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Cortical spreading depression (CSD) is a key pathogenetic step in migraine with aura. Dysfunctions of voltage-dependent and receptor-operated channels have been implicated in the generation of CSD and in the pathophysiology of migraine. Although a known correlation exists between migraine and release of the calcitonin gene-related peptide (CGRP), the possibility that CGRP is involved in CSD has not been examined in detail. We analyzed the pharmacological mechanisms underlying CSD and investigated the possibility that endogenous CGRP contributes to this phenomenon. CSD was analyzed in rat neocortical slices by imaging of the intrinsic optical signal. CSD was measured as the percentage of the maximal surface of a cortical slice covered by the propagation of intrinsic optical signal changes during an induction episode. Reproducible CSD episodes were induced through repetitive elevations of extracellular potassium concentration. AMPA glutamate receptor antagonism did not inhibit CSD, whereas NMDA receptor antagonism did inhibit CSD. Blockade of voltage-dependent sodium channels by TTX also reduced CSD. CSD was also decreased by the antiepileptic drug topiramate, but not by carbamazepine. Interestingly, endogenous CGRP was released in the cortical tissue in a calcium-dependent manner during CSD, and three different CGRP receptor antagonists had a dose-dependent inhibitory effect on CSD, suggesting a critical role of CGRP in this phenomenon. Our findings show that both glutamate NMDA receptors and voltage-dependent sodium channels play roles in CSD. They also demonstrate that CGRP antagonism reduces CSD, supporting the possible use of drugs targeting central CGRP receptors as antimigraine agents.M igraine is a common episodic headache disorder characterized by attacks that include various combinations of headache and neurologic, gastrointestinal, and autonomic symptoms. It is among the most common neurologic conditions, affecting ∼12-20% of the population. The International Headache Society classifies migraine into migraine without aura and migraine with aura, with aura defined as the complex of focal neurologic symptoms that most often precedes or accompanies an attack (1-3).Cortical spreading depression (CSD) is thought to represent a key pathogenetic step in migraine with aura (4, 5). First reported by Leão in 1944 (6), CSD is a wave of electrical activity (excitation followed by depression) that moves across the cerebral cortex after electrical or chemical stimulation. The pivotal event in the generation and propagation of CSD is a marked decrease in neuronal membrane resistance associated with massive increases in extracellular K + and neurotransmitters, as well as increases in intracellular Na + and Ca 2+ (7-9). Genetic and environmental factors modulate individual susceptibility by lowering the CSD threshold, and cortical excitation can cause sufficient elevation in extracellular K + and glutamate to initiate CSD (5,7,8,(10)(11)(12)(13)(14). Conversely, the CSD threshold also may be increased by factors that re...

These findings suggest an association between OSAS and diminished cerebral vasodilator reserve. This condition may be related to the increased susceptibility to cerebral ischemia in patients with OSAS, particularly evident in the early morning.

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