Saving nerves from damage. Protect the cell’s power houses.


Mention New York and you get a picture of the Brooklyn bridge

View of the Brooklyn Bridge from Manhattan; the East River is in the foreground
By Suiseiseki – Own work, CC BY-SA 3.0,

Mention Neurodegeneration and you get the brooklyn bridge of neurodegeneration. It is this picture showing axonal blebbing (green balloon) where the contents of the nerve escapes, because it has been cut. In the centre of an active MS lesion you can get over 10,000 blebs per square millimeter (Trapp et al. N. Eng J Med 1998. I may not be as bad as that so read on). So you want to stop those bleds forming.

Axonal transections in a multiple sclerosis lesion. Non-phosphorylated... |  Download Scientific Diagram
axon contents = green, myelin = red. Myelination = yellow (green+ red), demylination = green.

DoctorLove works on on pathology and often talks about pre-active microglial lesions, it is suggest that some may develop into MS lesions and others resolve. In this mouse study, they find swollen axons as a forerunner to axonal damage that occur due to energy defects because of effects on the cells energy supplt. This is made in things called mitochondria. In this paper they use a neat bit of microscopy so they can look through cells and they can do this in living beasties to look into the brain or spinal cord. In the mice these axons die, but don’t need to show demyelination. This is perhaps not surprising because mice are pretty bad demyelinating models. Mice tend to lose nerves when attacked by inflammation. In this study they treated beasties that had evidence of nerve swelling, using agents that blocked the oxidative stress. This saved nerves. This swelling occurs in MS

(lef) Mouse nerves in blue. 0=healthy nerve, 1=swollen nerve, 2 = fragmented nerve mitochondria blue……(right) = Axonal blob. However is it really transected? Image a ballon with a string (not straingt) on it. Cut it in the middle is it a blob with a thin bit. Now keep cutting and you have a blob with no string.

How do they do this?….It’s not important because this needs a trial ,not self-experiment.

So there is a way to save nerves. Will there be a trial on this?. It seems to me like it is worth a try?

However after doing the post, thinking it was a new paper, I realised it is a decade old so it never went anywhere…Why Not?

A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis. Nat Med. 17:495. 

In multiple sclerosis, a common inflammatory disease of the central nervous system, immune-mediated axon damage is responsible for permanent neurological deficits. How axon damage is initiated is not known. Here we use in vivo imaging to identify a previously undescribed variant of axon damage in a mouse model of multiple sclerosis. This process, termed ‘focal axonal degeneration‘ (FAD), is characterized by sequential stages, beginning with focal swellings and progressing to axon fragmentation. Notably, most swollen axons persist unchanged for several days, and some recover spontaneously. Early stages of FAD can be observed in axons with intact myelin sheaths. Thus, contrary to the classical view, demyelination-a hallmark of multiple sclerosis-is not a prerequisite for axon damage. Instead, focal intra-axonal mitochondrial pathology is the earliest ultrastructural sign of damage, and it precedes changes in axon morphology. Molecular imaging and pharmacological experiments show that macrophage-derived reactive oxygen and nitrogen species (ROS and RNS) can trigger mitochondrial pathology and initiate FAD. Indeed, neutralization of ROS and RNS rescues axons that have already entered the degenerative process. Finally, axonal changes consistent with FAD can be detected in acute human multiple sclerosis lesions. In summary, our data suggest that inflammatory axon damage might be spontaneously reversible and thus a potential target for therapy.

Disclaimer: please note that the opinions expressed here are those of the authors and do not reflect the positions of the Barts and the London School of Medicine and Dentistry, nor Barts Health NHS Trust or Queen Mary University London.

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  • Do you think this is why ALA seams to be so good at preserving brain volume loss?

    And could brain volume loss in MS be an issue with energy in the cell and getting fuel into the cell, and ketones could be a better source of fuel than glucose?

    • Data on ALA and BVL is at best meagre and needs repeating in a much larger cohort before any grand claims can be made for its efficacy.
      The same claims are made for ketogenic diets and though plausible the positive effects can tend to be grossly oversold. The downside of which can be an obvious increased risk of cardiovascular disease.

