Omega-3 Fatty Acids as Druggable Therapeutics for Neurodegenerative Disorders

Abstract

: Neurodegenerative disorders are commonly associated with a complex pattern of pathophysiological hallmarks, including increased oxidative stress and neuroinflammation, which makes their treatment challenging. Omega-3 Fatty Acids (O3FA) are natural products with reported neuroprotective, anti-inflammatory, and antioxidant effects. These effects have been attributed to their incorporation into neuronal membranes or through the activation of intracellular or recently discovered cell-surface receptors (i.e., Free-Fatty Acid Receptors; FFAR). Molecular docking studies have investigated the roles of O3FA as agonists of FFAR and have led to the development of receptor-specific targeted agonists for therapeutic purposes. Moreover, novel formulation strategies for targeted delivery of O3FA to the brain have supported their development as therapeutics for neurodegenerative disorders. Despite the compelling evidence of the beneficial effects of O3FA for several neuroprotective functions, they are currently only available as unregulated dietary supplements, with only a single FDA-approved prescription product, indicated for triglyceride reduction. This review highlights the relative safety and efficacy of O3FA, their drug-like properties, and their capacity to be formulated in clinically viable drug delivery systems. Interestingly, the presence of cardiac conditions such as hypertriglyceridemia is associated with brain pathophysiological hallmarks of neurodegeneration, such as neuroinflammation, thereby further suggesting potential therapeutic roles of O3FA for neurodegenerative disorders. Taken together, this review article summarizes and integrates the compelling evidence regarding the feasibility of developing O3FA and their synthetic derivatives as potential drugs for neurodegenerative disorders.

Pharmacological intervention in a transgenic mouse model improves Alzheimer's-associated pathological phenotype: Involvement of proteasome activation

“…Specifically, it has been demonstrated that n-3 fatty acid supplementation is able to improve AD-associated brain pathology in several transgenic mouse models of AD, including 5xFAD mice, to reduce amyloid plaque burden and to improve learning and memory [ 44 , 45 , 115 - 117 ]. The majority of the beneficial properties of PUFAs have been attributed to their reported neuroprotective, anti-inflammatory, and antioxidant effects [ 118 ] and specifically to their capability to change the composition of cell membranes, replacing cholesterol and promoting the non-amyloidogenic pathway of APP processing, thus decreasing the Aβ burden. Herein, we identify a previously unknown effect of n-3FAs on cellular proteostasis, namely through the conformational activation of the proteasome.…”

Nutrition-Based Approaches in Clinical Trials Targeting Cognitive Function: Highlights of the CTAD 2020

“…The effects of omega-3 polyunsaturated fatty acids (PUFA) on fighting inflammation and oxidative stress are well stablished in literature ( 1 , 2 ). Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), mainly, have been shown to have neuroprotective abilities through both vascular and neuronal mechanisms ( 3 , 4 ), being associated with reduced white matter hyperintensities (WMH) accumulation and delayed neurodegeneration ( 5 , 6 ). In this sense, trials based on omega-3 PUFA supplementation have been developed.…”

A simple and efficient metric quantifying druggable property of chemical small molecules

“…Chemical small molecules (CSMs) represent a big class of drugs which mainly function by binding with disease related target molecules [2]. Given the huge space of target molecules and CSMs, evaluating the druggable potential of both targets [3][4][5][6] and CSMs [7][8][9][10][11] is thus one of the hearts of drug discovery. For CSMs, it is known that a number of drug related properties (druggable properties) affect their druggable potential, for example human intestinal absorption, blood-brain barrier penetration [12], and some pharmacokinetic properties [13].…”