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ORIGINAL RESEARCH ARTICLE

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

Jens P. Dreier^*,,1, Jörg Kleeberg, Mesbah Alam^*, Sebastian Major^*,, Matthias Kohl-Bareis, Gabor C. Petzold^||, Ilya Victorov^¶, Ulrich Dirnagl^*,, Tiho P. Obrenovitch^# and Josef Priller^*,**

^* Department of Experimental Neurology and Department of Neurology, Charité Universitätsmedizin, Berlin, Berlin, Germany, Department of Neurology, Centre Universitaire Hospitalier Vaudois, Lausanne, Switzerland; RheinAhrCampus Remagen, University of Applied Sciences Koblenz, Remagen, Germany; ^|| Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts; ^¶ Laboratory of Experimental Neurocytology, Brain Research Institute, Moscow, Russia; ^# Pharmacology, School of Pharmacy, University of Bradford, Bradford, UK; and ^** Laboratory of Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Germany

To whom requests for reprints should be addressed at ¹ Department of Neurology, Charité, Humboldt Universität, Schumannstr. 20/21, 10117 Berlin, Germany. E-mail: jens.dreier{at}charite.de

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.

Key Words: migraine aura • spreading depression • endothelin-1 • stroke • vasospasm