Cortical spreading depression as a target for anti-migraine agents

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.

Figure 1

Mechanisms and structures involved in the pathogenesis of migraine with aura. CSD underlies aura symptoms. Initiation and propagation of CSD are determined by massive increases in extracellular potassium ion concentration and excitatory glutamate. CSD biochemical changes may trigger the activations of meningeal trigeminal endings and trigemino-vascular system, causing the headache phase. The latter can occur through matrix metalloproteases activation that increases vascular permeability and also through the release of nociceptive molecules from mastcells, including proinflammatory cytokines. The pain phase is due to peripheral and central sensitization of the trigeminal system, as well as to the release of CGRP, both peripherally and centrally. CGRP is considered a key mediator in migraine and, together with NO, is the main molecule responsible for vasodilation consequential to neurogenic inflammation. CGRP is also released from cortical slices during CSD and this calcium-dependent release can mediate the dilatation of cortical arterioles. Periacqueduttal gray matter (PAG), locus coeruleus (LC), nucleus of raphe magnum (NRM) are brainstem structures implicated in the processing of trigeminal pain. Functional and structural PAG abnormalities occurring in migraineurs, contribute to the hyper-excitability of trigeminal nociceptive pathways. Functional alteration of noradrenergic nuclei of the LC are believed to be involved in cortical vasomotor instability. Thus, dysfunction in brainstem pain-inhibiting circuitry may explain many facets of the headache phases, even in MwA. CSD participates in this dysregulation by antagonizing the suppressive effect exerted by NRM on the responses of trigeminal neurons. In this scenario, amitriptyline may influence CSD by preserving 5-HT and perhaps NA neurotransmission in the cortex and/or inhibiting high-voltage-activated (HVA) Ca²⁺ channels and Ca²⁺ currents. Propranolol, on the other hand, may reduce neuronal excitability and susceptibility to CSD via a beta-adrenergic blockage. Original brain template was designed by Patrick J. Linch, medical illustrator and C. Carl Jeffe, MD, cardiologist.

Figure 2

Main potential targets of currently utilized preventive drugs and those under-investigation for migraine. The mechanisms mediating CSD inhibition by several migraine preventive drugs are not completely understood. However, it is believed that this inhibitory action is exerted by influencing ion channels and neurotransmission. In particular, topiramate and valproate are believed to exert their antagonizing effects on CSD by blocking Na⁺ channels, inhibiting glutamatergic transmission and increasing GABaergic transmission. Topiramate, but not valproate, can also block L-type Ca²⁺ channels. Lamotrigine has a marked suppressive effect on CSD, which may be due to its selective action on Na⁺ channels. Furthermore, gabapentin is able to modulate the activities of P/Q- and, to a lesser extent, N-type high voltage-activated channels located presynaptically at the cortical level and controls the neurotransmitter release, in particular that of glutamate. This effect and the modulation of GABA-mediated transmission might explain CSD inhibition by gabapentin. Magnesium exerts an inhibitory effect on CSD by interfering with NMDA receptor function and reducing glutamatergic transmission as well as regulating glutamate uptake by astrocytes and modulating NO system in the cortex. The blockage of L-type Ca²⁺ channels may also account for the inhibitory effects of flunarizine on CSD (not shown). The novel benzopyran compound tonabersat seems to inhibit CSD in experimental models and has shown some efficacy in the prophylactic treatment of MwA. It is not known if tonabersat acts on gap-junctions in CNS, as it has already been demonstrated for trigeminal ganglion. CSD inhibition can also be achieved by CGRP-R blockage due to CGRP antagonists, such as olcegepant. This class of drugs might exert its inhibitory effects at both cortical neuronal and cerebrovascular levels.