Endothelin-1–Induced Spreading Depression in Rats Is Associated with a Microarea of Selective Neuronal Necrosis

Abstract

Two different theories of migraine aura exist: In the vascular theory of Wolff, intracerebral vasoconstriction causes migraine aura via energy deficiency, whereas in the neuronal theory of Leão and Morison, spreading depression (SD) initiates the aura. Recently, it has been shown that the cerebrovascular constrictor endothelin-1 (ET-1) elicits SD when applied to the cortical surface, a finding that could provide a bridge between the vascular and the neuronal theories of migraine aura. Several arguments support the notion that ET-1–induced SD results from local vasoconstriction, but definite proof is missing. If ET-1 induces SD via vasoconstriction/ischemia, then neuronal damage is likely to occur, contrasting with the fact that SD in the otherwise normal cortex is not associated with any lesion. To test this hypothesis, we have performed a comprehensive histologic study of the effects of ET-1 when applied topically to the cerebral cortex of halothane-anesthetized rats. Our assessment included histologic stainings and immunohistochemistry for glial fibrillary acidic protein, heat shock protein 70, and transferase dUTP nick-end labeling assay. During ET-1 application, we recorded (i) subarachnoid direct current (DC) electroencephalogram, (ii) local cerebral blood flow by laser-Doppler flowmetry, and (iii) changes of oxyhemoglobin and deoxyhemoglobin by spectroscopy. At an ET-1 concentration of 1 μM, at which only 6 of 12 animals generated SD, a microarea with selective neuronal death was found only in those animals demonstrating SD. In another five selected animals, which had not shown SD in response to ET-1, SD was triggered at a second cranial window by KCl and propagated from there to the window exposed to ET-1. This treatment also resulted in a microarea of neuronal damage. In contrast, SD invading from outside did not induce neuronal damage in the absence of ET-1 (n = 4) or in the presence of ET-1 if ET-1 was coapplied with BQ-123, an ET_A receptor antagonist (n = 4). In conclusion, SD in presence of ET-1 induced a microarea of selective neuronal necrosis no matter where the SD originated. This effect of ET-1 appears to be mediated by the ET_A receptor.

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References

Wolff HG. Headache and Other Head Pain (6th ed.). New York: Oxford University Press, 1963.

Leão AAP, Morison RS. Propagation of spreading cortical depression. J Neurophysiol8:33–45, 1945.

Nedergaard M, Hansen AJ. Spreading depression is not associated with neuronal injury in the normal brain. Brain Res449:395–398, 1988.

Lauritzen M. Pathophysiology of the migraine aura. The spreading depression theory. Brain117:199–210, 1994.

Hadjikhani N, Sanchez Del Rio M, Wu O, Schwartz D, Bakker D, Fischl B, Kwong KK, Cutrer FM, Rosen BR, Tootell RB, Sorensen AG, Moskowitz MA. Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc Natl Acad Sci U S A98: 4687–4692, 2001.

Janzen R, Tanzer A, Zschocke S, Dieckmann H. Postangiographische Spätreaktionen der Hirngefáße bei Migränekranken. Z Neurol201:24–42, 1972.

Lassen NA, Friberg L. Cerebral blood flow measured by xenon 133 using the intraarterial injection method or inhalation combined with SPECT in migraine research. In: Olesen J, Ed. Migraine and Other Headaches. The Vascular Mechanisms. New York: Raven Press, pp5–13, 1991.

Olesen J, Friberg L, Olsen TS, Andersen AR, Lassen NA, Hansen PE, Karle A. Ischaemia-induced (symptomatic) migraine attacks may be more frequent than migraine-induced ischaemic insults. Brain116:187–202, 1993.

Dichgans M, Mayer M, Uttner I, Bruning R, Muller-Hocker J, Rungger G, Ebke M, Klockgether T, Gasser T. The phenotypic spectrum of CADASIL: clinical findings in 102 cases. Ann Neurol44:731–739, 1988.

10.

Call GK, Fleming MC, Sealfon S, Levine H, Kistler JP, Fisher CM. Reversible cerebral segmental vasoconstriction. Stroke19:1159–1170, 1988.

11.

Bousser MG, Welch KM. Relation between migraine and stroke. Lancet Neurol4:533–542, 2005.

