Endothelin-1 a Potential Biomarker of Severity and Recovery from Optic Neuritis in MS, Study Suggests

Endothelin-1 (ET-1) — a molecule with potent blood vessel-narrowing (vasoconstrictive) properties — may be used as a biomarker of severity for optic neuritis in people with multiple sclerosis (MS), a small Italian study suggests. The molecule also may be a potential indicator of patients’ failure to recover from this inflammation of the optic nerve.

The researchers said that detecting ET-1 levels  may help to identify those individuals with MS who might benefit from anti-ET-1 therapies. One such therapy is Tracleer (bosentan), by Actelion Pharmaceuticals — approved for the treatment of pulmonary arterial hypertension — which is currently being evaluated as a potential treatment for MS in a Phase 2 trial in Belgium (2017-001253-13).

The study, “Increased Levels of Endothelin-1 in Cerebrospinal Fluid Are a Marker of Poor Visual Recovery after Optic Neuritis in Multiple Sclerosis Patients,” was published in the journal Disease Markers.

Cerebral blood flow is tightly regulated to meet the brain’s energetic demands. Cerebral hypoperfusion — decreased brain blood supply — has been reported in MS patients, and is directly associated with neurodegeneration, loss of myelin (the protective sheath around nerve fibers), and fatigue.

Researchers hypothesized that cerebral hypoperfusion in MS may be mediated by high levels of ET-1, released by reactive brain cells called astrocytes in MS lesions.

ET-1 induces vasoconstriction, or the tightening of blood vessels due to contraction of their muscular wall. Astrocytes are involved in the regulation of blood flow and inflammation, and respond to sites of nerve cell injury or chronic neurodegeneration by becoming “reactive.”

Optic neuritis results from inflammation and demyelination — loss of myelin — of the optic nerve, which transmits information from the eyes to the brain. Pain and temporary vision loss characterize the condition, and it is one of the most common first manifestations of MS.

According to the team, while most MS patients with optic neuritis recover completely within a few days or weeks, nearly 10% show incomplete recovery with permanent visual damage.

A previous study showed that optic neuritis also is associated with low brain blood supply. However, a potential link between ET-1 levels and this condition in MS remain unclear.

With this in mind, researchers in Italy evaluated whether the levels of ET-1 in MS patients with optic neuritis could be used as a biomarker to predict disease severity and recovery.

The team assessed ET-1 levels in the blood and cerebrospinal fluid (CSF) — the fluid surrounding the brain and spinal cord — of 16 people, to include 12 women and four men. The participants’ ages ranged from 20 to 53 years, and 10 (62.5%) of the individuals had optic neuritis as the first symptom of MS.

While five patients(31%) had a milder form of the condition, 11 participants (69%) were diagnosed with more “aggressive,” or severe, optic neuritis.

Results showed that patients with more severe optic neuritis had significantly higher levels of ET-1 in their CSF, but not in their blood, than those with a milder condition. A ratio of CSF to blood levels of ET-1 also was higher in the group with aggressive optic neuritis.

In contrast, no association was found between ET-1 levels and time of optic neuritis presentation.

“The detection of CSF ET-1 levels may allow identifying groups of ON [optic neuritis] patients potentially benefitting from treatment with ET-1 antagonists (e.g., bosentan),” the researchers said. This would be in contrast to treatment with systemic corticosteroids, which are commonly used to treat acute visual problems in MS patients, they added.

However, the team highlighted that future, and larger studies evaluating ET-1 and other biomarkers associated with reactive astrocytes are required to confirm these findings.

The results suggested that poor visual recovery from optic neuritis in MS may depend on blood hypoperfusion of the optic nerve induced by high levels of ET-1.

Thus ET-1 is “a potential prognostic marker of [optic neuritis] outcome in MS,” the researchers concluded.