Omega-3 fatty acids-physiological function
Although omega-3 fatty acids have not been directly linked with bruxism, they have been highly implicated in anxiety and emotional mood disorders (159), as well as in neuroinflammation and neurodegeneration (159-162). They are esterified into phospholipids in the sn-2 position of the cell membrane (160), playing a key role in the structure and function of the brain cell membrane. Overwhelming evidence signifies their involvement in hippocampal development and synaptic function (162).
Omega-3 fatty acids may be found in numerous brain regions, but more abundantly in the prefrontal cortex, hippocampus and hypothalamus (163). They have been classified into n-6 polyunsaturated fatty acids (PUFA) and n-3 PUFA, with their main metabolites being arachidonic acid and docosahexaenoic acid (DHA), respectively. The free forms of PUFA are transformed into specific derivatives, such as eicosanoids, specialized proresolving mediators (SPM) and endocannabinoids (eCBs), which strongly regulate inflammation (160). The eCBs are lipids produced by the membrane's fatty acids after neuronal stimulation and bind to cytochrome P450 carbonyl reductase 1(164). Activation of this receptor causes an inhibition in glutamate and GABA release from presynaptic neurons (165). Regulation of eCBs in the brain by PUFA has a strong impact on hippocampal synaptic plasticity and in eCB-dependent plasticity (166), while CB1-associated signaling pathways in the prefrontal cortex (PFC) and N.Acc are also affected. Another signaling pathway, GPR120, which functions as an omega-3 fatty acid receptor, signals DHA activity that is highly prominent in the hypothalamus and N.Acc (167), areas that are closely linked to the pathogenesis of anxiety and bruxism, as discussed earlier.
Consequences of omega-3 fatty acid insufficiency. As these substances cannot be synthesized, they can only be obtained through diet (168). However, in Western civilizations, there is a shift in the consumption of fatty acids towards n-6 and less towards n-3(169), resulting in an imbalance between the two types that is associated with serious consequences, as described below. A decrease in plasma DHA for 49 consecutive days has been shown to cause a 5% DHA reduction in the brain, with the prefrontal cortex and hippocampus being more sensitive (160). DHA, in particular, has been shown to influence neurite growth, synaptogenesis, synapsin and glutamate receptor subunit levels, as well as synaptic activity in hippocampal neurons. This has been supported by in vitro studies demonstrating impaired long-term potentiation, shorter neurites, fewer branches, and fewer synapsin-positive puncta in DHA-deficient cultures, while DHA supplementation appears to restore neurite growth and synaptogenesis (162).
Implication of omega-3 fatty acid deficiency in stress. Animal studies have also shown that n-3 PUFA deficiencies induce emotional and neuronal disturbances through adrenal activation that resemble those observed after social defeat stress (161,170,171). Similar to chronic stress, HPA hyperactivity, due to a reduction in CB1 receptor function, invokes a marked increase in corticosterone levels. This action, in combination with a disturbance in the GR-mediated signaling pathway, leads to neuronal atrophy of the PFC by means of pyramidal neuron arborization atrophy. The GR signaling pathway and its downstream target bone-derived neurotrophic factor have a crucial role in neuroplasticity (161,172). As discussed earlier, chronic stress exposure, as well as stress induced by DHA deficiency, eventually cause hippocampal degeneration and attenuation of the mesocortical dopaminergic tract (namely the vSub-VP-N.Acc pathway), whilst at the same time activating the BLA-VP-N.Acc pathway that induces rhythmic jaw activity and possibly bruxism.
Oxidative stress causes NO production, which activates microglia. The latter are glial cells of myeloid origin, important in maintaining brain homeostasis and in protecting nerve cells (173). Activation of microglia causes further production of NO and ROS, leading to neuroinflammation (174). DHA deficiency induces abnormal microglial activation through changes in their membrane fluidity and the modulation of several proinflammatory transcription factors (175). These changes are gender- and area-dependent. Adult females have more microglia than males in the paraventricular nucleus of the hypothalamus, amygdala and hippocampus, particularly in the dentate gyrus (175), which has a crucial role in controlling the HPA axis. This is probably the reason why females appear to be more vulnerable to stress and more prone to bruxism.
Effects of omega-3 supplementation. In vitro evidence has highlighted that application of eicosapentaenoic acid (EPA) on microglial cultures inhibits the production and expression of inflammatory enzymes, such as NO synthase and COX-2, as well as the production of proinflammatory cytokines (IL-1β, IL-6 and TNF-α) (174). Levine et al (176) demonstrated that application of EPA plus DHA increases microglial autophagy, an important process for the homeostasis of immune cells that are able to diminish inflammatory processes. Another SPM form of DHA, Neuroprotectin D1, seems to protect the brain from leukocyte infiltration, reducing cyclooxygenase-2 expression, cytokine production and microglia activation (177). An in vivo study by Lynch et al (178) reported that omega-3 supplementation, and particularly EPA, significantly reduced marker expression of microglial activation and production of IL-1β by microglia, while at the same time, there was an increase in anti-inflammatory IL-4 expression. In neuropathic pain and retina degeneration models, N-3 PUFA supplementation was shown to cause a reduction in microglial density/activation, which can be linked to reduced neuroinflammation (179,180).
In a study by Ferraz et al (159), it was concluded that supplementation of PUFAs to animals under restrained stress was able to counteract the anxiolytic effects by suppressing the HPA axis and reducing the plasma corticosterone levels. It was also shown that there is an increase in serotonin and dopamine levels particularly in the hippocampus, both of which constitute actions that further promote an increase in the brain-derived neurotrophic factor and synaptophysin expression, as well as hippocampal neurogenesis. Similar results were obtained in humans, as shown by Kiecolt-Glaser et al (181), where supplementation of EPA and DHA in medical students for 12 weeks appeared to successfully reduce the release of IL-6 and anxiety symptoms compared to controls.
Finally, noteworthy findings have also been obtained in individuals with morning headaches, a common symptom in bruxists. Morning headaches usually exhibit the characteristics of migraine (182). Numerous hypotheses have been made regarding the mechanism of their genesis, with oxidative stress and activation of the trigeminovascular pathway being the two most prevalent (183). In this context, the role of CGRP has been highlighted both as a mediator and a potential therapeutic target (184). First of all, the release of CGRP has also been shown to be regulated by oxylipin receptors in the trigeminal nerve endings and central pain processing pathways (185,186). Furthermore, a recent study by Marchetti et al (184) showed that supplementation of PUFAs at a ratio of 1.5 omega-6/1 omega-3 induced a marked reduction in migraine symptoms, frequency and pain intensity; the explanation given by the authors was that EPA, DHA and their SPM activate innate and adaptive immune systems, remove ROS, and inhibit COX-2 and NF-κB intracellular signaling pathways. Table I summarizes the main characteristics of the nutrients discussed in this section and evidence that highlights their potential implication in the etiopathogenesis of bruxism.