We propose that elevation of circulating thrombospondin-1 (TSP-1), a multifunction protein, in the blood could reduce brain-blood flow in some persons suffering from ME / CFS leading to a brain fog and post-exertional malaise (PEM). Conversely, a rapid decrease in TSP-1 blood levels in some ME / CFS patients could induce a hypotension resulting in orthostatic intolerance or even POTS.
WHY THIS STUDY MATTERS FOR ME
Vascular instabilities are part of a group of symptoms affecting several persons with MEu00a0/u00a0CFS. Current treatments to alleviate those symptoms are limited and often not very effective for MEu00a0/u00a0CFS. A more comprehension approach about the role of TSP-1 in MEu00a0/u00a0CFS pathophysiology could lead to pharmacological therapies that are more effective.
OUR KEY FINDINGS
- Application of a stress-test reveal a different physiological behavior of ME / CFS patients along three clusters (as defined initially with our diagnostic panel of circulating microRNAs).
- Cluster 1 encompasses MEu00a0/u00a0CFS patients showing no significant changes in TSP-1 blood level after stimulation versus the baseline values.
- Cluster 2 encompasses MEu00a0/u00a0CFS patients showing a drastic reduction in TSP-1 levels following the stress-test and regroups in our cohort all MEu00a0/u00a0CFS patients exhibiting an orthostatic intolerance with or without POTS.
- Cluster 3 encompasses MEu00a0/u00a0CFS patients showing a strong elevation of TSP-1 blood levels after the application of the stress-test. This group is developing more often a brain fog and develops more a severe PEM.
- Our preliminary experiments showed that exposition to TSP-1 proteins inhibits the signaling of membranous receptors, termed GPCR, when they are coupled to G inhibitory proteins (Gi). This discovery is important because it could explain neuroendocrine symptoms in MEu00a0/u00a0CFS patients having high circulating TSP-1 levels.
- The identification of a receptor interacting with TSP-1 could allow us to propose a therapeutic approach to relieve, prevent or reduce u201cbrain fogu201d and related symptoms in MEu00a0/u00a0CFS patients. Interestingly, u03b12u03b4-1 is the high affinity receptor for two commonly prescribed anti-epileptic, anti-neuropathic pain medications, gabapentin (NeurontinTM) and pregabalin (LyricaTM). Both drugs are being used off-label for MEu00a0/u00a0CFS and fibromyalgia patients, mostly for pain relief but some patients also report significant improvement of their u201cbrain fogu201d and neurocognitive symptoms.
- Search for the mechanisms causing the elevation of TSP-1 secretion and production in MEu00a0/u00a0CFS led us to explore a possible connection between the IDO2 metabolic trap given than inactivation of IDO2 by common mutations could increase tryptophan (Trp), an amino acid, at the cellular level. It is well known that such increase could lead to the elevation of proteins like TSP-1 due to their high content in Trp as a defense mechanism to prevent Trp accumulation, which could be toxic.
- Among other possible mechanisms, leading to higher TSP-1 levels, we intend to investigate if hyperglycemia and glucose intolerance could lead to an increase in TSP-1 levels in some MEu00a0/u00a0CFS patients.