New Clues Link Leptin and Microglia as Suspects
It has been one of the most elusive whodunits in medicine for over 40 years, with more suspects than Murder on the Orient Express, and enough red herrings to confound even the astute powers of deduction of Sherlock Holmes.
Solving a mystery with logic requires objective evidence, which in the case of fibromyalgia has been in short supply since the condition of unexplained muscle pain, fatigue and cognitive symptoms was first described centuries ago.
In modern times, the lack of measurable evidence that could be detected in medical tests led fibromyalgia to be labeled as a psychological condition. The patients, a great majority of whom were women, were often thought to be attention-seeking hypochondriacs. Office visits could easily become exercises in mutual frustration, which frequently led to followup referrals with a psychologist or rheumatologist, beginning what in many cases became a diagnostic odyssey that could take years.
As growing numbers of victims complained of similar patterns of symptoms, eventually the inescapable conclusion was that something real was afoot. Identifying exactly what is going on in the body during a flare, with limited sources of objective data, is the mystery research sleuths have focused on most recently.
Now, new clues that may not be the smoking gun—but bear witness to definite, measureable changes in body chemistry—seem to support a new theory of the “howdunit” of fibromyalgia and the means by which it creates havoc in the body.
The evidence that has become a topic of major interest at national conferences on pain came from two studies of leptin that were done by experimental psychophysiologist Jarrod Younger, PhD and his team at Stanford. They recently moved to UAB to set up Alabama’s first Neuroinflammation, Pain and Fatigue Laboratory.
“Elevated leptin levels seem to be implicated in chronic pain and fatigue, especially in women, who tend to have higher leptin levels than men. This could be one reason fibromyalgia is more common in women,” Younger said. “When the microglia in the brain’s immune system are exposed to too much leptin for too long, it doesn’t cause fibromyalgia directly, but it makes the microglia start behaving like an angry drunk, spoiling for a fight. Just about anything that comes along - stress, an illness, an injury - will trigger the microglia to start pumping cytokines and other proinflammatory substances into the central nervous system, resulting in pain and many of the symptoms we associate with the flu.”
Since much of the immune system defenses protecting the rest of the body are unable to breach the blood-brain barrier, the microglia are essentially the brain’s own immune system. Neuroinflammation from over activation of the microglia is also becoming a primary focus in recent research into myalgic encephalomyelitis, MS, Parkinson’s and Alzheimer’s.
Younger and his team are now recruiting volunteers for the first of dozens of planned studies funded by the NIH, the DOD, foundations and other contributors. The first study scheduled to launch within weeks will chart the levels of substances found in daily blood draws for a month and compare them to patient logs of changes in the intensity of symptoms to look for patterns and correlations.
“Right now, we really don’t have a technology to detect neuroinflammation. That’s why one of the goals of our research is to develop better tools for detecting and monitoring,” Younger said. “We’re looking at spectroscopy, using an fMRI as an MRS. We hope to detect tiny changes in brain temperature, which we think are likely to be present in neuroinflammation.”
Another upcoming study will look at the effects of injecting small amounts of endotoxins from the surface of bacteria to determine whether the response in those who have neuroinflammatory disorders is stronger or different than the response in those who do not.
Beyond diagnosis and monitoring, the ultimate goal of Younger’s research is finding better modes of treatment. In the first two clinical trials in humans, very low doses of naltrexone, a drug used for decades to treat addiction, showed positive results in reducing pain. Younger plans to continue his work with this drug and will be looking at other substances that may prove even more effective in calming hypersensitive microglia.
“Prescription anti-inflammatories that are now available aren’t very effective at getting through the blood-brain barrier. While we are waiting for new drugs to be developed and tested, we need to find better ways to help people who are suffering now,” Younger said.
Some new possibilities may be confirmed through research into Gulf War Syndrome that Younger’s lab will soon be doing for the Department of Defense.
“There has been a lot of research into botanicals that show anti-inflammatory activity, and are able to get past the blood-brain barrier,” Younger said. “We’ll be looking at curcumin from turmeric, resveratrol, boswellia, and several other botanical that have good data supporting their anti-inflammatory effects. We want to see whether we will be able to reduce neuroinflammation and ease symptoms with what we have available now.”
Pursing clues through research, Younger and his team may soon find answers that will finally solve the mystery of fibromyalgia in many cases and develop better ways to diagnose, monitor and treat neuroinflammatory disorders.