Cortical Spreading Depression Causes a Long-Lasting Decrease in Cerebral Blood Flow and Induces Tolerance to Permanent Focal Ischemia in Rat Brain

Abstract

Cortical spreading depression (CSD) has previously been shown to induce tolerance to a subsequent episode of transient cerebral ischemia. The objective of the present study was to determine whether CSD also induces tolerance to permanent focal ischemia and, if so, whether tolerance may be mediated by alterations in cerebral blood flow (CBF). Sprague-Dawley rats were preconditioned by applying potassium chloride to one hemisphere for 2 hours, evoking 19 +/- 5 episodes of CSD (mean +/- SD, n = 19). Three days later, the middle cerebral artery (MCA) was permanently occluded using an intraluminal suture. In a subset of animals, laser Doppler blood flow (LDF) was monitored over the parietal cortex before and during the first 2 hours of MCA occlusion. Preconditioning with CSD reduced the hemispheric volume of infarction from 248 +/- 115 mm3 (n = 18) in sham-conditioned animals to 161 +/- 81 mm3 (n = 19, P< 0.02). Similarly, CSD reduced the neocortical volume of infarction from 126 +/- 82 mm3 to 60 +/- 61 mm3 (P < 0.01). Moreover, preconditioning with CSD significantly improved LDF during MCA occlusion from 21% +/- 7% (n = 9) of preischemic baseline in sham-conditioned animals to 29% +/- 9% (n = 7, P< 0.02). Preconditioning with CSD therefore preserved relative levels of CBF during focal ischemia and reduced the extent of infarction resulting from permanent MCA occlusion. To determine whether CSD may have altered preischemic baseline CBF, [14 C]iodoantipyrine was used in additional animals to measure CBF 3 days after CSD conditioning or sham conditioning. CSD, but not sham conditioning, significantly reduced baseline CBF in the ipsilateral neocortex to values 67% to 75% of those in the contralateral cortex. Therefore, CSD causes a long-lasting decrease in baseline CBF that is most likely related to a reduction in metabolic rate. A reduction in the rate of metabolism may contribute to the induction of tolerance to ischemia after preconditioning with CSD.

Cortical Spreading Depression Increases the Phosphorylation of AMP-Activated Protein Kinase in the Cerebral Cortex

“…We also showed that pAMPKa is increased only at 24 h after CSD (no modification was seen at 2 and 4 h) suggested a potential link between CSD and neuroprotection through the fine-tuning of AMPK activation by modifying its phosphorylation state only after long-time after CSD induction. This is in agreement with previous studies showed that CSD enhances the ischemic tolerance to temporary focal ischemia after 24 h [12][13][14][15][16][17][18]. Moreover studies on gene expression data, based on time points similar to the present work, show that some genes start to modify their expression relatively late from the induction of CSD.…”

“…In humans, the CSD waves have also been reported, in particular in brain-injured patients [6,10] and in slices made from surgically removed brain tissue of patients [11]. Moreover, when CSD is induced 24 h prior to an artery occlusion (CSD-preconditioning), it enhances the ischemic tolerance to temporary focal ischemia, with a reduction in the size of the infarcted tissue [12][13][14][15][16][17][18]. The mechanism underlying such neuroprotection induced by CSD remains unclear.…”

Effect of ischemic preconditioning on cerebral blood flow after subsequent lethal ischemia in gerbils

“…The protective mechanism of ischemic preconditioning are reported to involve intracellular signal transduction pathway including endoplasmic reticulum and DNA repairing function (Saito et al, 2004;Hayashi et al, 2003;Sugawara et al, 2001). The relationship between preconditioning, induced by spreading depression, and the rCBF just before focal ischemia was reported to be relate to protective mechanisms of ischemic tolerance (Otori et al, 2003). However, the precise mechanism of ischemic tolerance is still unclear.…”

Meningeal Afferent Signaling and the Pathophysiology of Migraine

“…However, a change in extracellular pH within the dura remains to be demonstrated. Cortical spreading depression, which may contribute to migraine headache through activation of the trigeminovascular system, 79,80 was found to be associated with a decrease in dural blood flow 81,82 as well as cortical hypoxia, 80,82,83 events that may decrease the pH of the cortex and/or meninges.…”