated fatty acids (PUFAs) in proper brain function, our initial studies have focused on the role of ALA in mitigating myelin damage in animal models of MS.
In the early 1950s, dietary fatty acid intake was proposed as a factor affecting regional differences for MS prevalence. The main dietary PUFAs are either from the Omega 6 (n-6) or Omega 3 (n-3) series, denoting the position of the double bond from the methyl end of the fatty acid. Linoleic acid (LA; 18:2n-6) and alpha linolenic acid (ALA; 18:3n-3) are the essential dietary PUFAs as they cannot be synthesized in the body and are the building blocks for the bioactive long-chain PUFAs. Given the competition between the n-3 and n-6 families for biochemical pathways, the optimal dietary intake between n-6:n-3 fatty acids is thought to be 1-2:1 whereas the typical western diet contains 10:1. There is much speculation about the benefit of a high PUFA diet for MS, but a dearth of quantitative information on the impact of n-3 and n-6 PUFAs on myelination in the CNS.
Lipids comprise ~70% of the myelin sheath with over 700 unique species being identified. Due to high lipid content and role as a protective barrier, the myelin sheath is highly susceptible to oxidation. Oxidative stress has been shown to precede the onset of inflammation in MS and in experimental models of demyelination. Omega-3 fatty acids appear to be important in regulating oxidative stress levels: PUFAs can act as antioxidants and supplementation has beneficial effects on lipid peroxidation and antioxidant enzyme status. Docosahexaenoic acid (DHA; 22:6n-3) and eicosapentaenoic acid (EPA; 20:5n-3), the most abundant n-3 PUFAs in the brain, have been shown to promote resolution of neuroinflammation, act as a neurotrophins, modulate synaptic plasticity and inhibit cell death. Dietary ALA is equally effective in increasing levels of these long-chain n-3 PUFAs in the brain through biosynthesis, as direct dietary uptake. The overall objective of this research project was to identify components of flax that may be neuroprotective. Our working hypothesis is that ALA protects against myelin sheath damage and promotes myelin repair through antioxidant, anti-inflammatory and neurotrophic mechanisms. We propose that an ALA-enriched diet, which promotes optimal DHA and EPA levels in the brain, will decrease the extent of demyelination and increase remyelinaton efficiency compared to an LA-enriched diet.
We have made significant advances in determining a role for a main component of Flaxseed oil, alpha linolenic acid (ALA), in mitigating myelin degeneration. Initial studies using ex vivo organotypic cultures indicate that ALA both protects against demyelinating insults and promotes myelin repair. A manuscript is in preparation, and we anticipate publishing these results in early 2017. ALA may act in a number of ways to mitigate damage to the myelin sheath: (i) decrease cellular oxidative stress, (ii) inhibit inflammatory signaling cascades and (iii) support metabolic processes for cell survival and differentiation. Future studies will also focus on understanding the biological activity of PUFAs that promote brain health. To our knowledge, this is the first strong evidence showing a direct link between ALA and protection of the myelin sheath.
Furthermore, we have begun studies to determine the optimal dietary intake of ALA, in combination with other PUFAs, to protect against myelin degeneration in vivo. A Collaborative Innovation Development Grant from Saskatchewan Health Research Foundation has allowed us to move forward with a 1 year pilot project. With the nutritional expertise of Drs. Phyllis Paterson (University of Saskatchewan) and Richard Bazinet (University of Toronto), three PUFA rodent diets have been developed using Flaxseed oil to alter the n-6:n-3 composition in the brain. Phase I of the study has been completed, and phase II will be initiated in October 2016. Experiments have also initiated with Dr. Bogdan Popescu (Cameco MS Research Center, University of Saskatchewan) using synchrotron-based imaging techniques to investigate elemental and biochemical alterations in the brain associated with oxidative stress in our rodent diets. We kindly request that SaskFlax consider contributing an additional $10 000 towards the cost of Flaxseed oil diets for our SHRF-funded pilot project. These high-quality, nutritionally-balanced custom diets – including rigorous analysis of fatty acid composition by GC-FID/GC-MS at each stage: source oils, diets and brain tissue – come with a significant price tag. This additional support from SaskFlax will allow us to maximize our research findings together with the limited SHRF funds for cutting-edge biochemical analysis of tissue (i.e. synchrotron-imaging, gene expression qPCR arrays).
These studies provide a foundation to establish a role for ALA in preventing neuro-degeneration and to establish design parameters for optimizing nutritional benefits. Nutrition is a critical factor in complementary and alternative medicine (CAM) strategies which can be implemented in a relatively short time period and will reduce healthcare costs associated with chronic disease. The long-term objective is to translate this research to a clinical setting – guide nutritional counseling, impact patient care and improve the quality of life for individuals with MS. It may also have broader implications for clinical practice, as degeneration of the myelin sheath has become a prominent feature of many other neurological conditions (i.e. Alzheimer’s disease). Our hope is to continue to build on our findings and partner with SaskFlax to secure additional sources of funding for the development of Flax-based therapies. The research presented here will allow us to write strong grant proposals from national health research funding agencies, such as Canadian Institutes of Health Research (CIHR) and the Multiple Sclerosis Society of Canada (MSSOC), in the 2016-2017 competitions.
