title: Migraine prophylaxis, ischemic depolarizations, and stroke outcomes in mice.
abstract: OBJECTIVE
  Migraine with aura is an established stroke risk factor, and excitatory mechanisms such as spreading depression (SD) are implicated in the pathogenesis of both migraine and stroke. Spontaneous SD waves originate within the peri-infarct tissue and exacerbate the metabolic mismatch during focal cerebral ischemia. Genetically enhanced SD susceptibility facilitates anoxic depolarizations and peri-infarct SDs and accelerates infarct growth, suggesting that susceptibility to SD is a critical determinant of vulnerability to ischemic injury. Because chronic treatment with migraine prophylactic drugs suppresses SD susceptibility, we tested whether migraine prophylaxis can also suppress ischemic depolarizations and improve stroke outcome.
  
  
  METHODS
  We measured the cortical susceptibility to SD and ischemic depolarizations, and determined tissue and neurological outcomes after middle cerebral artery occlusion in wild-type and familial hemiplegic migraine type 1 knock-in mice treated with vehicle, topiramate or lamotrigine daily for 7 weeks or as a single dose shortly before testing.
  
  
  RESULTS
  Chronic treatment with topiramate or lamotrigine reduced the susceptibility to KCl-induced or electric stimulation-induced SDs as well as ischemic depolarizations in both wild-type and familial hemiplegic migraine type 1 mutant mice. Consequently, both tissue and neurological outcomes were improved. Notably, treatment with a single dose of either drug was ineffective.
  
