Eicosapentaenoic acid (EPA) is an essential nutrient and an omega-3 from the family of polyunsaturated fatty acids (PUFAs). Since the human body cannot synthesize PUFAs, dietary supplements containing EPA are needed to support certain normal physiological functions. Found abundantly in natural sources such as fish, hemp oil, and flaxseed oil, EPA is known for its anti-inflammatory, neuroprotective, and cardiovascular activities.
Recent studies have demonstrated the effects of EPA in reducing mortality following myocardial infarction (heart attack), improving insulin resistance, reducing blood lipid levels and inhibition of platelet aggregation. Omega-3 PUFAs have also been shown to decrease inflammatory responses following COVID-19 infection.
Despite the broad spectrum of its therapeutic effects, the molecular target(s) and underlying mechanism of action of EPA remain elusive.
Deciphering the mechanism of action of EPA
The Japanese team led by Takaaki Miyaji identifies a new molecular target of EPA: “Given that EPA significantly attenuates inflammatory and neuropathic pain, there is a strong possibility that there is an important molecular target of EPA linked to neuropathy”. Researchers reveal that eicosapentaenoic acid reduces pain by inhibiting vesicular nucleotide transporter-mediated release of adenosine triphosphate (ATP).
Specifically, the study identifies the vesicular nucleotide transporter as a novel target of eicosapentaenoic acid (EPA) and highlights the mechanism underlying the analgesic effect of EPA.
- During neurological, metabolic and immunological disturbances, “purinergic” chemical transmission, a form of extracellular signaling mediated by purine derivatives, leads to the binding of energy carriers such as adenosine triphosphate (ATP) to “purinoreceptors”, which which induces and exacerbates neuropathic disorders and inflammatory pain perception. This binding is mediated by a vesicular nucleotide transporter (VNUT), which thus becomes the key molecule in the initiation of purinergic signaling. The researchers hypothesized that EPA targets VNUT, thereby blocking purinergic chemical transmission and reducing pain perception.
A validated hypothesis: scientists are validating this complex mechanism, both in vitro, using a human-derived VNUT, and in vivo, using a VNUT-deficient mouse model. This effect is confirmed only with EPA and its metabolites, and not with docosahexaenoic acid, another omega-3 fatty acid, thus suggesting that a specific omega-3 fatty acid structure is required for VNUT inhibition. .
- In a mouse model of neuropathic pain and deficient in VNUT, the EPA does not accentuate the pain because the inhibitory effect of the EPA cannot be exerted on the VNUT. Similarly, insulin resistance induced by neuropathic pain is shown to be reduced by EPA treatment in “normal” mice but not in VNUT-deficient mice.
EPA, a powerful painkiller with fewer side effects: thus, low concentrations of EPA completely and reversibly inhibit the release of ATP from neurons, without inhibiting the release of other neurotransmitters. Compared to other drugs, EPA therefore demonstrates a higher analgesic effect with fewer side effects. These analgesic effects of EPA can be extended to the management of chronic pain associated with several other situations including chemotherapy and conditions including diabetes, rheumatism, gout or inflammation. Moreover, purinergic chemical transmission is also associated with various conditions, including Alzheimer’s disease and depression, for which EPA might be explored as a therapeutic strategy.
More broadly, EPA and its metabolites might be better exploited in the management of chronic pain, as an alternative to opioids, and without their side effects. The identified targets will also allow the development of new treatment and prevention strategies targeting purinergic chemical transmission for inflammatory, neurological and metabolic diseases.