The antiviral effects of
interferon on enteroviral RNA infections in our cells work through the release of
RNase L.
Interferon triggers the release of RNase L in cells, which in turn destroys viral RNA in the cell. But in ME/CFS it is known that the RNase L gets chopped up (cleaved), making it less effective at destroying the viral RNA in the cell.
Now, it is
calpain that actually does the chopping up of RNase L.
So I was thinking that taking
calpain activation inhibitors might help prevent RNase L being chopped up, which would then allow it to do its work of clearing out enteroviral RNA from out cells. There are in fact a number of calpain inhibitors:
Calpain activation inhibitors:
• Taurine 50 mg per kg (= 4 grams dose for a man) markedly reduced m-calpain activity.
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• Glutathione inhibits calpain activity.
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• Luteolin reduced calcium influx and inhibited calpain activation.
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Then there also are some drugs that inhibit calpain, such as
calpeptin and
calpastatin.
Calpain is activated when there is a calcium influx into cells such as neurons and astrocytes, which occurs when the NMDA receptors on these cells are activated. It thus occurred to me that in ME/CFS there may be a vicious circle going on in the brain, with NMDA activation, calcium influx, calpain activation and RNase L cleaving, which is as follows:
Vicious circle in the brains of ME/CFS patients involving NMDA activation, calcium influx, calpain activation and RNase L cleaving
(1) Due to brain infection and the resultant brain inflammation, ME/CFS patients may have high extracellular glutamate in the brain, since brain inflammation is hypothesized to elevate glutamate.
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(2) Extracellular glutamate in the brain over-activates the NMDA receptors on brain cells, thus causing excessive calcium influx to the cell, and high intracellular calcium.
(3) High intracellular calcium activates calpain, which then cleaves the RNase L and prevents viral clearance.
(4) This then maintains the viral infection in the brain, leading to further brain inflammation, which completes the vicious circle.
If this vicious circle model is correct, then another way to inhibit calpain activation would be to reduce extracellular glutamate in the brain, and/or block NMDA receptor activation.
Dr Kenny De Meirleir published a book focusing on RNase L in ME/CFS, and this book examines how high levels of calpain in ME/CFS act to chop up RNase L.
Of the two main types of calpain,
μ-calpain and
m-calpain (also called calpain 1 and calpain 2), De Meirleir says it is m-calpain that is linked to the cleavage of proteins the PBMCs of ME/CFS patients (ref:
here).
