Omega-3 Essential Fatty Acids Modulate Initiation and Progression of Neurodegenerative Disease

Abstract

The significance of the selective enrichment in omega-3 essential fatty acids in photoreceptors and synaptic membranes of the nervous system has remained, until recently, incompletely understood. While studying mechanisms of cell survival in neural degeneration, we discovered a docosanoid synthesized from unesterified docosahexaenoic acid (DHA) by a 15-lipoxygenase (15-LOX), which we called neuroprotectin D1 (NPD1; 10R,17S-dihydroxy-docosa-4Z,7Z,11E,13E,15E,19Z hexaenoic acid). This lipid mediator is a docosanoid because it is derived from the 22 carbon (22C) precursor DHA, unlike eicosanoids, which are derived from the 20 carbon (20C) arachidonic acid (AA) family member of essential fatty acids. We discovered that NPD1 is promptly made in response to oxidative stress, as a response to brain ischemia-reperfusion, and in the presence of neurotrophins. NPD1 is neuroprotective in experimental brain damage, in oxidative-stressed retinal pigment epithelial (RPE) cells, and in human brain cells exposed to amyloid-beta (Abeta) peptides. We thus envision NPD1 as a protective sentinel, one of the very first defenses activated when cell homeostasis is threatened by imbalances in normal neural function. We provide here, in three sections, recent experimental examples that highlight the specificity and potency of NPD1 spanning beneficial bioactivity during initiation and early progression of neurodegeneration: (1) during retinal signal phototransduction, (2) during brain ischemia-reperfusion, and (3) in Alzheimer's disease (AD) and stressed human brain cell models of AD. From this experimental evidence, we conclude that DHA-derived NPD1 regulation targets upstream events of brain cell apoptosis, as well as neuro-inflammatory signaling, promoting and maintaining cellular homeostasis, and restoring neural and retinal cell integrity.

Evolutionary alteration of ALOX15 specificity optimizes the biosynthesis of antiinflammatory and proresolving lipoxins

“…Genomic LOX sequences occur in two domains (Bacteria, Eukarya) of terrestrial life (3). In mammals, LOXs have been implicated in the biosynthesis of lipid mediators (4,5), but they may also play a role in cell differentiation (6,7), apoptosis (8) and pathogenesis of inflammatory (9), hyperproliferative (10), and neurological (11) disorders. Targeted gene inactivation in mice provided useful information on the functionality of Alox12B (12R-lipoxygenase) (12) and Aloxe3 (epidermal lipoxygenase-3) (13), but Alox5 (5-lipoxygenase)- (14), Alox15- (15), and Alox12-deficient mice (16) do not show major defects unless challenged otherwise.…”

Supplementation of omega 3 fatty acids improves oxidative stress in activated BV2 microglial cell line

“…DHA is not merely a structural membrane component but also a modulator of crucial neurochemical processes, gene expression, synaptic plasticity, memory formation and intracellular calcium concentration (Calder, 2009;Crawford, 2006;McNamara & Carlson, 2006;Sergeeva et al, 2005). In addition, similarly to what was observed in a number of inflammatory based systemic disorders, DHA and its peroxidated (cyclopentenone neuroprostanes) or enzymatically generated (neuroprotectins and resolvins) derivatives display potent antiinflammatory functions in psychiatric disorders as well as in acute and chronic neurodegenerative conditions (Bazan, 2006;Belayev et al, 2011;Calder, 2009;Ebert et al, 2009;Groeger et al, 2010;Musiek et al, 2008;Palacios-Pelaez et al, 2010).…”

Unsaturated Fatty Acids and Pain

“…7) Moreover, clinical studies found therapeutic effects of n-3 PUFAs against the risk of cardiovascular events, attention deficit hyperactivity disorder, 8) Alzheimer's disease, 9) depression, 10,11) and various other degenerative neurological disorders. 12) Thus, it has become apparent that n-3 PUFAs are involved in a variety of physiological functions.…”