Abstract
ObjectivesSpreading depolarizations (SD) likely manifest as aura in migraineurs. Triggers are unknown although vascular events have been implicated. Direct carotid puncture has been reported to trigger migraine with aura. The potent vasoconstrictor endothelin-1 (ET-1), which can be released from the endothelium under pathological conditions, may play a role. Here, we tested whether intracarotid ET-1 infusion triggers SD and whether systemic ET-1 infusion increases the susceptibility to SD.MethodsCarotid infusions were performed in mice (C57BL/6, male) through a catheter placed at the carotid bifurcation via the external carotid artery. Intracarotid ET-1 (1.25 nmol/ml) was infused at various rates (2–16 μl/min) with or without heparin in the catheter and compared with vehicle infusion (PBS with 0.01% acetic acid) or sham-operated mice (n = 5). Systemic infusions ET-1 (1 nmol/kg, n = 7) or vehicle (n = 7) infusions were performed in rats (Sprague-Dawley, male) via the tail vein. Electrical SD threshold and KCl-induced SD frequency were measured after the infusion.ResultsIntracarotid infusion of saline (n = 19), vehicle (n = 7) or ET-1 (n = 12) all triggered SDs at various proportions (21%, 14% and 50%, respectively). These were often associated with severe hypoperfusion prior to SD onset. Heparinizing the infusion catheter completely prevented SD occurrence during the infusions (n = 8), implicating microembolization from carotid thrombi as the trigger. Sham-operated mice never developed SD. Systemic infusion of ET-1 did not affect the electrical SD threshold or KCl-induced SD frequency.ConclusionIntravascular ET-1 does not trigger or increase susceptibility to SD. Microembolization was the likely trigger for migraine auras in patients during carotid puncture.
Highlights
Spreading depolarization (SD), and associated spreading depression, is a slowly propagating wave of pandepolarization involving all cell types in cerebral gray matter, and likely underlies migraine aura [1]
A total of 19 mice received saline infusions (1.5 μl/min) prior to vehicle (n = 7) or ET-1 (n = 12) infusions at various rates and timelines indicated on Fig. 1a
SD occurrence appeared more frequent during ET-1 infusions, when adjusted per volume of infusion it did not differ among the groups (1.22 ± 0.64 SDs/ml saline, 0.14 ± 0.14 SDs/ml vehicle, 1.43 ± 0.53 SDs/ml ET-1; p = 0.19, Kruskal-Wallis test; Fig. 1b lower panel)
Summary
Spreading depolarization (SD), and associated spreading depression, is a slowly propagating wave of pandepolarization involving all cell types in cerebral gray matter, and likely underlies migraine aura [1]. How such an intense depolarization event is triggered in apparently otherwise healthy brains of migraineurs is unknown. Direct carotid puncture can trigger aura in migraine patients [2, 3]. Patients with arteriovenous malformations [6] or cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADA SIL) often present with frequent auras [7]. Migraine with aura is associated with an increased risk of stroke [10]
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