August 09, 2022
Release Subtitle:
Study finds that eicosapentaenoic acid, an omega-3 fatty acid, inhibits
an important signaling molecule, thereby reducing chronic pain
Release Summary Text:
Eicosapentaenoic acid (EPA)—an omega-3 fatty acid—is known to reduce
both neuropathic and inflammatory pain, but the underlying molecular
targets for EPA remain unknown. Researchers from Okayama University have
now identified ‘vesicular nucleotide transporter’ as a novel molecular
target of EPA, and elucidated mechanisms underlying the analgesic effect
of EPA. Their findings suggest that nutrient-based EPA may serve as an
effective pain-relief alternative with minimal side-effects compared to
opioids.
Full text of release:
Eicosapentaenoic acid (EPA) is an essential nutrient belonging to the
omega-3 group of polyunsaturated fatty acids (PUFAs). As the human body
cannot synthesize PUFAs, dietary supplements containing EPA are required
for normal physiological functions. Found abundantly in natural sources
like fish, hemp oil, and linseed oil, EPA is known to exhibit
anti-inflammatory, neuroprotective, and cardiovascular protective
activities. Additionally, recent studies have demonstrated its
therapeutic effects in reducing mortality risk after myocardial
infarction, improving insulin resistance, reducing blood lipid levels,
and inhibiting platelet aggregation. Omega-3 PUFAs have also been shown
to decrease inflammatory responses following COVID-19 infection. Despite
the wide spectrum of its therapeutic effects, the molecular target(s)
and the underlying mechanism of EPA’s action remain elusive.
Research Professor Takaaki Miyaji from Okayama University, Japan, and
his team of researchers have now uncovered a novel molecular target of
EPA in their recent work published in the journal Proceedings of the National Academy of Sciences of the United States of America (PNAS)
on July 18, 2022. Explaining the rationale behind their study, Research
Professor Miyaji, the corresponding author of this paper, says, “Conventional
molecular targets such as COX-2 inhibitors can explain the
anti-inflammatory and analgesic effects for inflammatory pain, but not
neuropathic pain, of EPA. However, since EPA significantly attenuates
both inflammatory and neuropathic pain, there is a strong possibility
that there exists another important molecular target of EPA related to
neuropathy.” Diving deeper, the team, thus, sought to understand
the mechanism of action of EPA in alleviating both inflammatory and
neuropathic pain.
During neurological, metabolic, and immunological disruptions,
“purinergic” chemical transmission (a form of extracellular signaling
mediated by purine derivatives), leads to the binding of energy carriers
like adenosine triphosphate (ATP) to “purinoreceptors,” which induces
and exacerbates neuropathic 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.
Research Professor Miyaji and his team tested this hypothesis both in-vitro, using human derived VNUT, and in-vivo, using a VNUT-deficient mouse model.
They found that EPA competes with chlorine ions that normally activate
VNUT and inhibits VNUT-mediated release of ATP. Moreover, they observed
this effect with EPA and its metabolites only, and not with
docosahexaenoic acid, another omega-3 fatty acid, thus, suggesting that
the structure of omega-3 fatty acids with side chains is necessary for
VNUT inhibition.
Further, they induced neuropathic pain in wild-type and VNUT-deficient
mice using chemotherapeutic agents that are used in cancer treatment.
Notably, EPA accentuated pain in wild-type animals, but not in
VNUT-deficient mice, thus corroborating their earlier finding on the
inhibitory effect of EPA on VNUT. Similarly, insulin resistance induced
by neuropathic pain has been shown to be reduced by EPA treatment in
wild-type, but not in VNUT-deficient mice.
“We found that low concentrations of EPA
completely and reversibly inhibited the release of ATP from neurons,
without inhibiting the release of other neurotransmitters. Compared with
other drugs, EPA demonstrated a higher analgesic effect and fewer side
effects,” explains Research Professor Miyaji.
Besides, neuropathic pain and associated insulin resistance, the
analgesic effects of EPA can be further extended to chronic pain
associated with several other conditions like chemotherapy, diabetes,
rheumatism, gout, sciatic nerve ligation, and inflammation.
Additionally, purinergic chemical transmission is also associated with a
variety of conditions including Alzheimer’s disease and depression, for
which EPA can be explored as a therapeutic strategy.
Moreover, opioids and other pain-relief medications can have long-term
side effects and result in addictions. In the absence of optimal drug
treatments with fewer side effects, chronic pain leads to a decreased
quality of life, besides increasing the economic burden of treatment.
With this discovery, ‘nutrient-based EPA’ and its metabolites can be
indicated in the management of chronic pain, while also keeping
potential side effects at bay.
Elaborating the long-term implications of their research, Research Professor Miyaji adds,
“Our results can help develop novel nutrient-based treatment and
prevention strategies by targeting purinergic chemical transmission for
inflammatory, neurological, and metabolic diseases, without the adverse
side-effects of conventional pain-relieving medications.”
Who wouldn’t be excited at the prospect of having safer and natural pain relief strategies? We certainly are!
Release URL:
https://www.eurekalert.org/news-releases/961154
Reference:
Vesicular nucleotide transporter is a molecular target of eicosapentaenoic acid for neuropathic and inflammatory pain treatment
Journal: Proceedings of the National Academy of Sciences of the United States of America
DOI:10.1073/pnas.2122158119
Contact Person:Takaaki Miyaji
Takaaki Miyaji is a research professor affiliated with the Advanced
Science Research Center at the Okayama University, Japan. He completed
his doctoral studies from Okayama University in 2009 before embarking on
his professional journey. His research spans across life sciences, such
as pharmaceuticals, nutrition, health sciences, and pharmacology.
Research Professor Miyaji along with his peers, was the first in the
world to identify a Vitamin C transporter in plants. He is also the
recipient of the 2018 Young Scientists’ Prize of Commendation for
Science and Technology. He wishes to contribute to the domain of life
sciences with his research expertise.
https://www.okayama-u.ac.jp/eng/research_highlights/index_id166.html
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