Hyperexcitable interneurons trigger cortical spreading depression in an Scn1a migraine model

Cortical spreading depression (CSD) and depolarization waves are associated with dramatic failure of brain ion homeostasis, efflux of excitatory amino acids from nerve cells, increased energy metabolism and changes in cerebral blood flow (CBF). There is strong clinical and experimental evidence to suggest that CSD is involved in the mechanism of migraine, stroke, subarachnoid hemorrhage and traumatic brain injury. The implications of these findings are widespread and suggest that intrinsic brain mechanisms have the potential to worsen the outcome of cerebrovascular episodes or brain trauma. The consequences of these intrinsic mechanisms are intimately linked to the composition of the brain extracellular microenvironment and to the level of brain perfusion and in consequence brain energy supply. This paper summarizes the evidence provided by novel invasive techniques, which implicates CSD as a pathophysiological mechanism for this group of acute neurological disorders. The findings have implications for monitoring and treatment of patients with acute brain disorders in the intensive care unit. Drawing on the large body of experimental findings from animal studies of CSD obtained during decades we suggest treatment strategies, which may be used to prevent or attenuate secondary neuronal damage in acutely injured human brain cortex caused by depolarization waves.

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Tonabersat, a Gap-Junction Modulator: Efficacy and Safety in Two Randomized, Placebo-Controlled, Dose-Ranging Studies of Acute Migraineceph

Cephalalgia ◽

10.1111/j.1468-2982.2009.01974.x ◽

2009 ◽

Vol 29 (2_suppl) ◽

pp. 17-27 ◽

Cited By ~ 31

Author(s):

SD Silberstein ◽

J Schoenen ◽

H Göbel ◽

HC Diener ◽

AH Elkind ◽

...

Keyword(s):

Adverse Events ◽

North American ◽

Cortical Spreading Depression ◽

Spreading Depression ◽

Plasma Concentrations ◽

International Study ◽

Maximum Plasma ◽

Serious Adverse Events ◽

Double Blind ◽

Dose Ranging

Tonabersat is a novel benzopyran derivative that blocks the cortical spreading depression proposed to be associated with migraine attacks. The ability of single oral doses of 15, 25, 40 and 80 mg of tonabersat to relieve the symptoms of moderate to severe migraine was evaluated in 859 migraineurs enrolled in two dose-ranging, double-blind, randomized, placebo-controlled, parallel-group trials, one international and the other North American. In the international study, significantly more patients given tonabersat than given placebo experienced relief of headache pain at 2 h (15 mg, 36.8%; 40 mg, 40.7%), the principal efficacy variable, and at 4 h (40 mg, 63.0%) and complete abolition of headache at 4 h (40 mg, 34.3%). None of the primary or secondary efficacy variables indicated significant differences between tonabersat and placebo in the North American study. Tonabersat was generally well tolerated, with dizziness and nausea the most common side-effects. Serious adverse events were uncommon, and no patient withdrew from either study because of adverse events. These results suggest a possible interplay between tonabersat pharmacokinetics (the relatively long time required to reach maximum plasma concentrations) and patient characteristics (previous triptan exposure) in the management of acute migraine attacks. Based on the pharmacokinetics and actions on cortical spreading depression, tonabersat may have potential value in migraine prophylaxis.

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