Recurrent spreading depression (SD) causes early opening of the blood-brain barrier (BBB)

Abstract

SD is a depolarization wave propagating at a rate of about 3 mm/min in the cerebral cortex. It is characterized by an amplitude reduction of the electrocorticographic activity, a rise of the extracellular potassium to 60 mM and a reduction of the extracellular volume. Typical changes of cerebral blood flow (CBF) accompany SD, which consist of a short lasting spreading hyperemia followed by a long lasting spreading oligemia. SD is triggered by electrical, mechanical or toxic factors and is probably involved in the pathogenesis of migraine, focal ischemia, head trauma and cerebral hemorrhage. SD is assumed to be the pathophysiological correlate of the migraine aura. We have recently observed a patient with familial hemiplegic migraine (FHM) type II and a long-lasting migraine aura with fluctuating neurological symptoms. Quantitative analysis of early gadolinium-enhanced MR images revealed a left-hemispheric, cortical blood brain-barrier (BBB) disruption preceding delayed cortical edema in this ATP1A2 mutation carrier. As we know from the work by Strong et al. repetitive SDs can occur in the human brain tissue, which could explain the fluctuating symptoms in our FHM patient. Additionally, a recent publication by Gursoy-Ozdemir et al. showed a delayed enhancement of BBB permeability and subsequent cortical oedema following a single SD. Based on these observations, we studied here whether recurrent SD causes early BBB disruption in the rat cortex in vivo. We triggered SD with artificial cerebrospinal fluid (ACSF) containing a potassium concentration ([K+]ACSF) of 130 mM at an open parietal cranial window. SDs were monitored with an intracortical potassium sensitive microelectrode and laser-Doppler flowmetry. We also recorded the propagation of SDs to a distant closed frontal cranial window using an epidural Ag-AgCl electrode. BBB integrity was evaluated quantitatively by analyzing fluorescence in brain sections following the peripheral injection of Evan's Blue or Lucifer yellow. At the occipital window, [K+]ACSF evoked several SDs in all animals. In the first group (n = 10), one or more SDs propagated to the frontal window. In contrast, in the second group (n = 9), pretreatment with MK-801 (5 mg/kg BW i.v.), abolished SD propagation. Within two hours after the onset of the first SD, significantly enhanced fluorescence intensity at the frontal cortex was only measured in animals from group 1 with multiple propagated SDs. In conclusion, we provide evidence that repetitive SDs significantly increase blood-brain barrier permeability within two hours after the onset.