Migration of Cortical Spreading Depression (CSD) in Adult Rats can be Inhibited by Norepinephrine, Clonidine, Yohimbine, and Propranolol

Spreading depression is thought to be a neuronal mechanism that expands the penumbra zone after focal brain ischemia. Furthermore, cortical spreading depression (CSD) is assumed to be a neuronal mechanism underlying migraine aura. Interestingly, the sizes of the penumbra after both focal ischemia and migraine are significantly influenced by adrenergic agonists and antagonists. In human migraine beta-adrenoreceptor blockers are efficiently used for prophylaxis. The particular action of these adrenergic drugs is unknown, but vascular effects are often discussed. Alternatively, it is conceivable that adrenergic compounds act on the neuronal events that are involved in the pathophysiology during ischemia and migraine. Indeed, propranolol efficiently blocked SD in a retinal preparation where no vessels were present. To study whether adrenergic agonists or antagonists influence CSD, we applied different drugs topically to an area of the exposed cortex of anaesthetized adult rats (sodium thiopental, 100mg/kg, i.p.) and observed the migration of CSD-related DC potential deflections with glass microelectrodes at cortical depths of 800 and 1200µm in front of and behind the treated area. The adrenergic agonists norepinephrine (1 mM) and clonidine (0.56 mM) blocked reversibly the migration of CSD. The beta-blocker propranolol (250µM to 1mM) dose-dependently diminished migration velocity or even blocked migration of CSD. The alpha2-antagonist yohimbine (1.75 mM) showed a similar effect as norepinephrine, probably via its affinity to inhibitory 5-HT1A receptors. None of the substances in the concentrations used had an influence on regional cerebral blood flow or on systemic arterial blood pressure. The results show that alpha2-agonists, and beta-adrenoceptor antagonists can inhibit the migration of CSD. Thus, the interference of these compounds with CSD may contribute to their beneficial effect. The effect of beta-receptor antagonists in human migraine needs further exploration, because only a subgroup of migraine patients suffers from migraine with aura and because CSD does not directly activate the trigeminal nociceptive system. Supported by IZKF Jena (IZKF B378–10102).