Theophylline Produces Accelerated Remyelination in the Central Nervous System of Mice

The myelin sheathing around axons is necessary for the proper function of nervous system tissue. Demyelinating conditions such as multiple sclerosis, an autoimmune disease in which the immune system attacks myelin, well illustrate the severe consequences that result from a sizable loss of myelin. Unfortunately, the integrity of myelin sheathing declines with age for everyone, most likely the result of disruption and damage in the oligodendrocyte cell population responsible for maintaining these structures. Evidence suggests that this contributes to cognitive decline and other issues. Thus it is worth keeping an eye on progress towards therapies that might enhance the generation and repair of myelin sheathing. The work noted here is an example of the type, in which the drug theophylline is shown to improve recovery from myelin loss in mice.

Neurons are composed of axons, i.e., long fiber-like extensions that transmit signals to other cells. Many of them are surrounded by a myelin sheath, a thick fatty layer that protects them and helps to transfer stimuli rapidly. Without myelin, the functional capacity of neurons - and therefore of the whole nervous system - is limited and neurons can easily degenerate. Multiple sclerosis (MS) is one of the diseases associated with myelin sheath degradation. MS patients suffer successive episodes of demyelination resulting in a progressive loss of function of their nervous system. Remyelination of the axons can prevent this.

Intact myelin sheaths are a prerequisite for the healthy functioning of the peripheral and central nervous systems. If the peripheral nervous system (PNS) is damaged, in an accident involving injury to the arms or legs for example, the axons and their myelin sheaths can recover relatively well. However, the central nervous system (CNS) is completely different in this regard as there is no efficient restoration of the axons and therefore of the myelin sheath after a lesion. This means that CNS injuries usually result in permanent paralysis - as in the case of MS when loss of myelin leads to axon degeneration. Further, the capacity of the body to remyelinate decreases dramatically with age.

Researchers recently investigated how remyelination occurs in both peripheral and central nervous systems of mice. The neuroscientists identified a protein called eEF1A1 as a key factor in the process and found that eEF1A1 activated by acetylation prevents the remyelination process, but if eEF1A1 is deactivated by deacetylation, myelin sheaths can be rebuilt. The protein that deacetylates eEF1A1 is the enzyme called histone deacetylase 2 (HDAC2).

The researchers decided to try to control this process by boosting HDAC2 activity and its synthesis in cells. This was achieved by using the active substance theophylline, which has long been used in the treatment of asthma. In a mouse model, the use of theophylline over a period of four days resulted in significant recovery. Restoration of myelin sheaths was particularly impressive in the PNS, where they recovered completely. Regeneration also improved in the CNS, as there was rapid and efficient rebuilding of myelin sheaths in both young and old mice. A low dose of the active substance was sufficient to trigger the improvements - a big plus with regard to the known side effects of theophylline, which occur at higher doses.

Link: https://www.uni-mainz.de/presse/aktuell/11912_ENG_HTML.php

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'In laboratory experiments, a chemical compound found in the shell of the cashew nut (anacardic acid) promotes the repair of myelin...'
https://www.sciencedaily.com/releases/2020/08/200817191737.htm

'In vitro, the addition of the compound to rat cells most responsible for myelination -- oligodendrocyte precursor cells, or OPCs -- spurred induction of IL-33 and rapidly increased the expression of myelin genes and proteins, including dose-dependent increases in myelin basic protein;

In two animal models of demyelination, treatment with the compound increased the relative presence of IL-33-expressing OPCs and led to reduced paralysis;

In an animal model of demyelination treated with the compound, dissection and electron microscopy showed dose-dependent increases in myelination.'

Posted by: Jones at September 1st, 2020 1:39 PM

Our dog has Degenerative Myelopthy. We want to try theophylline to help her restore her myelin sheath. Can you tell me what dose we should try? She is a 62 lb. Boxer. We have a friend with MS also, and we've told her about the study. She would like to know more too.
thank you,

Jeff

Posted by: Jeffrey Stevens at December 30th, 2020 4:46 PM
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