Docosahexaenoic acid protects motor function and increases dopamine synthesis in a rat model of Parkinson's disease via mechanisms associated with increased protein kinase activity in the striatum.

Parkinson's disease (PD) is a devastating neurodegenerative disease that leads to motor deficits and selective destruction of nigrostriatal dopaminergic neurons. PD is typically treated by dopamine replacement agents; however, dopamine replacement loses effectiveness in the later stages of the disease. Here, we describe the neuroprotective effects of the omega-3 fatty acid docosahexaenoic acid (DHA) in the medial forebrain bundle 6-hydroxydopamine (6-OHDA) model of advanced-stage PD in rats. We show that daily administration of DHA protects against core symptoms of PD, including deficits in postural stability, gait integrity, and dopamine neurochemistry in motor areas of the striatum. Our results also demonstrate that DHA increases striatal dopamine synthesis via phosphorylation of the rate-limiting catecholamine synthesizing enzyme tyrosine hydroxylase, in a manner dependent on the second messenger-linked protein kinases PKA and PKC. We also show that DHA specifically reverses dopamine loss in the nigrostriatal pathway, with no effect in the mesolimbic or mesocortical pathways. This suggests that DHA is unlikely to produce pharmacotherapeutic or adverse effects that depend on dopamine pathways other than the nigrostriatal pathway. To our knowledge, previous reports have not examined the effects of DHA in such an advanced-stage model, documented that the dopamine synthesizing effects of DHA in vivo are mediated through the activation of protein kinases and regulation of TH activity, or demonstrated specificity to the nigrostriatal pathway. These novel findings corroborate the beneficial effects of omega-3 fatty acids seen in PD patients and suggest that DHA provides a novel means of protecting patients for dopamine neurodegeneration.

Omega-3 Fatty Acids as Druggable Therapeutics for Neurodegenerative Disorders.

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.

Free-fatty acid receptor-4 (GPR120): Cellular and molecular function and its role in metabolic disorders.

Over the last decade, a subfamily of G protein-coupled receptors that are agonized by endogenous and dietary free-fatty acids (FFA) has been discovered. These free-fatty acid receptors include FFA2 and FFA3, which are agonized by short-chained FFA, as well as FFA1 and FFA4, which are agonized by medium-to-long chained FFA. Ligands for FFA1 and FFA4 comprise the family of long chain polyunsaturated omega-3 fatty acids including α-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), suggesting that many of the long-known beneficial effects of these fats may be receptor mediated. In this regard, FFA4 has gathered considerable interest due to its role in ameliorating inflammation, promoting insulin sensitization, and regulating energy metabolism in response to FFA ligands. The goal of this review is to summarize the body of evidence in regard to FFA4 signal transduction, its mechanisms of regulation, and its functional role in a variety of tissues. In addition, recent endeavors toward discovery of small molecules that modulate FFA4 activity are also presented.

Fish oil and flax seed oil supplemented diets increase FFAR4 expression in the rat colon.

BACKGROUND AND OBJECTIVE: Omega-3 fatty acids, such as α-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), are polyunsaturated fatty acids (PUFA) that have long been associated with anti-inflammatory activity and general benefit toward human health. Over the last decade, the identification of a family of cell-surface G protein-coupled receptors that bind and are activated by free-fatty acids, including omega-3 fatty acids, suggest that many effects of PUFA are receptor-mediated. One such receptor, free-fatty acid receptor-4 (FFAR4), previously described as GPR120, has been shown to modulate anti-inflammatory and insulin-sensitizing effects in response to PUFA such as ALA and DHA. Additionally, FFAR4 stimulates secretion of the insulin secretagogue glucagon-like peptide-1 (GLP-1) from the GI tract and acts as a dietary sensor to regulate energy availability. The aim of the current study was to assess the effects of dietary omega-3 fatty acid supplementation on FFAR4 expression in the rat colon. METHODS: Sprague-Dawley rats were fed control soybean oil diets or alternatively, diets supplemented with either fish oil, which is enriched in DHA and EPA, or flaxseed oil, which is enriched in ALA, for 7 weeks. GLP-1 and blood glucose levels were monitored weekly and at the end of the study period, expression of FFAR4 and the inflammatory marker TNF-α was assessed. RESULTS: Our findings indicate that GLP-1 and blood glucose levels were unaffected by omega-3 fatty acid supplementation, however, animals that were fed fish or flaxseed oil-supplemented diets had significantly heightened colonic FFAR4 and actin expression, and reduced expression of the pro-inflammatory cytokine TNF-α compared to animals fed control diets. CONCLUSIONS: These results suggest that similar to ingestion of other fats, dietary-intake of omega-3 fatty acids can alter FFAR4 expression within the colon.

A novel phenylaminotetralin radioligand reveals a subpopulation of histamine H(1) receptors.

Previously, (-)-trans-1-phenyl-3-N,N-dimethylamino-1,2,3,4-tetrahydronaphthalene ([-]-trans-H(2)-PAT) was shown to activate stereospecifically histamine H(1) receptors coupled to modulation of tyrosine hydroxylase activity in guinea pig and rat forebrain in vitro and in vivo. Furthermore, the novel radioligand [(3)H](-)-trans-H(2)-PAT was shown to label selectively H(1) receptors in guinea pig and rat brain with high affinity (K(D), ~0.1 and 0.5 nM, respectively) and a B(max) about 50 and 15%, respectively, of that observed for the H(1) antagonist radioligand [(3)H]mepyramine. In the current study, [(3)H](-)-trans-H(2)-PAT-labeled cloned guinea pig and human H(1) receptors in Chinese hamster ovary (CHO) cell membranes with high affinity (K(D), ~0.08 and 0.23 nM, respectively) and a B(max) about 15% of that observed for [(3)H]mepyramine. The binding of H(2)-PAT to H(1) receptors in both CHO-H(1) cell lines was stereoselective with the (-)-trans-isomer having affinity (K(i), ~1.5 nM) about 4-, 20-, and 50-times higher than the (-)-cis-, (+)-trans-, and (+)-cis-isomers, respectively; the affinity of (-)-trans-H(2)-PAT was unaffected by excess GTP. In functional assays, (-)-trans-H(2)-PAT was a full antagonist of histamine H(1)-mediated stimulation of phospholipase C (PLC) and [(3)H]inositol phosphates (IP) formation in CHO-H(1) cells, a full inverse agonist of constitutively active H(1) receptors in COS-7-H(1) cells, and a full competitive antagonist (pA(2) = 9.2) of histamine H(1)-mediated contraction of guinea pig ileum. It is concluded that (-)-trans-H(2)-PAT is an antagonist at H(1) receptors coupled to PLC/IP formation and smooth muscle contraction. Meanwhile, the observation that [(3)H](-)-trans-H(2)-PAT labels only a subpopulation of H(1) receptors and that (-)-trans-H(2)-PAT activates H(1) receptors coupled to modulation of tyrosine hydroxylase suggests that there may be post-translational H(1) receptor heterogeneity.