• Welcome to Phoenix Rising!

    Created in 2008, Phoenix Rising is the largest and oldest forum dedicated to furthering the understanding of, and finding treatments for, complex chronic illnesses such as chronic fatigue syndrome (ME/CFS), fibromyalgia, long COVID, postural orthostatic tachycardia syndrome (POTS), mast cell activation syndrome (MCAS), and allied diseases.

    To become a member, simply click the Register button at the top right.

Multitasking Biomolecules in ME/CFS Pathogenesis - Alain Moreau - OMF Working Group Meeting September 8-11, 2020

raghav

Senior Member
Messages
809
Location
India
OUR HYPOTHESIS: We propose that elevation of circulating thrombospondin-1 (TSP-1) levels could induce a brain fog and PEM in ME/CFS by reducing brain-blood flow. Conversely, a rapid decrease in blood TSP-1 levels could induce an orthostatic intolerance or even POTS
 

raghav

Senior Member
Messages
809
Location
India
THERAPEUTIC OPTIONS FOR ME/CFS PATIENTS

How to decrease plasma TSP-1 levels or block its signaling action?
o Interestingly, α2δ-1 is the high affinity receptor for TSP-1 in the brain.

o Two commonly prescribed anti-epileptic, anti-neuropathic pain medications, gabapentin (NeurontinTM) and pregabalin (LyricaTM) are targeting α2δ-1 receptor. Both drugs are being used off-label for ME/CFS and fibromyalgia patients.

o Vitamin D3 supplementation for 12 weeks markedly reduced TSP1 levels by almost 2.5 fold (522.7 ± 379.8 ng/mL vs 206.7 ± 204.5 ng/mL, p<0.001.1

o Low-dose of cyclophosphamide.

o Hyperbaric oxygenation therapy could be effective to decrease blood TSP-1 levels but it remains to be tested by a clinical trial. A direct link between TSP-1 activity and hyperoxic condition has not been made yet.3 1 Amarasekera AT, et al. Vitamin D supplementation lowers thrombospondin-1 levels and blood pressure in healthy adults. PLoS O
 

raghav

Senior Member
Messages
809
Location
India
THE PROBLEM: Little is known about the mechanism underlying lipid metabolism alteration occurring in ME/CFS
14 MULTITASKING BIOMOLECULES (2) Role of SMPDL3B in ME/CFS pathophysiology

OUR HYPOTHESIS: We propose that sphingomyelin phosphodiesterase acid-like 3b (SMPDL3B) is involved in ME/CFS pathogenesis by modulating innate immunity and lipid metabolism. We have identified SMPDL3B as a possible alternative target of Rituximab in ME/CFS pathogenesis. Bita Rostami Dr. Wesam Elremaly 15 LIPID-MODIFYING ENZYME SMPD

PRELIMINARY DATA
Possible role of SMPDL3B in ME/CFS pathogenesis
Hypermethylation of SMPDL3B gene occurs in ME/CFS
 
Last edited:

raghav

Senior Member
Messages
809
Location
India
Slide 18

THERAPEUTIC OPTION FOR ME/CFS PATIENTS How to increase Smpdl3b gene expression?
AMPK agonist

5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR)

The entorhinal cortex (EC) is an area of the brain located in the medial temporal lobe and functions as a hub in a widespread network for memory, navigation and the perception of time. The EC is the main interface between the hippocampus and neocortex. 18 THERAPEUTIC OPTION FOR ME/CFS PATIENTS How to increase Smpdl3b gene expression? AMPK agonist o The parahippocampal gyrus (PaHcG), which includes the entorhinal cortex, is involved in aspects of limbic function as well as memory retrieval and storage. o Reduced connectivity in ME/CFS participants between PaHcG and regions that encompassed left postcentral gyrus (i.e., primary sensory cortex) and supramarginal gyrus suggests abnormality in the link between memory and bodily sensation.1 o Such lower connectivity was strongly correlated to higher fatigue ratings of ME/CFS participants. 1 19 IMPORTANCE OF ENTORHINAL CORTEX
 

raghav

Senior Member
Messages
809
Location
India
IMPORTANCE OF ENTORHINAL CORTEX
Possible link between memory, bodily sensation and fatigue rating in ME/CFS

o The parahippocampal gyrus (PaHcG), which includes the entorhinal cortex, is involved in aspects of limbic function as well as memory retrieval and storage.
o Reduced connectivity in ME/CFS participants between PaHcG and regions that encompassed left postcentral gyrus (i.e., primary sensory cortex) and supramarginal gyrus suggests abnormality in the link between memory and bodily sensation.1
o Such lower connectivity was strongly correlated to higher fatigue ratings of ME/CFS participants. 1
 

