Hypoxia in multiple sclerosis; is it the chicken or the egg?

Abstract

Over the past 50 years, intense research effort has taught us a great deal about multiple sclerosis. We know that it is the most common neurological disease affecting the young-middle aged, that it affects two to three times more females than males, and that it is characterized as an autoimmune disease, in which autoreactive T lymphocytes cross the blood-brain barrier, resulting in demyelinating lesions. But despite all the knowledge gained, a key question still remains; what is the initial event that triggers the inflammatory demyelinating process? While most research effort to date has focused on the immune system, more recently, another potential candidate has emerged: hypoxia. Specifically, a growing number of studies have described the presence of hypoxia (both 'virtual' and real) at an early stage of demyelinating lesions, and several groups, including our own, have begun to investigate how manipulation of inspired oxygen levels impacts disease progression. In this review we summarize the findings of these hypoxia studies, and in particular, address three main questions: (i) is the hypoxia found in demyelinating lesions 'virtual' or real; (ii) what causes this hypoxia; and (iii) how does manipulation of inspired oxygen impact disease progression?

Keywords: Multiple sclerosis; blood vessels; blood–brain barrier integrity; hypoxia; inflammation.

Figure 1

Model proposing a vascular trigger of hypoxia and demyelination. In this model, cerebrovascular dysfunction leads to hypoperfusion, triggering a transient hypoxic state in vulnerable areas of the CNS (vascular watershed areas), which results in blood–brain barrier (BBB) disruption and localized leak of serum proteins (fibrinogen, fibronectin and vitronectin) leading to microglial activation. The activated microglia then release cytotoxic factors (cytokines, MMPs, ROS and NO), which damage oligodendrocytes, leading to cell death and demyelination. This, in turn, triggers release of myelin antigenic fragments that stimulate T lymphocytes on surveillance, leading ultimately to a full-blown autoimmune response. MMP = matrix metalloproteinase; NO = nitric oxide; ROS = reactive oxygen species.