No abstract

Decreased cerebral blood flow (CBF) may contribute to the pathology of multiple sclerosis (MS), but the underlying mechanism is unknown. We investigated whether the potent vasoconstrictor endothelin-1 (ET-1) is involved. We found that, compared with controls, plasma ET-1 levels in patients with MS were significantly elevated in blood drawn from the internal jugular vein and a peripheral vein. The jugular vein/peripheral vein ratio was 1.4 in patients with MS vs. 1.1 in control subjects, suggesting that, in MS, ET-1 is released from the brain to the cerebral circulation. Next, we performed ET-1 immunohistochemistry on postmortem white matter brain samples and found that the likely source of ET-1 release are reactive astrocytes in MS plaques. We then used arterial spin-labeling MRI to noninvasively measure CBF and assess the effect of the administration of the ET-1 antagonist bosentan. CBF was significantly lower in patients with MS than in control subjects and increased to control values after bosentan administration. These data demonstrate that reduced CBF in MS is mediated by ET-1, which is likely released in the cerebral circulation from reactive astrocytes in plaques. Restoring CBF by interfering with the ET-1 system warrants further investigation as a potential new therapeutic target for MS.M ultiple sclerosis (MS) is a poorly understood chronic disorder of the CNS, characterized by focal inflammatory demyelinating lesions and degenerative processes (1). Immune responses play a crucial role in the pathogenesis of focal lesions that constitute the pathological substrate for relapses. However, the underlying mechanism of the progressive degeneration of axons, which is the primary determinant of long-term disability in MS, is not clear (2), and treatment is lacking.A number of studies found that cerebral blood flow (CBF) is globally impaired in early diagnosed relapsing-remitting MS and primary progressive MS, indicating that it is an integral part of the disease that is already present at the time of diagnosis (3-5). Animal studies have shown that chronic hypoperfusion of the brain can lead to neurodegenerative changes, including axonal degeneration (6).The underlying mechanism of reduced CBF in MS is unknown. Plasma levels of the potent vasoconstrictor endothelin-1 (ET-1) (7) were found to be elevated in patients with MS (8), and this was associated with alterations of extraocular blood flow (9). The reason for the increase in ET-1 levels in MS was unclear, and the findings have not received much attention. We hypothesized that ET-1 might play a role in reducing CBF in MS. ResultsInternal Jugular Vein ET-1 Levels. Individuals with critical illness and systemic conditions known to be associated with increased levels of ET-1 were excluded (10). Ten subjects with MS according to the revised McDonald criteria (11) and 10 matched control subjects were included. Patients with MS were autonomously seeking treatment at the department of cardiovascular and thoracic surgery of Onze-Lieve-Vrouw Ziekenhuis Aalst for so-c...

The exact pathogenesis of multiple sclerosis (MS) is incompletely understood. Although auto-immune responses have an important role in the development of hallmark focal demyelinating lesions, the underlying mechanism of axonal degeneration, the other key player in MS pathology and main determinant of long-term disability, remains unclear and corresponds poorly with inflammatory disease activity. Perfusion-weighted imaging studies have demonstrated that there is a widespread cerebral hypoperfusion in patients with MS, which is present from the early beginning to more advanced disease stages. This reduced cerebral blood flow (CBF) does not seems to be secondary to loss of axonal integrity with decreased metabolic demands but appears to be mediated by elevated levels of the potent vasospastic peptide endothelin-1 in the cerebral circulation. Evidence is evolving that cerebral hypoperfusion in MS is associated with chronic hypoxia, focal lesion formation, diffuse axonal degeneration, cognitive dysfunction, and fatigue. Restoring CBF may therefore emerge as a new therapeutic target in MS.