Induction of Tolerance to Focal Ischemia in Rat Brain: Dissociation between Cortical Lesioning and Spreading Depression

Abstract

Summary: Cortical application of KCl has previously been shown to induce tolerance to a subsequent episode of cerebral ischemia. KCl triggers recurrent episodes of cortical spreading depression and produces a small lesion at the cortical application site. To determine whether a cortical lesion alone is sufficient to induce tolerance to ischemia, the authors used 5-mol/L NaCl to precondition rat brain 3 days before permanent occlusion of the middle cerebral artery. NaCl produced a small lesion at the application site without evoking cortical spreading depression. Preconditioning with 5-mol/L NaCl significantly attenuated the decrease in CBF after middle cerebral artery occlusion and reduced the volume of cortical infarction by 35%. The results show that a small cortical lesion, by itself, is sufficient to induce tolerance to ischemia.

CBF Changes Associated with Focal Ischemic Preconditioning in the Spontaneously Hypertensive Rat

“…In contrast to earlier blood flow studies that examined only acute occlusion intervals (Alkayed et al, 2002;Barone et al, 1998;Chen et al, 1996;Dawson et al, 1999;Matsushima and Hakim, 1995;Matsushima et al, 1996), the present work identifies a delayed increase in CBF at the margin of the ischemic territory in PC animals. This is consistent with improvement in microvascular filling noted in LPS-preconditioned rats (Dawson et al, 1999), and with recent laser Doppler measurements in brains preconditioned by cortical lesions (Muramatsu et al, 2004). There appear to be two distinct mechanisms underlying the perfusion effects relevant to PC.…”

“…A laser Doppler evaluation in the SHR had been interpreted to exclude perfusion effects (Barone et al, 1998), although a trend toward increased relative flow could be detected during the 2-h interval evaluated. More recently, significant flow recovery has been noted in the SpragueDawley strain after PC by cortical injury (Muramatsu et al, 2004). The volumetric analysis applied in the present study avoids the limitations of monitoring at specific anatomical loci, and shows a consistent flow threshold for infarction in naïve, sham, and preconditioned brain (Figure 2).…”

“…As noted above, there is strong evidence that contralateral CBF after permanent MCA occlusion was in fact better maintained in the sham and PC groups ( Figure 4A). Nevertheless, it is possible that small cortical lesions could have been produced occasionally by either sham or PC surgery, and by analogy with the PC effects of intentional cortical lesioning (Muramatsu et al, 2004) these might account for the rare small infarcts seen in the sham group ( Figure 4C). As noted in the previous study, decreased baseline CBF in such hemispheres would be expected to be associated with reduced metabolic rate in response to the prior injury (Pappius, 1981;Yoshino et al, 1991), which would also contribute to overall protection.…”

“…A role of perfusion changes in PC has been largely discounted, based on numerous studies that failed to identify cerebral blood flow (CBF) differences between naïve and preconditioned animals during acute intervals after subsequent occlusion, using autoradiographic (Alkayed et al, 2002;Chen et al, 1996;Dawson et al, 1999), hydrogen clearance (Matsushima and Hakim, 1995;Matsushima et al, 1996) or laser Doppler measurements (Barone et al, 1998). Recent results indicate that basal CBF might even be reduced in a preconditioned hemisphere, perhaps secondary to decreases in metabolic rate after treatments that produce cortical injury (Muramatsu et al, 2004;Otori et al, 2003). However, no previous studies combined quantitative CBF measurements with volumetric assessments of the territory below ischemic flow thresholds over an extended time course.…”

Exploitation of the spreading depolarization-induced cytotoxic edema for high-resolution, 3D mapping of its heterogeneous propagation paths

“…However, it was less surprising that the SD threshold was reduced in the WT mice. This finding could be related to previous observations in naïve rats that a KCl crystal, another artificial SD trigger associated with local injury (20), elicited only one or very few SDs and their repetition rate was dramatically reduced once ω-agatoxin IVA was applied to the brain surface (19).…”