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Review
.2022 May 12;23(10):5390.
doi: 10.3390/ijms23105390.

Roles of the Unsaturated Fatty Acid Docosahexaenoic Acid in the Central Nervous System: Molecular and Cellular Insights

Affiliations
Review

Roles of the Unsaturated Fatty Acid Docosahexaenoic Acid in the Central Nervous System: Molecular and Cellular Insights

Ana B Petermann et al. Int J Mol Sci..

Abstract

Fatty acids (FAs) are essential components of the central nervous system (CNS), where they exert multiple roles in health and disease. Among the FAs, docosahexaenoic acid (DHA) has been widely recognized as a key molecule for neuronal function and cell signaling. Despite its relevance, the molecular pathways underlying the beneficial effects of DHA on the cells of the CNS are still unclear. Here, we summarize and discuss the molecular mechanisms underlying the actions of DHA in neural cells with a special focus on processes of survival, morphological development, and synaptic maturation. In addition, we examine the evidence supporting a potential therapeutic role of DHA against CNS tumor diseases and tumorigenesis. The current results suggest that DHA exerts its actions on neural cells mainly through the modulation of signaling cascades involving the activation of diverse types of receptors. In addition, we found evidence connecting brain DHA and ω-3 PUFA levels with CNS diseases, such as depression, autism spectrum disorders, obesity, and neurodegenerative diseases. In the context of cancer, the existing data have shown that DHA exerts positive actions as a coadjuvant in antitumoral therapy. Although many questions in the field remain only partially resolved, we hope that future research may soon define specific pathways and receptor systems involved in the beneficial effects of DHA in cells of the CNS, opening new avenues for innovative therapeutic strategies for CNS diseases.

Keywords: CNS tumors; DHA; GPR40; cell survival; docosahexaenoic acid; neural morphology; synaptic function.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
DHA roles in the CNS. Schematic representation of the main roles of DHA on the CNS, including structural, physiological, and therapeutic effects. Detailed information about these roles is properly developed on each section of this review.
Figure 2
Figure 2
DHA signaling pathways in neuron survival, morphology, and synaptic function. (A) DHA can promote neuron survival by different mechanisms, including the induction of cAMP response element-binding (CREB) and nuclear factor erythroid 2-related factor 2 (NRF2) pathways, or apoptosis inhibition by reducing the activities of caspase-3 and caspase-8. (B) Regarding neural morphology, DHA can trigger the activation of retinoid X receptor (RXR) and the G-protein coupled receptor GPR40/FFAR1, which can increase intracellular calcium by activation of Gq/PLC/IP3 or by activation of the tyrosine kinase Trk-B receptor (Trk-B-R) by its activator, brain-derived neurotrophic factor (BDNF), with subsequent activation of the CREB pathway. This latter axis can also be activated by the DHA metabolite DEA (synaptomide), which induces a GPR110-mediated increase in cAMP levels. (C) The effects of DHA and DEA on synaptic function include the expression of synaptic proteins, such as postsynaptic receptors or scaffolding proteins (left scheme), which lead to an enhancement of synaptic communication (middle scheme). Additionally, DHA exert a direct effect on ion channels, modulating their gating properties (right scheme). Whether DEA is also able to modulate the activity of ion channels is unknown.
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