title: Cerebral hypoperfusion in multiple sclerosis is reversible and mediated by endothelin-1.
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.
authors.affiliation: Department of Neurology, Universitair Ziekenhuis Brussel, 1090 Brussels, Belgium.
authors.forename: Miguel
authors.initials: M
authors.lastname: D'haeseleer
authors.forename: Roel
authors.initials: R
authors.lastname: Beelen
authors.forename: Yves
authors.initials: Y
authors.lastname: Fierens
authors.forename: Melissa
authors.initials: M
authors.lastname: Cambron
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Vanbinst
authors.forename: Christian
authors.initials: C
authors.lastname: Verborgh
authors.forename: Johan
authors.initials: J
authors.lastname: Demey
authors.forename: Jacques
authors.initials: J
authors.lastname: De Keyser
mesh_terms: D001253:Astrocytes / Q000378:metabolism*; D000077300:Bosentan; D002560:Cerebrovascular Circulation / Q000187:drug effects* / Q000502:physiology; D019332:Endothelin-1 / Q000037:antagonists & inhibitors* / Q000097:blood / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000503:physiopathology*; D013113:Spin Labels; D018709:Statistics, Nonparametric; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D019332:Endothelin-1; D013113:Spin Labels; D013449:Sulfonamides; D000077300:Bosentan