Wishful

Senior Member
Messages
5,756
Location
Alberta
Interesting, but the TSP-1 hypothesis doesn't seem to fit real-life ME. Surely there are various events each day that would rapidly change cerebral blood flow, which should then affect ME symptoms, but I haven't experienced anything like that. Are there no other drugs that increase blood flow? Nitroglycerine maybe? If VitD for 12 weeks "markedly reduces TSP-1", does brainfog also reduce markedly?
 

raghav

Senior Member
Messages
809
Location
India
TSP-1 Role in ME.jpg
 

Alvin2

The good news is patients don't die the bad news..
Messages
3,027
Does anyone on PR have experience with Pregabalin or Gabapentin improving cognitive function?
 
Messages
30
Here is a cut-and-paste for the reference of Vitamin D3 reducing TSP-1 and possibly reducing blood pressure as well. It appears to be D3/2000IU/daily.
Vitamin D supplementation lowers thrombospondin-1 levels and blood pressure in healthy adults
DOI: 10.1371/journal.pone.0174435

Introduction: Vitamin D insufficiency, defined as 25-hydroxyvitamin D (25(OH)D) levels < 75nmol/L is associated with cardio-metabolic dysfunction. Vitamin D insufficiency is associated with inflammation and fibrosis, but it remains uncertain whether these anomalies are readily reversible. Therefore, we aimed to determine the effects of vitamin D supplementation on markers of: 1) nitric oxide (NO) signaling, 2) inflammation, and 3) fibrosis, in healthy volunteers with mild hypovitaminosis.
Methods: Healthy volunteers (n = 35) (mean age: 45 ± 11 years) with 25(OH)D levels <75nmol/L, received vitamin D supplementation (Ostelin ® capsules 2000IU) for 12 weeks. Resting systolic and diastolic blood pressures (BP) were assessed. Routine biochemistry was examined. Plasma concentrations of asymmetric dimethylarginine (ADMA), thrombospondin-1 (TSP-1), plasminogen activator inhibitor-1 (PAI-1), hs-CRP, activin-A, and follistatin-like 3 (FSTL3) were quantitated.

Results: Vitamin D administration for 12 weeks significantly increased 25-(OH)D levels (48.8 ± 16 nmol/L to 100.8 ± 23.7 nmol/L, p<0.001). There was significant lowering of systolic and diastolic BP, while there was no significant change in lipid profiles, or fasting insulin. Plasma concentrations of ADMA, hs-CRP, PAI-1, activin A, and FSTL-3 did not change with vitamin D supplementation. However, there was a marked reduction of TSP-1 (522.7 ± 379.8 ng/mL vs 206.7 ± 204.5 ng/mL, p<0.001).

Conclusions: Vitamin D supplementation in vitamin D insufficient, but otherwise healthy individuals markedly decreased TSP-1 levels and blood pressure. Since TSP-1 suppresses signaling of NO, it is possible that the fall in BP is engendered by restoration of NO effect.
 

rel8ted

Senior Member
Messages
451
Location
Usa
Does anyone on PR have experience with Pregabalin or Gabapentin improving cognitive function?
Tried both. Gabapentin caused significant weight gain with no improvements. Lyrica gave minor nerve pain improvement for a short time, but I ended up worse off. Neither improved cognition.
 

Alvin2

The good news is patients don't die the bad news..
Messages
3,027
Tried both. Gabapentin caused significant weight gain with no improvements. Lyrica gave minor nerve pain improvement for a short time, but I ended up worse off. Neither improved cognition.
D'oh