I don't think anyone has figured out the exact mechanism, but LDN may work for ME/CFS because it:
- Blocks TLR-4 on microglia (anti-inflammatory).
- Inhibits TLR-9 expression.
- Increases levels of met-enkephalin (opioid growth factor) and its receptor.
- Transiently blocks mu-, delta- and kappa-opioid receptors, which is thought then up-regulates endorphins.
- May reduce peroxynitrite and may thereby increase astrocyte glutamate transport.
- Has an effect the nociceptin system.
- Is a prokinetic which helps treat SIBO (some ME/CFS patients have worsened symptoms due to comorbid SIBO).
Experimental autoimmune encephalopathy (EAE)-induced hippocampal neuroinflammation and memory deficits are prevented with the non-opioid TLR2/TLR4 antagonist (+)-naltrexone 01.21
Multiple sclerosis (MS) is associated with burdensome memory impairments and preclinical literature suggests that these impairments are linked to neuroinflammation.
Previously, we have shown that toll-like receptor 4 (TLR4) antagonists, such as (+)-naltrexone [(+)-NTX], block neuropathic pain and associated spinal inflammation in rats.
Here we extend these findings to first demonstrate that (+)-NTX blocks TLR2 in addition to TLR4. Additionally, we examined in two rat strains whether (+)-NTX could attenuate learning and memory disturbances and associated neuroinflammation using a low-dose experimental autoimmune encephalomyelitis (EAE) model of MS.
EAE is the most commonly used experimental model for the human inflammatory demyelinating disease, MS.
This low-dose model avoided motor impairments that would confound learning and memory measurements.
Fourteen days later, daily subcutaneous (+)-NTX or saline injections began and continued throughout the study.
Contextual and auditory-fear conditioning were conducted at day 21 to assess hippocampal and amygdalar function.
With this low-dose model, EAE impaired long-term, but not short-term, contextual fear memory; both long-term and short-term auditory-cued fear memory were spared.
This was associated with increased mRNA for hippocampal interleukin-1β (IL-1β), TLR2, TLR4, NLRP3, and IL-17 and elevated expression of the microglial marker Iba1 in CA1 and DG regions of the hippocampus, confirming the neuroinflammation observed in higher-dose EAE models.
Importantly, (+)-NTX completely prevented the EAE-induced memory impairments and robustly attenuated the associated proinflammatory effects.
These findings suggest that (+)-NTX may exert therapeutic effects on memory function by dampening the neuroinflammatory response in the hippocampus through blockade of TLR2/TLR4.
This study suggests that TLR2 and TLR4 antagonists may be effective at treating MS-related memory deficits.