In a sleep deprivation-induced CFS mouse model, edible bird's nest (EBN) improved motor function and cognition, reduced neuronal damage, and preserved synaptic structures in the prefrontal cortex. Metabolomic analyses identified the dipeptide valyl-tryptophan (Val-Trp) as a bioactive metabolite that shifts microglia from a pro-inflammatory to a homeostatic state via inhibition of the NF-κB signaling pathway.

Neuroinflammation and microglial activation are considered central mechanisms in ME/CFS. The identification of a specific bioactive dipeptide (Val-Trp) as an NF-kB inhibitor could open up a new therapeutic approach for the modulation of neuroinflammation.

The study shows that the viral protein EBNA1 stabilizes the cellular enzyme DDX5, which then activates the expression of BZLF1 – the main switch for EBV reactivation. The active compound FL118 can induce the degradation of DDX5 and thereby inhibit viral replication. The research was conducted in the context of EBV-associated epithelial tumors.

EBV reactivation is considered an important trigger and perpetuating factor in ME/CFS and Long COVID. An agent that specifically blocks EBV reactivation via the EBNA1/DDX5/BZLF1 axis could theoretically also be of therapeutic interest in patients with chronic EBV reactivation.

In a mouse model of Gulf War Illness (GWI) – a condition characterized by chronic fatigue, neuroinflammation, and dysbiosis – spermidine restored microbial diversity and strengthened the intestinal barrier. It reduced the release of the pro-inflammatory molecule HMGB1 from the gut, which diminished damage to the blood-brain barrier and the activation of microglia in the brain. Mechanistically, spermidine acts via the AhR/Nrf2/HO-1 signaling pathway.

ME/CFS and PVFS share central features with GWI: chronic fatigue, neuroinflammation, gut dysbiosis and impaired intestinal barrier. HMGB1-mediated activation of microglia and the gut-brain axis mechanism are highly relevant. Spermidine, as a well-tolerated, orally available agent, could be an interesting repurposing candidate.

The systematic review with meta-analysis of 14 studies and 968 patients shows that midodrine achieves significantly better symptom response rates in pediatric POTS patients than placebo (RR 1.52) and beta-blockers (RR 1.16). The evidence in adults remains limited. Side effects such as hypertension (8.2%) and gastrointestinal complaints (3.4%) are moderate.

POTS frequently occurs in ME/CFS and Long COVID and is closely linked to autonomic dysfunction. Midodrine, as a vasoconstrictive alpha-agonist, improves tissue perfusion and could therefore also be a therapeutic option for ME/CFS patients with orthostatic intolerance.

In a mouse model of diabetes and brain ischemia, administration of LDN (1 mg/kg) led to restoration of previously reduced VEGF levels in plasma and brain tissue. In addition, the number of reactive astrocytes increased in the motor cortex, caudate nucleus, and hippocampus, indicating protection against astrocytic cell death. The cytokine response was not significantly altered by LDN.

LDN is used off-label in ME/CFS and Long COVID. This study provides mechanistic evidence for how LDN could exert neuroprotective effects through VEGF modulation and astrocyte protection – both relevant to the neuroinflammation and vascular dysfunction discussed in ME/CFS.

The study investigated the acetylcholinesterase inhibitor pyridostigmine in hypertensive rats with autonomic dysregulation and chronic inflammation. Long-term treatment reduced arrhythmias, lowered CRP in plasma as well as MCP-1 and TNF-alpha expression. However, in normotensive control animals, pyridostigmine worsened the duration of ischemic arrhythmia.

Pyridostigmine is increasingly being used off-label in ME/CFS and POTS patients. The study shows possible cardioprotective and anti-inflammatory effects in autonomic dysfunction - a core symptom of ME/CFS - but warns against use in individuals without autonomic imbalance.