In conclusion, our findings indicate that mifepristone may play a pivotal role in the control of inflammatory responses and suggest a new clinical application for mifepristone — Chen et. al
Natural Killer Cells
In the last blog we looked at the potential for an antibiotic called minocycline to be repurposed to reduce neuroinflammation in ME/CFS and or FM. Now we look at an abortion inducing drug, no less, that can enhance natural killer cell functioning.
Natural killer cell functioning is a big deal in Chronic Fatigue Syndrome. No immune factor has been studied more or found to be more consistently abnormal. Several new NK cell studies were reviewed at the IACFS/ME Conference. The CDC is working on a cheaper, more accessible NK cell functioning test, and Dr. Sonya Marshall-Gradisnik of PHANU recently co-authored a dense chapter on natural killer cells and ME/CFS in a medical book.
Doctors report that some people with ME/CFS demonstrate extraordinarily low natural killer levels. Dr. Andreas Kogelnik has said if he had a good natural killer cell booster he would be giving it out like candy to those with this disorder.
NK cells are a big deal.
Drug repurposing has become a big deal as well. The CFIDS Association and the Klimas Research group at Nova Southeastern University are dedicated to finding new drugs for this disorder that have already been FDA approved but have slipped by clinicians, and, of course, Dr. Pridgen is testing combinations of antivirals and anti-inflammatories for use in Fibromyalgia and ME/CFS.
Throw the need to boost NK cell functioning in ME/CFS and drug repurposing together and what do you get? Perhaps you get a drug used to induce abortions that boosts NK cell functioning at the same time. Perhaps you get a drug that does that by affecting a system – the HPA axis – that’s under duress in ME/CFS. Perhaps you get a drug that appears to works effectively (now in combination with another drug) that prompts the autonomic nervous system to boost immune responses. Perhaps you get RU486 – Mifepristone.
Mifepristone increases the cytotoxicity of uterine natural killer cells by acting as a glucocorticoid antagonist via ERK activation. Chen Y, Wang Y, Zhuang Y, Zhou F, Huang L. PLoS One. 2012;7(5):e36413. doi: 10.1371/journal.pone.0036413. Epub 2012 May 1.
Mifepristone’s abortion-inducing properties appear to be due to its ability to increase natural killer cell functioning enough to disturb the attachment of the embryo to the placenta. Natural killer cells serve dual purposes in the placenta: in their latent state they support placental growth, but, if their cytotoxic properties are turned on, they can inhibit it as well. It’s intriguing, given the number of gynecological abnormalities CDC studies have found in women with ME/CFS, that natural killer cells are the most abundant immune cell during embryo implantation and early placental development. Could reduced NK cell functioning be impairing placental growth?
Anti-Glucocorticoid Properties Spell Caution
For years researchers thought progesterone regulated NK cell functioning in the uterus, but recently it’s become clear that high cortisol levels reduce NK cell cytotoxicity in the uterus.
Mifepristone in an anti-glucocorticoid; it actually blocks cortisol’s ability to bind to glucocorticoid receptors on our cells and that could spell trouble for people with ME/CFS or FM with low cortisol levels or a poorly functioning HPA axis.
Another study examing mifepristone’s effects on bi-polar patients with normal HPA axis functioning, however, found that mifepristone increased the “cortisol awakening response” (CAR). The CAR refers to a dramatic increase in cortisol that normally occurs about a half hour we wake. It’s the CAR that’s disturbed in ME/CFS.
Natural Killer Cells
Studies indicate low-dose mifepristone increases NK cell cytotoxicity and perforin expression. Perforin is the substance NK cells uses to ‘drill holes’ into invading cells and studies suggest reduced perforin expression is hampering natural killer cell functioning in ME/CFS.
Gulf War Syndrome Connection
The authors concluded mifepristone should be explored further in other diseases, and it is indeed — in Gulf War Syndrome. A 2008 GWS study — still listed as recruiting patients according to Clinicaltrials.gov — is giving low dose mifepristone (200 mg/day, about half of what’s used to treat Cushing’s disease and a third of what’s used to induce abortions) to GWS patients to see if their overall health and cognitive function improved and if it relieved their depression and PTSD.
Another indirect connection to ME/CFS also exists. About 20 years ago, a study led by ME/CFS and herpesvirus researcher Ron Glaser infected mice with herpes simplex viruses, put them into restraints (as a way to stress them) and then watched their immune systems tumble.
Specifically, the stressed-out herpesvirus-infected mice weren’t able to mount normal cytokine and cytotoxic T-cell responses, their immune cells were not able to penetrate the infected areas, and their herpes simplex levels went up. The mice also became more susceptible to further infections.
The Glaser team then used mifepristone to restore (by blocking glucocorticoid receptors) the cytokine responses, but the T-cell cytotoxic activity remained inhibited. They restored full T-cell cytotoxic activity by using a beta blocker called nadolol. The intersection of a herpes virus infection, natural killer cells, and autonomic nervous system functioning in this study is intriguing.
Mifepristone also appears to have neuroprotective properties – particularly with regard to the hippocampus.
With studies underway examining its effectiveness in GWS as well as prostate, brain, and nervous system cancers, ‘stress sensitivity’, Cushing’s disease, depression, and its ‘original’ use for abortion, mifepristone is getting a good workout at the clinical level.
Mifepristone’s anti-glucocorticoid properties suggest it may not be appropriate for HPA axis suppressed ME/CFS patients but it’s cortisol enhancing properties suggest that it might be. However the mifepristone saga ends up, it and minocycline provide examples of the surprises that await as researchers dig deeper into how drugs work, and this provides hope that better drugs for ME/CFS and Fibromyalgia are already, without our knowing it, among us.