Omega 3 Fatty Acids: Novel Neurotherapeutic Targets for Cognitive Dysfunction in Mood Disorders and Schizophrenia?

Abstract

An increasing body of evidences from preclinical as well as epidemiological and clinical studies suggest a potential beneficial role of dietary intake of omega-3 fatty acids for cognitive functioning. In this narrative review, we will summarize and discuss recent findings from epidemiological, interventional and experimental studies linking dietary consumption of omega-3 fatty acids to cognitive function in healthy adults. Furthermore, affective disorders and schizophrenia (SZ) are characterized by cognitive dysfunction encompassing several domains. Cognitive dysfunction is closely related to impaired functioning and quality of life across these conditions. Therefore, the current review focues on the potential influence of omega-3 fatty acids on cognition in SZ and affective disorders. In sum, current data predominantly from mechanistic models and animal studies suggest that adjunctive omega-3 fatty acid supplementation could lead to improved cognitive functioning in SZ and affective disorders. However, besides its translational promise, evidence for clinical benefits in humans has been mixed. Notwithstanding evidences indicate that adjunctive omega-3 fatty acids may have benefit for affective symptoms in both unipolar and bipolar depression, to date no randomized controlled trial had evaluated omega-3 as cognitive enhancer for mood disorders, while a single published controlled trial suggested no therapeutic benefit for cognitive improvement in SZ. Considering the pleiotropic mechanisms of action of omega-3 fatty acids, the design of well-designed controlled trials of omega-3 supplementation as a novel, domain-specific, target for cognitive impairment in SZ and affective disorders is warranted.

Fig. (1)

Molecular structures of the two precursors for omega-3 and omega-6 fatty acids: alpha-Linolenic acid (ALA) and Linolenic acid (LA).

Fig. (2)

Metabolic pathways of n-3 and n-6 PUFAs and their resulting eicosanoids with main functions. Abbreviations: COX: cyclooxygenases, LOX: lipoxygenases, HETEs: hydroxyeicosatetraenoic acids, HPETE: hydroperoxyeicosatetraenoic acids, LTB4: leukotriene B4.

Fig. (3)

Omega-3 fatty acids enhance BDNF synthesis and signalling in neurons and also influence cannabinoid-mediated synaptic plasticity. (A) BDNF binds cognate TrKB receptors and activates PLC-γ, ERK/MAPK and Akt/PKB intracellular signalling pathways. Activation of PLC-γ leads to the release of calcium from the endoplasmatic reticulum and to the activation of CAMKII, which phosphorylates CREB and activates gene transcription. Activation of ERK/MAPK pathway also regulates transcription through CREB phosphorylation, whereas PI3K phosphorylates and activates Akt/PKB and mTOR, regulating translation. DHA enhances neurotrophic signalling by the PI3K/Akt BDNF signal transduction pathway. DHA also activates the MAPK pathway; activated MAPK then phosphorylates CREB which translocates into the nucleus and activates BDNF gene transcription. (B) Endocannabinoids (eCBs) are signalling lipids produced from PUFAs present in membrane phospholipids. PUFAs are released from the postsynaptic membrane by phospholipase A2 (PLA2) in response to neuronal activation. eCB released in the synaptic cleft can bind presynaptic cannabinoid receptor type 1 (CB1) on the presynaptic neuron. Activation of CB1 leads to inhibition of neurotransmitter release and synaptic activity. In rodents that are fed a n3-PUFA enriched diet, such eCB-mediated long-term depression (LTD) is inhibited at excitatory synapses, whereas rodents fed a diet chronically low in n-3 PUFAs has this form of eCB-mediated synaptic plasticity specifically interrupted. Abbreviations: BDNF- brain-derived neurotrophic factor; CAMKII- Calciumcalmodulin kinase II; CREB- cAMP-response element-binding protein; DHA-Docosahexaenoic acid; n-3-n-3 PUFAs; ERK- extracellularsignal- regulated kinases; MAPK- Mitogen-activated protein kinases; PI3K- Phosphoinositide 3-kinase; Akt/PKB- Protein kinase B; mTORMechanistic target of rapamycin.