There is mounting evidence that the brain blood supply is affected in MS. Perfusion MRI studies have found that blood flow is globally impaired in the normal appearing brain of both relapsing and progressive forms of MS. Interestingly, there appears to be an association between this and cognitive (memory and intelligence) dysfunction in MS. In animal models, chronic hypoperfusion of the brain appears to lead to energy failure in the mitochondrion (the power house of every cell) through oxygen starvation, releasing free radicals and finally resulting in axonal degeneration. This theory is further backed up by the fact that there is a predilection for MS lesions in the anterior and occipital horns of the lateral ventricles, in the so-called watershed regions of the arterial circulation susceptible to hypoperfusion (see figure below).
Energy failure caused by mitochondrial dysfunction is therefore thought to be a major contributor in axonal degeneration in MS. N-acetylaspartate or NAA synthesized in the mitochondria, is both a marker of neuro-axonal mitochondrial function and integrity. Studies looking at NAA in normal appearing brain tissue in MS have found that NAA is more likely to be reduced in progressive MS compared to RRMS and those without MS.
So, what if you can reverse both at the source by increasing cerebral perfusion?
That is exactly what one group are trying to achieve (see abstract below). It is too early to say what the outcome will be as they have just started the work; but I thought it would be useful to look at their strategy in greater detail.
The ROCHIMS (Role Of Cerebral Hypoperfusion In MS) study will be using the vasoactive agent bosentan (endothelin-1 blocker) to explore whether prolonged treatment can restore cerebral blood and enhance NAA levels, reflecting improved mitochondrial function and axonal integrity. The underlying hypothesis is that reduced blood flow in MS is mediated by endothelin-1 in the brain circulation.
Bosentan is already licensed for pulmonary arterial hypertension (Actelion Pharmaceuticals) and has been shown to reduce the number of ulcers in the fingers in those with scleroderma (10% develop pulmonary arterial hypertension). It can cause liver damage and is category X for pregnancy (studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience) meaning that women must not become pregnant whilst taking it.
In cerebral malaria, endothelin-1 induced vasculopathy has been demonstrated to contribute to the evolution of cerebral malaria. Reduced brain endothelial activation in a mouse model of cerebral malaria prevented blood-brain barrier disruption, cerebral vasconstriction, that eventually lead to improved cognitive function and improved survival in the infected mice.
The ROCHIMS study commenced recruitment in Sep 2017 and is expected to end recruitment in Apr 2019; so watch this space!
Trials. 2019 Mar 14;20(1):164. doi: 10.1186/s13063-019-3252-4.
Role of cerebral hypoperfusion in multiple sclerosis (ROCHIMS): study protocol for a proof-of-concept randomized controlled trial with bosentan.
Hostenbach S, Pauwels A, Michiels V, Raeymaekers H, Van Binst AM, Van Merhaeghen-Wieleman A, Van Schuerbeek P, De Keyser J, D’Haeseleer M.
Background: Axonal degeneration is related to long-term disability in patients with multiple sclerosis (MS). The underlying mechanism remains ill understood but appears to involve axonal energetic dysfunction. A globally impaired cerebral blood flow (CBF) has been observed in the normal-appearing white matter (NAWM) of patients with MS, which is probably related to astrocytic overexpression of endothelin-1 (ET-1). Cerebral hypoperfusion has been associated with reduced mitochondrial activity and disabling symptoms (e.g. fatigue and cognitive decline) of MS. Countering this process could therefore be beneficial in the disease course. Short-term CBF restoration with a single 62.5-mg dose of the ET-1 receptor antagonist bosentan has already been demonstrated in patients with MS.
Methods: The ROCHIMS study is a proof-of-concept double-blind randomized clinical trial in which patients with relapsing-remitting MS will receive either 62.5 mg bosentan or matching placebo twice daily during 28 ± 2 days. Clinical evaluation and brain magnetic resonance imaging (MRI) will be performed at baseline and treatment termination. Based on previous work, we expect a global increase of CBF in the individuals treated with bosentan. The primary outcome measure is the change of N-acetyl aspartate in centrum semiovale NAWM, which is a marker of regional axonal mitochondrial activity. Other parameters of interest include changes in fatigue, cognition, motor function, depression, and brain volume.
Discussion: We hypothesize that restoring cerebral hypoperfusion in MS patients improves axonal metabolism. Early positive effects on fatigue and cognitive dysfunction related to MS might additionally be detected. There is a medical need for drugs that can slow down the progressive axonal degeneration in MS, making this an important topic of interest.