Michael Hoffmann

Because of the variable progression of Amyotrophic Lateral Sclerosis, it is difficult for physicians to combine the important findings meaningful. Since the late 1980s, it was well documented that in ALS patients a change in the interaction between the sympathetic and parasympathetic nervous system exists. However this finding is largely ignored by physicians. The regulation of blood pressure here seems to be particularly affected, because incidence of high blood pressure in ALS patients compared to control groups is significantly reduced. The blood pressure is directed by signals from the baroreceptors to a specific area of the brain, the medulla oblongata. From here arise the pyramidal tract and the hypoglossal nerve, the latter innervates the muscles of the tongue. It may be a coincidence for a physician that both the pyramidal tract and the tongue muscles are major pathologic targets in ALS. Also, hand muscle wasting in ALS may be random event for a physician. However, especially the muscles of the hands after e.g. handgrips massively activate the sympathetic nervous system, which regulates blood pressure. Consequently, in a number of ALS cases specifically the muscles of which significantly influence blood pressure in active phycical exercise are affected. In addition, which may be unknown to the physician , the effect of the drug riluzole seems to base upon modulation of blood pressure. The fact that aspirin lowers the life expectancy dramatically in ALS is not understood for a physician, but indeed aspirin modulates sensitivity of the Metaboreflex, which regulates blood pressure via the sympathetic nervous system ( see below).

 

The important question to be asked is: If the sympathetic nervous system in Amyotrophic Lateral Sclerosis patients is more active, why is blood pressure not increased ?
 
The answer can be derived in the following manner: A working muscle activates the Metaboreflex. This system is required to supply the muscles with sufficient oxygen, which is needed to generate energy by its mitochondria. Among other things, it comes in response to a rise in blood pressure and constriction of blood vessels, which increase blood flow. This response is driven by the activity of the sympathetic nervous system and its mediators epinephrine and norepinephrine. As soon as the muscle works, it gets more oxygen delivered by blood flow. Oxygen is energy-rich and has a particular tendency to form free radicals inside mitochondria. This could damage the cell, if this would not be prevented by the action of so-called uncouplers. The working muscle needs to consider whether it uses the oxygen to produce energy, or whether the risk of cell damage is greater and should therefore uncouple. In principle, these two options are kept in balance in healthy people.

 

In Amyotrophic Lateral Sclerosis this regulation does not work properly. The muscle is already showing an increased activity of its uncouplers. This reduces the potential energy content and the ability to form new energy via oxygen in the mitochondria. As a result, the muscle signals via the Metaboreflex and the sympathetic nervous system to the medulla oblongata, to supply more oxygen to compensate the energy deficit. This happens continuously, leading to an over- stimulation of the sympathetic nervous system. If the announcement of uncoupling takes place , it tries simultaneously via other metabolic pathways to resolve the energy deficit , e.g. by increased fat burning. Therefore, ALS patients are slim usually because they increasingly use fat storage for energy generation. As the muscle is already uncoupled and has a higher energy demand, especially during physical exercise, it must uncouple continuously. This is the derailment , which brings about the emergence of ALS. In principle, all substances which are to trigger an ALS suspected are uncoupling agents. These include, in particular heavy metals such as cadmium or some doping agents such as dinitrophenol. It should also be noted that thyroid hormones induce uncoupling , so that will be explain muscle wasting in hyperthyroidism. At this point it has to be noted, that multiple forms of ALS must exist, each whith its own biomolecular cause. However, only one specific ALS is discussed here.

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Thus, the answer to the above asked question is: The dominant Metaboreflex, which is continuously controlled by the muscle uncoupling and the sympathetic nervous system prevents arterial baroreflex, thus can not boost blood pressure. Therefore, in ALS patients blood pressure in general is not increased, and can not be adjusted, for example, detectable by the Schellong test. An increase in blood pressure by certain substances or per se is always associated with a better prognosis in Amyotrophic Lateral Sclerosis patients. This is because an increased blood pressure is an indicator that the causes of this disruption are obviously fought or inhibited, which can slow the progression of ALS. Therefore Riluzole / Rilutek has a positive effect in some way. Furtheron, the sex ratio of ALS incidence could be explained by modulation of the baroreflex, which can control the metaboreflex, by estrogen.

 

Risk factors for the development of Amyotrophic Lateral Sclerosis and options for therapy
 
If the here presented hypothesis is proved in future clinical studies, substances must be tested that can prevent the progression of that specific amyotrophic lateral sclerosis. The key question is then: How can I turn off the over-stimulation of the sympathetic nervous system via the Metaboreflex? Possible targets are formed from the systems involved. The main objective of uncoupling can be in the muscle cells, a combination of all points of attack, however, seems likely.

 

I) The enhanced decoupling muscle
Therapy: Substances exist that may inhibit the uncoupling of mitochondria as e.g. genipin. This substance is contained in extracts from Gardenia fruit extracts. In addition, creatine may be useful as an alternative energy source.
Risk factor: should be to avoid applications that are found to induce uncoupling. This includes the electric therapy after muscle injury.

 

II) The dominant Metaboreflex
Therapy: Caffeine has a direct impact on the strength of the Metaboreflex, because it inhibits its mediators. The cooling of a muscle causes a reduction of the Metaboreflex.
Risk Factors: Aspirin has the opposite effect and should be avoided. Also Weight loss sensitizes the Metaboreflex.

 

III) The excessively active sympathetic nervous system
Therapy: Classical music inhibits this system as well as frequent yawning, however to a lesser proportion only. The ACE inhibitor benazepril in this regard has an effect on the sympathetic nervous system, but it also modulates blood pressure. Therefore, the use of this drug needs to be discussed.
Risk factors: heat increases the signals of the muscle to the sympathetic nervous system. Excitement and stress deliver adrenaline and noradrenaline negative factors.

 

It remains finally to be noted that studies on rodents are not useful and lead to controversial results which provide false leads. Rodents control their movement in particular not extrapyramidal, as a human does. Therefore, the effects on the medulla oblongata and the effects in humans are not to be reproduced in animal experiments. For example, aspirin is a positive influence in SOD mutant mice (a model for amyotrophic lateral sclerosis), and caffeine has a negative impact, so basically just the opposite of the situation in human. This is one reason why the physicians remain in this respect on the spot.

 

references
As the quotations or references are very extensive, I would like to refer to my previous publications under the point nerodegenerative diseases, where the corresponding citations can be found easily. The here presented text should be "understandable" and legible. For detailed information or for discussions you can contact me by email.