12.

Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature332:411–415, 1988.

13.

Dreier JP, Kleeberg J, Petzold G, Priller J, Windmuller O, Orzechowski HD, Lindauer U, Heinemann U, Einhaupl KM, Dirnagl U. Endothelin-1 potently induces Leao’s cortical spreading depression in vivo in the rat: a model for an endothelial trigger of migrainous aura? Brain125: 102–112, 2002.

14.

Gallai V, Sarchielli P, Firenze C, Trequattrini A, Paciaroni M, Usai F, Palumbo R. Endothelin 1 in migraine and tension-type headache. Acta Neurol Scand89:47–55, 1994.

15.

Kallela M, Färkkilä M, Saijonmaa O, Fyhrquist F. Endothelin in migraine patients. Cephalgia18:329–332, 1998.

16.

Hasselblatt M, Kohler J, Volles E, Ehrenreich H. Simultaneous monitoring of endothelin-1 and vasopressin plasma levels in migraine. Neuroreport10:423–425, 1999.

17.

Tzourio C, El Amrani M, Poirier O, Nicaud V, Bousser MG, Alperovitch A. Association between migraine and endothelin type A receptor (ETA −231 A/G) gene polymorphism. Neurology56:1273–1277, 2001.

18.

Kleeberg J, Petzold GC, Major S, Dirnagl U, Dreier JP. ET-1 induces cortical spreading depression via activation of the ETA receptor/phospholipase C pathway in vivo. Am J Physiol Heart Circ Physiol286: H1339–H1346, 2004.

19.

Kohl M, Lindauer U, Royl G, Kuhl M, Gold L, Villringer A, Dirnagl U. Physical model for the spectroscopic analysis of cortical intrinsic optical signals. Phys Med Biol45:3749–3764, 2000.

20.

Dreier JP, Ebert N, Priller J, Megow D, Lindauer U, Klee R, Reuter U, Imai Y, Einhaupl KM, Victorov I, Dirnagl U. Products of hemolysis in the subarachnoid space inducing spreading ischemia in the cortex and focal necrosis in rats: a model for delayed ischemic neurological deficits after subarachnoid hemorrhage? J Neurosurg93:658–666, 2000.

21.

Herrera DG, Maysinger D, Almazan G, Funnel R, Cuello AC. Analysis of c-Fos and glial fibrillary acidic protein (GFAP) expression following topical application of potassium chloride (KCl) to the brain surface. Brain Res784:771–781, 1998.

22.

Dreier JP, Korner K, Ebert N, Gorner A, Rubin I, Back T, Lindauer U, Wolf T, Villringer A, Einhaupl KM, Lauritzen M, Dirnagl U. Nitric oxide scavenging by hemoglobin or nitric oxide synthase inhibition by N-nitro-L-arginine induces cortical spreading ischemia when K⁺ is increased in the subarachnoid space. J Cereb Blood Flow Metab18: 978–990, 1998.

23.

Wolf T, Lindauer U, Reuter U, Back T, Villringer A, Einhaupl K, Dirnagl U. Noninvasive near infrared spectroscopy monitoring of regional cerebral blood oxygenation changes during peri-infarct depolarizations in focal cerebral ischemia in the rat. J Cereb Blood Flow Metab17:950–954, 1997.

24.

Kohl M, Lindauer U, Dirnagl U, Villringer A. Separation of changes in light scattering and chromophore concentrations during cortical spreading depression in rats. Opt Lett23:555–557, 1998.

25.

Nallet H, MacKenzie ET, Roussel S. The nature of penumbral depolarizations following focal cerebral ischemia in the rat. Brain Res842:148–158, 1999.

26.

Busch E, Gyngell ML, Eis M, Hoehn-Berlage M, Hossmann KA. Potassium-induced cortical spreading depressions during focal cerebral ischemia in rats: contribution to lesion growth assessed by diffusion-weighted NMR and biochemical imaging. J Cereb Blood Flow Metab16:1090–1099, 1996.

27.

Takano K, Latour LL, Formato JE, Carano RA, Helmer KG, Hasegawa Y, Sotak CH, Fisher M. The role of spreading depression in focal ischemia evaluated by diffusion mapping. Ann Neurol39:308–318, 1996.

