General anesthesia is one of the greatest innovations of
modern medicine. Even within the history of that innovation there have
been tremendous improvements ranging from the administration of ether in the
1960s to very closely monitored combinations of opioids, benzodiazepines, and
inhaled anesthetics in more modern times. The mechanism of action of opioids
and benzodiazepines at the receptor level are known, but the effects of inhaled
anesthetics have been more of a source of speculation. I first became aware of this as an
undergraduate taking physical chemistry (1) when I read about Linus Pauling’s hypothesis
(2). He suggested that microcrystalline
hydrates form from the reaction of anesthetic gases and water molecules at the
membrane surface. Those microcrystalline hydrates then interfere with synaptic
transmission leading to loss of consciousness. Pauling was a physical chemist
who was awarded the Nobel Prize for his work on the hydrogen bond and wrote
about many general anesthetics as not working through hydrogen bond
mechanisms. He was also very optimistic
about the role of physical chemistry in biological systems. Interestingly he
briefly discusses how general anesthesia and the mechanism are important for psychobiology (2):
“The progress that has been made in the field
of molecular biology during this period has related in the main to somatic and
genetic aspects of physiology, rather than to psychic. We may now have reached
the time when a successful molecular attack on psychobiology, including the
nature of encephalonic mechanisms, consciousness, memory, narcosis, sedation,
and similar phenomena, can be initiated. As one of the steps in this attack I
have formulated a rather detailed theory of general anesthesia, which is
described in the following paragraphs.” (p. 15)
He provides an elaborate physical chemistry rationale for
the hydrate-microcrystal theory of anesthesia in this paper. Pauling’s work comes on the cusp of the era of
molecular biology – a field that he is credited with creating. In his original explanation he discussed
x-ray crystallography of crystals and new biologically active protein
structures continue to undergo this analysis when they are isolated and
purified.
Fast forward to a paper I just read in Current Biology
a few days ago (3). It is written in the context of no clear mechanism of action
for volatile inhaled anesthetics since their first observed effects noted over
a century ago despite numbers speculative papers including papers from the past
decade in this same journal. The authors
suggest that a disruption in electron transport in the mitochondria
specifically Complex I of 4 transport
proteins is the area responsible for the effects of general anesthesia. Before
getting to their experiment, a few words about this system.
Electron transport, oxidative phosphorylation, and ATP
synthesis are all tightly coupled processes occurring over 5 proteins known as mitochondrial
complexes (Complexes I-V). Before the
era of molecular and structural biology, these processes were partially deduced
using in vitro methods looking at chemical reactions in mitochondrial
preparations and specific reactions that affect each step. The cofactors were
determined along with the overall stoichiometry of the process. With greater
emphasis on structural and molecular biology there have been additional
hypotheses about the specifics of electron transfer across the complexes and
how ATP synthesis occurs. Although there
is much evidence to support various hypotheses about how all of these processes
occur – in all of my reading it does not appear to be settled science. In fact, some authors talk about emergent properties
of this system that cannot be defined by what is known about the current components
(10). The discussion of emergent properties
is interesting on at least a couple of levels. First, that kind of discussion is
routine in consciousness research. There are no clear-cut biological mechanisms
that generate a conscious state and it is discussed as an emergent property of
the brain. Second, the minimum requirements of a biological system to create emergent
properties is never really discussed. Does the mitochondrial system of electron
transport, generating a proton gradient, ATP synthesis, and tightly couple
oxidation and phosphorylation qualify?
This mechanism may have implications for the science of consciousness. In humans who are in good health and have no known brain diseases - general anesthesia and non-REM (NREM) sleep are considered to the the only states of unconsciousness. During that time the thalamus appears to be inactivated (13). There have been several studies showing that some people dream during NREM sleep so that is not a clear boundary. But in the case of this mechanism questions would include considering the synaptic mechanisms as well as the global neuroanatomical mechanisms as well as the issue of emerging properties of biological systems of varying complexity. What does it mean if a smaller system with emergent properties can turn off a larger system with emergent properties? What is the relationship of the emergent properties between systems?
Moving on to the paper – the authors start by pointing out that neurotransmitter recycling in neurons is dependent on ATP and endocytosis. Further - that Complex I of the mitochondrial electron transport chain (ETC) is the rate limiting step in this process and that disrupting it causes sensitivity to volatile anesthetics (VA). Knockout mice (for a protein in Complex I) were physiologically normal but much more sensitive to VA. The authors hypothesized that VAs decrease presynaptic ATP production by the ETC (oxidative phosphorylation) leading to decreased endocytosis and neurotransmitter cycling, and that the inhibition of Complex I was the primary mechanism. They conduct a number of experiments to illustrate the effects of VA (isoflurane) on the ETC chain looking at perturbations would increase the effect and decrease the effect and conclude that their hypotheses are supported by the data. They conclude that Complex I inhibition may be the mechanism of action of isoflurane. If supported by other studies the mystery of the mechanism of action of VA may be solved after 170 years.I continue to be astonished at the trajectory of brain science
and all of the factors that are needed for these advancements. Even at the level in this paper the
suggestion is that the proposed hypothesis will require additional work. This research occurs at the intersection of a
series of historical hypotheses about the mitochondrial ETC and parallel hypotheses
about the mechanism of action of volatile anesthetic gases. The scientific work
and hypothesizing was built both on previous discovery and advances in technology. In this area advancement was slow and is
still not completely settled in either research area. A lot of science discussed
in the press seems to suggest that there are arbitrary time frames or amounts
of investment for advances and that is obviously not true.
George Dawson, MD, DFAPA
References:
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Graphics Credit:
Misrani A, Tabassum S, Yang L Mitochondrial Dysfunction and Oxidative Stress in Alzheimer’s Disease. Front. Aging Neurosci. 2021; 13:617588. doi: 10.3389/fnagi.2021.617588
