Abstract
Spreading depression (SD) is a slowly propagating wave of neuronal and glial depolarization lasting a few minutes, that can develop within the cerebral cortex or other brain areas after electrical, mechanical or chemical depolarizing stimulations. Cortical SD (CSD) is considered the neurophysiological correlate of migraine aura. It is characterized by massive increases in both extracellular K+ and glutamate, as well as rises in intracellular Na+ and Ca2+. These ionic shifts produce slow direct current (DC) potential shifts that can be recorded extracellularly. Moreover, CSD is associated with changes in cortical parenchymal blood flow.CSD has been shown to be a common therapeutic target for currently prescribed migraine prophylactic drugs. Yet, no effects have been observed for the antiepileptic drugs carbamazepine and oxcarbazepine, consistent with their lack of efficacy on migraine. Some molecules of interest for migraine have been tested for their effect on CSD. Specifically, blocking CSD may play an enabling role for novel benzopyran derivative tonabersat in preventing migraine with aura. Additionally, calcitonin gene-related peptide (CGRP) antagonists have been recently reported to inhibit CSD, suggesting the contribution of CGRP receptor activation to the initiation and maintenance of CSD not only at the classic vascular sites, but also at a central neuronal level. Understanding what may be lying behind this contribution, would add further insights into the mechanisms of actions for “gepants”, which may be pivotal for the effectiveness of these drugs as anti-migraine agents.CSD models are useful tools for testing current and novel prophylactic drugs, providing knowledge on mechanisms of action relevant for migraine.
Highlights
Spreading depression (SD) is an intense self-propagating wave of depolarization involving neuronal and glial cells in the cerebral cortex, subcortical gray matter or retina, irrespective of functional divisions or arterial territories
A number of mechanisms have been shown to have a role in fostering cortical SD (CSD) wave initiation and propagation including: ion diffusion, membrane ionic currents, osmotic effects, spatial buffering, neurotransmitter substances, gap junctions, metabolic pumps, and synaptic connections (Figure 1)
Experimental findings to date suggest that chronic daily administration of certain migraine prophylactic drugs dose-dependently suppress CSD
Summary
Spreading depression (SD) is an intense self-propagating wave of depolarization involving neuronal and glial cells in the cerebral cortex, subcortical gray matter or retina, irrespective of functional divisions or arterial territories. Experimental studies have suggested an involvement of gap-junctions in CSD by regulating the milieu around active neurons including extracellular K+, pH and neurotransmitter levels (especially glutamate and GABA), as well as propagating intercellular Ca2+ waves [128].
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