The “Which came first – the chicken or the egg?” dilemma is a classic philosophical question used to characterize a situation in which there is a lack of clarity on which circumstance precedes the other. Interestingly, scientists have tried to answer the question from an evolutionary point of view, thus putting the matter to rest—but that is a topic for another time.
Yang and Dunn, in their study on multiple sclerosis (MS) disease progression, wrote “hypoxia has been associated with MS for years” and that it “may be critical in the context of MS.” However, Halder and Milner, in their paper titled “Hypoxia in multiple sclerosis; is it the chicken or the egg?”, pose an interesting question: does hypoxia drive disease progression, or is the opposite the case?
In their review, they attempted to answer 3 main questions:
- Is the hypoxia found in demyelinating lesions “virtual” or “real”?
- What then causes this hypoxia?
- How does manipulation of inspired oxygen impact disease progression?
Examining the Evidence
The question of whether hypoxia found in demyelinating lesions is “virtual” or “real” rests on the notion of whether true oxygen deficiency occurs, or whether energy demands simply outstrip supply. Halder and Milner wrote:
“studies of axonal pathology in multiple sclerosis samples revealed marked suppression of mitochondrial respiratory chain complexes, supporting the hypothesis that inflammation-associated nitric oxide (NO) or reactive oxygen species (ROS) inhibits mitochondrial function in chronically demyelinated axons, resulting in reduced ATP production, which is then outstripped by the increased energy demand of hyperexcitable demyelinated axons, thus creating an energy-deficient metabolic crisis, a situation termed histotoxic or virtual hypoxia.”
However, Halder and Milner conceded that there is also much evidence that supports the theory that true hypoxia occurs in MS. They wrote, “Over the past 5–6 years, studies of multiple sclerosis patients and the animal multiple sclerosis model, experimental autoimmune encephalomyelitis (EAE), have demonstrated that oxygen deficiency exists within demyelinating lesions.”
Yang and Dunn also support the notion that true hypoxia can be observed in MS. They wrote, “Several groups have used magnetic resonance imaging (MRI) and showed that patients with MS have reduced cerebral blood flow (CBF) compared to controls, which is likely caused by impaired vasodilation.” This ultimately has the effect of impairing neuronal function due to hypoxia-induced metabolic stress.
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One of the most significant drivers of hypoxia in MS is inflammation. There are a variety of mechanisms that cause this to happen. Yang and Dunn wrote, “ROS that are released during inflammation can damage the vascular endothelium and reduce the endothelial smooth muscles’ ability to relax and cause vasodilation.” In addition, inflammation can also cause the physical obstruction of small blood vessels, which is a phenomenon similar to that seen in ischemic stroke.
However, Halder and Milner suggest that while inflammation can cause hypoxia, hypoxia can also cause inflammation (hence the chicken or the egg dilemma). They wrote that “transient hypoxic episodes triggered by vascular dysfunction could lead to inflammation,” resulting in what has been coined the “hypoxia-inflammatory cycle.” Perhaps characterizing the association between hypoxia and inflammation as being circulatory in nature is the best way to describe their reciprocal relationship.
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In a nod to this theory, Yang and Dunn wrote, “It is difficult to determine whether hypoxia or inflammation is the primary event. However, it is likely that hypoxia exacerbates inflammation and vice versa, thereby creating a hypoxia–inflammation cycle. Thus, hypoxia could not only be a potential biomarker of pro-inflammatory activities, but also a therapeutic target.”
Halder and Milner went on to describe contradicting studies on the impact of oxygen manipulation on MS progression. For example, a clinical study demonstrated that hyperbaric oxygen therapy alleviated clinical symptoms in a majority of MS patients studied. However, another clinical study showed that experimental mice that were put under chronic mild hypoxic conditions demonstrated a reduction in neurological deficits.
Halder and Milner proposed an explanation for these seemingly contradictory findings. They wrote, “If hypoxia is an early trigger of at least some types of multiple sclerosis, it follows that oxygen supplementation at an early stage of lesion development could overcome this oxygen deficit, thus preventing the pathological cascade leading to demyelination.”
However, “if oxygen therapy is applied at a later stage of lesion development, for instance, during the remission phase, it might fail, not just because it is too late to prevent the hypoxic-inflammatory cycle, but also because oxygen supplementation may prevent monocyte apoptosis during clinical remission,” they wrote. In other words, it all boils down to when in the MS disease stage that oxygen supplementation is applied.
Targeting the Hypoxia-Inflammation Cycle
It is clear that two processes are observed in MS: hypoxia and inflammation. The latest evidence suggests that one triggers the other, and vice versa, meaning that future therapies need to be able to target both strategically.
Halder and Milner concluded that “while it seems likely that hypoxia plays a pivotal role in triggering the pathogenesis of demyelinating disease, more studies are required to determine the cause of this hypoxia, how it can be prevented or overcome, and at what time point of disease progression, manipulation of inspired oxygen might become a realistic therapeutic option in multiple sclerosis.”
Halder SK, Milner R. Hypoxia in multiple sclerosis; is it the chicken or the egg? Brain. Published online December 22, 2020. doi:10.1093/brain/awaa427
Yang R, Dunn JF. Multiple sclerosis disease progression: contributions from a hypoxia-inflammation cycle. Mult Scler. Published online July 27, 2018. doi:10.1177/1352458518791683