28.

Nedergaard M, Hansen AJ. Characterization of cortical depolarizations evoked in focal cerebral ischemia. J Cereb Blood Flow Metab13:568–574, 1993.

29.

Muller M, Somjen GG. Na(+) and K(+) concentrations, extra- and intracellular voltages, and the effect of TTX in hypoxic rat hippocampal slices. J Neurophysiol83:735–745, 2000.

30.

Nowicky AV, Duchen MR. Changes in [Ca2+]i and membrane currents during impaired mitochondrial metabolism in dissociated rat hippocampal neurons. J Physiol507:131–145, 1998.

31.

Gill R, Andine P, Hillered L, Persson L, Hagberg H. The effect of MK-801 on cortical spreading depression in the penumbral zone following focal ischaemia in the rat. J Cereb Blood Flow Metab12:371–379, 1992.

32.

Mies G, Iijima T, Hossmann KA. Correlation between peri-infarct DC shifts and ischaemic neuronal damage in rat. Neuroreport4:709–711, 1993.

33.

Hartings JA, Rolli ML, Lu XC, Tortella FC. Delayed secondary phase of peri-infarct depolarizations after focal cerebral ischemia: relation to infarct growth and neuroprotection. J Neurosci23:11602–11610, 2003.

34.

Selman WR, Lust WD, Pundik S, Zhou Y, Ratcheson RA. Compromised metabolic recovery following spontaneous spreading depression in the penumbra. Brain Res999:167–174, 2004.

35.

Macrae M, Robinson MJ, Graham DI, Reid JL, McCulloch J. Endothelin-1-induced reductions in cerebral blood flow: dose dependency, time course, and neuropathological consequences. J Cereb Blood Flow Metab13:276–284, 1993.

36.

Fuxe K, Bjelke B, Andbjer B, Grahn H, Rimondini R, Agnati LF. Endothelin-1 induced lesions of the frontoparietal cortex of the rat. A possible model of focal cortical ischaemia. Neuroreport8:2623–2629, 1997.

37.

Wilmshurst PT, Nightingale S, Walsh KP, Morrison WL. Effect on migraine of closure of cardiac right-to-left shunts to prevent recurrence of decompression illness or stroke or for haemodynamic reasons. Lancet356:1648–1651, 2000.

38.

Kruit MC, van Buchem MA, Hofman PA, Bakkers JT, Terwindt GM, Ferrari MD, Launer LJ. Migraine as a risk factor for subclinical brain lesions. JAMA291:427–434, 2004.

39.

Kruit MC, Launer LJ, van Buchem MA, Terwindt GM, Ferrari MD. MRI findings in migraine. Rev Neurol (Paris).161:661–665, 2005.

40.

Goadsby PJ. Is migraine a progressive disorder? Considering the clinical implications of new research data on migraine and brain lesions. Med J Aust182:103–104, 2005.

41.

Saito R, Graf R, Hubel K, Taguchi J, Rosner G, Fujita T, Heiss WD. Halothane, but not alpha-chloralose, blocks potassium-evoked cortical spreading depression in cats. Brain Res699:109–115, 1995.

42.

Nedergaard M, Cooper AJ, Goldman SA. Gap junctions are required for the propagation of spreading depression. J Neurobiol28:433–444, 1995.

43.

Blomstrand F, Venance L, Siren AL, Ezan P, Hanse E, Glowinski J, Ehrenreich H, Giaume C. Endothelins regulate astrocyte gap junctions in rat hippocampal slices. Eur J Neurosci19:1005–1015, 2004.

44.

Boillot A, Vallet B, Marty J, Auclerc A, Barale F. Effects of halothane, enflurane and isoflurane on contraction of rat aorta induced by endothelin-1. Br J Anaesth75:761–767, 1995.

45.

Venance L, Premont J, Glowinski J, Giaume C. Gap junctional communication and pharmacological heterogeneity in astrocytes cultured from the rat striatum. J Physiol1510:429–440, 1998.

46.

Linde R, Schmalbruch IK, Paulson OB, Madsen PL. The Kety-Schmidt technique for repeated measurements of global cerebral blood flow and metabolism in the conscious rat. Acta Physiol Scand165:395–401, 1999.