Background: Natalizumab inhibits adherence of leukocytes to the cerebral endothelium. Since leukocytes play a role in regulating vascular tone, natalizumab may also affect cerebral vasoregulation. The aim of this observational study was to investigate whether neurovascular coupling and cerebral autoregulation are altered following routine clinical infusion of natalizumab in patients with relapsing-remitting multiple sclerosis. Methods: In 18 patients receiving regular infusion of 300 mg natalizumab, neurovascular coupling to visual stimulation and dynamic cerebral autoregulation (phase and gain of 0.1-Hz oscillations) were measured by transcranial Doppler ultrasound (before, and 2 h and 2 days after the infusion). A repeated examination 28 days after infusion served as a control situation. Results: Neurovascular coupling was altered 2 h and 2 days after infusion with an overshooting initial hemodynamic response. After 28 days, neurovascular coupling was similar to values before the infusion. Dynamic cerebral autoregulation, cerebral blood flow velocity and pulsatility index in the middle and posterior cerebral artery were unaltered. Conclusion: Natalizumab infusion is associated with a temporarily increased initial hyperemia to functional activation. Such a hyperreactivity suggests an increased bioavailability of nitric oxide during functional activation.

Keywords:
Cerebral autoregulation, Cerebral blood flow, Multiple sclerosis, Natalizumab, Neurovascular coupling
1.
Iadecola C: Neurovascular regulation in the normal brain and in Alzheimer’s disease. Nat Rev Neurosci 2004;5:347–360.
2.
Hill MA, Sun Z, Martinez-Lemus L, Meininger GA: New technologies for dissecting the arteriolar myogenic response. Trends Pharmacol Sci 2007;28:308–315.
3.
Morton J, Coles B, Wright K, Gallimore A, Morrow JD, Terry ES, Anning PB, Morgan BP, Dioszeghy V, Kuhn H, Chaitidis P, Hobbs AJ, Jones SA, O’Donnell VB: Circulating neutrophils maintain physiological blood pressure by suppressing bacteria and IFNγ-dependent iNOS expression in the vasculature of healthy mice. Blood 2008;111:5187–5194.
4.
Gavins F, Yilmaz G, Granger DN: The evolving paradigm for blood cell-endothelial cell interactions in the cerebral microcirculation. Microcirculation 2007;14:667–681.
5.
Polman CH, O’Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, Phillips JT, Lublin FD, Giovannoni G, Wajgt A, Toal M, Lynn F, Panzara MA, Sandrock AW: A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006;354:899–910.
6.
Rosengarten B, Osthaus S, Auch D, Kaps M: Effects of acute hyperhomocysteinemia on the neurovascular coupling mechanism in healthy young adults. Stroke 2003;34:446–451.
7.
Rosengarten B, Paulsen S, Molnar S, Kaschel R, Gallhofer B, Kaps M: Acetylcholine esterase inhibitor donepezil improves dynamic cerebrovascular regulation in Alzheimer patients. J Neurol 2006;253:58–64.
8.
Uzuner N, Ozkan S, Gucuyener D, Ozdemir G: Cerebral blood flow velocity changes to visual stimuli in patients with multiple sclerosis. Mult Scler 2002;8:217–221.
9.
Buerk DG, Ances BM, Greenberg JH, Detre JA: Temporal dynamics of brain tissue nitric oxide during functional forepaw stimulation in rats. Neuroimage 2003;18:1–9.
10.
Engelhardt B: Immune cell entry into the central nervous system: involvement of adhesion molecules and chemokines. J Neurol Sci 2008;274:23–26.
11.
Barkalow FJ, Goodman MJ, Gerritsen ME, Mayadas TN: Brain endothelium lack one of two pathways of P-selectin-mediated neutrophil adhesion. Blood 1996;88:4585–4593.
12.
Kaul S, Padgett RC, Heistad DD: Role of platelets and leukocytes in modulation of vascular tone. Ann NY Acad Sci 1994;714:122–135.
13.
Zhang R, Wilson TE, Witkowski S, Cui J, Crandall GG, Levine BD: Inhibition of nitric oxide synthase does not alter dynamic cerebral autoregulation in humans. Am J Physiol Heart Circ Physiol 2004;286:H863–H869.
14.
Reinhard M, Waldkircher Z, Timmer J, Weiller C, Hetzel A: Cerebellar autoregulation dynamics in humans. J Cereb Blood Flow Metab 2008;28:1605–1612.
15.
Sheremata WA, Vollmer TL, Stone LA, Willmer-Hulme AJ, Koller M: A safety and pharmacokinetic study of intravenous natalizumab in patients with MS. Neurology 1999;52:1072–1074.
16.
Calabresi PA, Giovannoni G, Confavreux C, Galetta SL, Havrdova E, Hutchinson M, Kappos L, Miller DH, O’Connor PW, Phillips JT, Polman CH, Radue EW, Rudick RA, Stuart WH, Lublin FD, Wajgt A, Weinstock-Guttman B, Wynn DR, Lynn F, Panzara MA: The incidence and significance of anti-natalizumab antibodies: results from AFFIRM and SENTINEL. Neurology 2007;69:1391–1403.
17.
Hutchinson M: Natalizumab: a new treatment for relapsing remitting multiple sclerosis. Ther Clin Risk Manag 2007;3:259–268.
18.
Stich O, Janowitz D, Rauer S: Spontaneous intracerebral hemorrhage in a patient with multiple sclerosis and tumefactive demyelinating lesion. Mult Scler 2009;15:517–519.
© 2010 S. Karger AG, Basel
2010
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.