Acupuncture Tames Cytokine Storm, Improves Mouse Survival Via Specific Neural Pathways

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A team of researchers led by neuroscientists at Harvard Medical School has successfully used acupuncture to dampen a potentially fatal inflammatory response known as a cytokine storm, in mice with systemic inflammation. The team’s studies showed how acupuncture activated different signaling pathways that triggered either a pro-inflammatory or an anti-inflammatory response in animals with bacterially induced systemic inflammation.

The results of the experiments also indicated that three factors determined how acupuncture affected response: site, intensity, and timing of treatment. Where in the body the stimulation occurred, how strong it was, and when the stimulation was administered yielded dramatically different effects on inflammatory markers and survival. “Most Western medicine has been focusing on blocking the neural pathways of pain to relieve the symptoms, but there are so many pain pathways and so many ways to open each of them,” said research lead Qiufu Ma, PhD, professor of neurobiology in the Blavatnik Institute at Harvard Medical School and a researcher at Dana-Farber Cancer Institute.

The investigators believe that the experiments will help to define the neuroanatomical mechanisms underlying acupuncture, and offer a roadmap for harnessing the technique to help treat inflammatory diseases. “Our findings represent an important step in ongoing efforts not only to understand the neuroanatomy of acupuncture but to identify ways to incorporate it into the treatment arsenal of inflammatory diseases, including sepsis,” added Ma, who, together with colleagues, reported on their work in Neuron, in a paper titled, “Somatotopic Organization and Intensity Dependence in Driving Distinct NPY-Expressing Sympathetic Pathways by Electroacupuncture.”

Although rooted in traditional Chinese medicine, acupuncture has recently become more integrated into Western medicine, particularly for the treatment of chronic pain and gastrointestinal disorders. The approach involves mechanical stimulation of certain points on the body’s surface—known as acupoints. Targeted stimulation is believed to trigger nerve signaling, which can remotely affect the function of internal organs corresponding to specific acupoints. However, the basic mechanisms underlying acupuncture’s action and effect have not been fully elucidated.

With a starting point inspired in the core ideology of traditional Chinese medicine—which is to treat a disease by addressing the root cause—Ma and his team aimed to target inflammation, a common source of human diseases and pain. “During the past two decades, nerve stimulation has been emerging as a potential therapeutic regimen to treat systemic inflammation,” the authors noted. As a neurobiologist who studies the fundamental mechanisms of pain, Ma had been curious about the biology of acupuncture for years. He was intrigued by prior research demonstrating that using acupuncture in mice could alleviate systemic inflammation by stimulating the vagal-adrenal axis—a signaling pathway in which the vagus nerve carries signals to the adrenal glands—to trigger the glands to release dopamine. More recent previous research had also shown that vagus-nerve stimulation could dampen inflammatory responses and lessen symptoms of rheumatoid arthritis. However, while previous studies have shown how direct vagal-nerve stimulations in the neck region can help reduce inflammation, such experimental approaches to vagal-nerve stimulation typically required invasive procedures.

With this in mind, Ma and his team set out to investigate whether and how electric stimulation using acupuncture, which only involves inserting thin needles through the skin, can modulate inflammation. For their reported study, the researchers applied a technique called electroacupuncture, rather than the traditional manual approach that involves the insertion of ultra-thin needles just under the skin in various areas of the body. Instead of needles, electroacupuncture uses very thin electrodes inserted into the skin and into the connective tissue, offering better control of stimulation intensities.

Through their studies in mice, the team showed that acupuncture stimulation influenced how animals coped with cytokine storm, the rapid release of large amounts of inflammation-fuelling cytokines. The phenomenon has gained particular attention over recent months as a complication of severe COVID-19, but this aberrant immune reaction can occur in the setting of any infection, and has been long known to physicians as a hallmark of sepsis, an organ-damaging, often-fatal inflammatory response to infection. “For patients suffering sepsis, the high fatality rate is often caused by excessive release of pro-inflammatory cytokines, referred to as the cytokine storm,” they wrote. Sepsis is estimated to affect 1.7 million people in the United States and 30 million people worldwide each year.