      • Yes a larger ALA trial is long over due, I know a lot of people see benefits for their overall health also with Lipoic acid such as energy levels, reduction in nerve pain etc

        Keto diet can be beneficial for the heart if the right fats are used and processed foods are avoided. The quality of the food is crucial as with any diet. Healthy fats arnt the enemy, and any reduction in inflammation is good for the heart, which a reduction in inflammation, healthy keto would provide, if done correctly and also it’s not for everyone.

        Hopefully further study’s will solve this and hopefully on a larger scale not small inconclusive ones.

        I think lifestyle factors have the best effect on BVL. Exercise is one of them, especially HIIT exercise. Coincidentally this boosts mitrocondrial function.

    • Mabe preventing ROS and oxidative stress

      Ala acts on the cell anti oxidantive pathway


      The mechanism and action of lipoic acid when supplied externally to an organism is controversial. Lipoic acid in a cell seems primarily to induce the oxidative stress response rather than directly scavenge free radicals. This effect is specific for RLA.[4] Despite the strongly reducing milieu, LA has been detected intracellularly in both oxidized and reduced forms.[36] LA is able to scavenge reactive oxygen and reactive nitrogen species in a biochemical assay due to long incubation times, but there is little evidence this occurs within a cell or that radical scavenging contributes to the primary mechanisms of action of LA.[4][37] The relatively good scavenging activity of LA toward hypochlorous acid (a bactericidal produced by neutrophils that may produce inflammation and tissue damage) is due to the strained conformation of the 5-membered dithiolane ring, which is lost upon reduction to DHLA. In cells, LA is reduced to dihydrolipoic acid, which is generally regarded as the more bioactive form of LA and the form responsible for most of the antioxidant effects and for lowering the redox activities of unbound iron and copper.[38] This theory has been challenged due to the high level of reactivity of the two free sulfhydryls, low intracellular concentrations of DHLA as well as the rapid methylation of one or both sulfhydryls, rapid side-chain oxidation to shorter metabolites and rapid efflux from the cell. Although both DHLA and LA have been found inside cells after administration, most intracellular DHLA probably exists as mixed disulfides with various cysteine residues from cytosolic and mitochondrial proteins.[32] Recent findings suggest therapeutic and anti-aging effects are due to modulation of signal transduction and gene transcription, which improve the antioxidant status of the cell. However, this likely occurs via pro-oxidant mechanisms, not by radical scavenging or reducing effects.[4][37][39]

      All the disulfide forms of LA (R/S-LA, RLA and SLA) can be reduced to DHLA although both tissue specific and stereoselective (preference for one enantiomer over the other) reductions have been reported in model systems. At least two cytosolic enzymes, glutathione reductase (GR) and thioredoxin reductase (Trx1), and two mitochondrial enzymes, lipoamide dehydrogenase and thioredoxin reductase (Trx2), reduce LA. SLA is stereoselectively reduced by cytosolic GR whereas Trx1, Trx2 and lipoamide dehydrogenase stereoselectively reduce RLA. (R)-(+)-lipoic acid is enzymatically or chemically reduced to (R)-(-)-dihydrolipoic acid whereas (S)-(-)-lipoic acid is reduced to (S)-(+)-dihydrolipoic acid.[40][41][42][43][44][45][46] Dihydrolipoic acid (DHLA) can also form intracellularly and extracellularly via non-enzymatic, thiol-disulfide exchange reactions.[47]

      RLA may function in vivo like a B-vitamin and at higher doses like plant-derived nutrients, such as curcumin, sulforaphane, resveratrol, and other nutritional substances that induce phase II detoxification enzymes, thus acting as cytoprotective agents.[39][48] This stress response indirectly improves the antioxidant capacity of the cell.[4]

      The (S)-enantiomer of LA was shown to be toxic when administered to thiamine-deficient rats.[49][50]

      Several studies have demonstrated that SLA either has lower activity than RLA or interferes with the specific effects of RLA by competitive inhibition.[5

  • I am wondering if in the registries add on drugs are reported. If so data could be easily extracted and matched with people taking nothing and some results could be taken seeing the disease trajectories. Then additional conclusion on add-on could be made… why isn’t this done?
    E.g. I think many take vD and ALA and database should be filled by this kind of information beside treatment and disease markers…

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