Thursday, August 1, 2013

The ALS/Anesthetics Hypothesis

Note: This hypothesis has been revised. Please read Anesthetics and Glucocorticoids for ALS for the latest.
Abstract

Amyotrophic lateral sclerosis is a rare and fatal neurodegenerative disease that strikes mostly older adults. This hypothesis is based on the finding that ALS is primarily an immune system disorder. Researchers have identified an elevated inflammatory response in ALS patients that is manifested during both presymptomatic and later stages of the disease. This inflammation is thought to be responsible for its rapid progression. Identifying the cause and nature of the inflammatory response is the key to formulating an effective therapy. Even though researchers have known about the innate immune response in ALS patients for more than a decade, attempts at using traditional anti-inflammatory drugs have not been very successful. The reason is that researchers have not yet identified the cause of the inflammation. There are many types of inflammations and many types of anti-inflammatory substances. By identifying the exact cause of ALS inflammation, we can formulate an effective therapy to eliminate it. We believe that eliminating the cause will not only stop progression, but will also bring the disease into full remission, short of regenerating dead motor neurons. We hypothesize that certain anesthetics such as propofol and sevoflurane can fully eliminate the cause of the inflammation.

The Cause of ALS Inflammation

ALS inflammation is caused by a deficiency in certain neurotransmitter receptors (or neuroreceptors), primarily the GABA-A alpha-1 and glycine alpha-1 receptors. A deficiency means that the receptors lack their normal affinity for their neurotransmitters and, as a result, fail to activate properly. These receptors are used extensively by the inhibitory neurons in the brain stem and spinal cord to control the activation of motor neurons. A deficiency causes an abnormal increase in the activity of the motor neurons and this, in turn, leads to a pathological condition known as neuronal excitotoxicity. But, and this is the crux of this argument, the same receptors are also used by innate immune system cells such as monocytes. If monocytic receptors are functioning normally, they respond to the normal level of neurotransmitters in the cerebrospinal fluid and this inhibits the activity of the monocytes. During an infection, messenger immune molecules are used to block the receptors. The ensuing decrease in inhibition activates the monocytes in order to fight the infection. However, if the receptors are deficient, the monocytes are no longer properly inhibited and the result is the chronic and destructive inflammatory response we observe in ALS patients.

The Therapy

An effective ALS therapy must not only suppress ALS inflammation, it must also eliminate the cause. Doing so will kill two birds with one stone because it eliminates neuronal excitotoxicity as well. It just so happens that certain anesthetics, such as propofol and sevoflurane, can potentiate all the known deficient receptors in ALS patients. Potentiation is the key. It consists of increasing a receptor's affinity for its neurotransmitter, restoring it to its normal functioning level. But what sets these anesthetics apart is that the induced potentiation does not disappear after the drug is eliminated from the body. It can last for days and even weeks. Part of this hypothesis is that, by fully eliminating the chronic inflammatory response, the disease can be put into full remission.

Experimental Confirmation

Although no official trials have been conducted to test this hypothesis, at least a dozen patients have reported significant and, at times, spectacular improvements in their symptoms after undergoing anesthesia with the anesthetics propofol and sevoflurane. Based on their reports, we can deduce a number of therapeutic principles. The optimum propofol dose seems to be about 800 mg. Anything below 200 mg does not seem to be very effective. We also have good reasons to believe that a mixture of propofol and sevoflurane is much more effective than propofol alone.

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