The team began by giving mice 15-minute electroacupuncture at 3 mA, at a specific site on the abdomen. This acupoint, dubbed ST25, has been associated with nerves of the spleen, which is a major organ involved in immune responses. The team then simulated life-threatening inflammation by injecting mice with a compound called lipopolysaccharide (LPS). The researchers found that in animals treated using electroacupuncture before LPS administration, the serum levels of pro-inflammatory molecules were significantly lower than they were in control mice, and the electroacupuncture-treated animals’ survival rates also more than doubled. However, when the team gave mice the electroacupuncture after the LPS shot, the electroacupuncture-treated mice had much greater inflammation than those that were untreated, and did not survive.

By comparing the effect of electroacupuncture in mice with altered nervous systems, the team determined that high-intensity stimulation at the abdomen could excite norepinephrine-producing nerves that connect the spine and spleen. The norepinephrine then activated a particular type of receptors in the spleen that suppressed pro-inflammatory molecules. But when LPS was introduced first, another type of splenic receptors—pro-inflammatory in this case—became highly expressed, and the subsequent electroacupuncture therapy further enhanced inflammation.

“We were really surprised to find that the same input has completely opposite outcomes in different disease stages,” Ma said. “But a lot of the time, a patient would only come to us if they already have the disease. So we wanted to find out if there is a way to reduce inflammation as a treatment.”

To investigate this the team then conducted electroacupuncture at a different acupoint, this time on the hind legs of mice. They found that stimulation at a low intensity of 0.5 mA for 15 minutes could significantly reduce levels of pro-inflammatory molecules either before or after LPS-injection. The animals’ survival rate after electroacupuncture also increased by 1-fold or more. Further experiments in the genetically modified mice model suggested that low-level electroacupuncture applied at the hind legs reduced inflammation, not through the spleen, but through a different neural pathway involving the vagus nerves and the adrenal glands.

“Using endotoxin-induced systemic inflammation as a model, we found that electroacupuncture stimulation (ES) drives sympathetic pathways in somatotopy- and intensity-dependent manners,” the researchers stated. “Low-intensity ES at hind limb regions drives the vagal-adrenal axis, producing anti-inflammatory effects that depend on NPY+ adrenal chromaffin cells. High-intensity ES at the abdomen activates NPY+ splenic noradrenergic neurons via the spinal-sympathetic axis; these neurons engage incoherent feed forward regulatory loops via activation of distinct adrenergic receptors (ARs), and their ES-evoked activation produces either anti- or pro-inflammatory effects due to disease-state-dependent changes in AR profiles.”

“This observation underscores the idea that if practiced inappropriately, acupuncture could have detrimental results, which I don’t think is something people necessarily appreciate,” Ma said. “Our study illustrated that electroacupuncture has neuroanatomic basis, but its efficacy and safety on humans need to be validated in clinical trials,” he added. “There are still many questions unanswered about this medical practice and thus a lot of room to do more research.”

The researchers believe the study represents an important step in mapping the neuroanatomy of acupuncture. “The findings that acupuncture stimulation modulates systemic inflammation in somatotopy-, intensity-, and disease-state-dependent manners should help to improve acupuncture practice,” they noted.

Much more work will be needed to confirm their findings through further research in animals and in humans, and to carefully define the optimal parameters for acupuncture stimulation. Nevertheless, the authors believe, these early findings point to the potential to one day using electroacupuncture as a versatile form of treatment, whether as an adjunctive therapy for sepsis in the intensive care unit, or for more targeted treatment of site-specific inflammation, such as in inflammatory diseases of the gastrointestinal tract. “The revelation of somatotopic organization and intensity dependency in driving distinct autonomic pathways could form a road map for optimizing stimulation parameters to improve both efficacy and safety in using acupuncture as a therapeutic modality,” they wrote.

Another possible use of the approach, Ma said, would be to help modulate inflammation resulting from cancer immune therapy, which, while lifesaving, can sometimes trigger cytokine storm due to overstimulation of the immune system. Acupuncture is already used as part of integrative cancer treatment to help patients cope with side effects of chemotherapy and other cancer treatments. “ … the revelation of somatotopic organization and intensity dependence in driving distinct autonomic pathways could help to optimize stimulation parameters and improve both efficacy and safety in using acupuncture to treat systemic inflammation,” the investigators concluded.

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