  
  CONCLUSIONS
  These data underscore the importance of hyperexcitability as a mechanism for increased stroke risk in migraineurs, and suggest that migraine prophylaxis may not only prevent migraine attacks but also protect migraineurs against ischemic injury.
authors.affiliation: From the Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown (K.E.-H., J.H.L., N.Y., E.S.Y., A.D., Y.W., Y.Z., A.C., B.S., C.A.); Department of Neurology (M.D.F., A.M.J.M.v.d.M), and Department of Human Genetics, Leiden University Medical Centre, The Netherlands (A.M.J.M.v.d.M); and Stroke Service and Neuroscience Intensive Care Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston (C.A.).
authors.forename: Katharina
authors.initials: K
authors.lastname: Eikermann-Haerter
authors.affiliation: From the Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown (K.E.-H., J.H.L., N.Y., E.S.Y., A.D., Y.W., Y.Z., A.C., B.S., C.A.); Department of Neurology (M.D.F., A.M.J.M.v.d.M), and Department of Human Genetics, Leiden University Medical Centre, The Netherlands (A.M.J.M.v.d.M); and Stroke Service and Neuroscience Intensive Care Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston (C.A.).
authors.forename: Jeong Hyun
authors.initials: JH
authors.lastname: Lee
authors.affiliation: From the Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown (K.E.-H., J.H.L., N.Y., E.S.Y., A.D., Y.W., Y.Z., A.C., B.S., C.A.); Department of Neurology (M.D.F., A.M.J.M.v.d.M), and Department of Human Genetics, Leiden University Medical Centre, The Netherlands (A.M.J.M.v.d.M); and Stroke Service and Neuroscience Intensive Care Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston (C.A.).
authors.forename: Nilufer
authors.initials: N
authors.lastname: Yalcin
authors.affiliation: From the Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown (K.E.-H., J.H.L., N.Y., E.S.Y., A.D., Y.W., Y.Z., A.C., B.S., C.A.); Department of Neurology (M.D.F., A.M.J.M.v.d.M), and Department of Human Genetics, Leiden University Medical Centre, The Netherlands (A.M.J.M.v.d.M); and Stroke Service and Neuroscience Intensive Care Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston (C.A.).
authors.forename: Esther S
authors.initials: ES
authors.lastname: Yu
authors.affiliation: From the Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown (K.E.-H., J.H.L., N.Y., E.S.Y., A.D., Y.W., Y.Z., A.C., B.S., C.A.); Department of Neurology (M.D.F., A.M.J.M.v.d.M), and Department of Human Genetics, Leiden University Medical Centre, The Netherlands (A.M.J.M.v.d.M); and Stroke Service and Neuroscience Intensive Care Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston (C.A.).
authors.forename: Ali
authors.initials: A
authors.lastname: Daneshmand
authors.affiliation: From the Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown (K.E.-H., J.H.L., N.Y., E.S.Y., A.D., Y.W., Y.Z., A.C., B.S., C.A.); Department of Neurology (M.D.F., A.M.J.M.v.d.M), and Department of Human Genetics, Leiden University Medical Centre, The Netherlands (A.M.J.M.v.d.M); and Stroke Service and Neuroscience Intensive Care Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston (C.A.).
authors.forename: Ying
authors.initials: Y
authors.lastname: Wei
authors.affiliation: From the Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown (K.E.-H., J.H.L., N.Y., E.S.Y., A.D., Y.W., Y.Z., A.C., B.S., C.A.); Department of Neurology (M.D.F., A.M.J.M.v.d.M), and Department of Human Genetics, Leiden University Medical Centre, The Netherlands (A.M.J.M.v.d.M); and Stroke Service and Neuroscience Intensive Care Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston (C.A.).
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: From the Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown (K.E.-H., J.H.L., N.Y., E.S.Y., A.D., Y.W., Y.Z., A.C., B.S., C.A.); Department of Neurology (M.D.F., A.M.J.M.v.d.M), and Department of Human Genetics, Leiden University Medical Centre, The Netherlands (A.M.J.M.v.d.M); and Stroke Service and Neuroscience Intensive Care Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston (C.A.).
authors.forename: Anil
authors.initials: A
authors.lastname: Can
authors.affiliation: From the Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown (K.E.-H., J.H.L., N.Y., E.S.Y., A.D., Y.W., Y.Z., A.C., B.S., C.A.); Department of Neurology (M.D.F., A.M.J.M.v.d.M), and Department of Human Genetics, Leiden University Medical Centre, The Netherlands (A.M.J.M.v.d.M); and Stroke Service and Neuroscience Intensive Care Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston (C.A.).
authors.forename: Buse
authors.initials: B
authors.lastname: Sengul
authors.affiliation: From the Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown (K.E.-H., J.H.L., N.Y., E.S.Y., A.D., Y.W., Y.Z., A.C., B.S., C.A.); Department of Neurology (M.D.F., A.M.J.M.v.d.M), and Department of Human Genetics, Leiden University Medical Centre, The Netherlands (A.M.J.M.v.d.M); and Stroke Service and Neuroscience Intensive Care Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston (C.A.).
authors.forename: Michel D
authors.initials: MD
authors.lastname: Ferrari
authors.affiliation: From the Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown (K.E.-H., J.H.L., N.Y., E.S.Y., A.D., Y.W., Y.Z., A.C., B.S., C.A.); Department of Neurology (M.D.F., A.M.J.M.v.d.M), and Department of Human Genetics, Leiden University Medical Centre, The Netherlands (A.M.J.M.v.d.M); and Stroke Service and Neuroscience Intensive Care Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston (C.A.).
authors.forename: Arn M J M
authors.initials: AM
authors.lastname: van den Maagdenberg
authors.affiliation: From the Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown (K.E.-H., J.H.L., N.Y., E.S.Y., A.D., Y.W., Y.Z., A.C., B.S., C.A.); Department of Neurology (M.D.F., A.M.J.M.v.d.M), and Department of Human Genetics, Leiden University Medical Centre, The Netherlands (A.M.J.M.v.d.M); and Stroke Service and Neuroscience Intensive Care Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston (C.A.). cayata@partners.org.
authors.forename: Cenk
authors.initials: C
authors.lastname: Ayata
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002545:Brain Ischemia; D020864:Calcium Channels, N-Type / Q000235:genetics; D018890:Chemoprevention; D013181:Cortical Spreading Depression / Q000187:drug effects* / Q000235:genetics; D005632:Fructose / Q000031:analogs & derivatives* / Q000494:pharmacology; D055879:Gene Knock-In Techniques; D020244:Infarction, Middle Cerebral Artery; D000077213:Lamotrigine; D051379:Mice; D008881:Migraine Disorders / Q000517:prevention & control*; D020521:Stroke; D000077236:Topiramate; D014227:Triazines / Q000494:pharmacology*
chemical_list: D000927:Anticonvulsants; D020864:Calcium Channels, N-Type; D005632:Fructose; D000077213:Lamotrigine; D000077236:Topiramate; D014227:Triazines
keywords: cortical spreading depression; lamotrigine; middle cerebral artery occlusion; migraine; prophylaxis; stroke; topiramate