Peri-infarct depolarizations during focal ischemia in the awake Spontaneously Hypertensive Rat. Minimizing anesthesia confounds in experimental stroke

Abstract

Anesthesia profoundly impacts peri-infarct depolarizations (PIDs), but only one prior report has described their monitoring during experimental stroke in awake animals. Since temporal patterns of PID occurrence are model specific, the current study examined PID incidence during focal ischemia in the awake Spontaneously Hypertensive Rat (SHR), and documented the impact of both prior and concurrent isoflurane anesthesia. For awake recordings, electrodes were implanted under isoflurane anesthesia 1 day to 5 weeks prior to occlusion surgery. Rats were then subjected to permanent or transient (2 hour) tandem occlusion of the middle cerebral and ipsilateral common carotid arteries, followed by PID monitoring for up to 3 days. Comparison perfusion imaging studies evaluated PID-associated hyperemic transients during permanent ischemia under anesthesia at varied intervals following prior isoflurane exposure. Prior anesthesia attenuated PID number at intervals up to 1 week, establishing 2 weeks as a practical recovery duration following surgical preparation to avoid isoflurane preconditioning effects. PIDs in awake SHR were limited to the first 4 hours after permanent occlusions. Maintaining anesthesia during this interval reduced PID number, and prolonged their occurrence through several hours following anesthesia termination. Although PID number otherwise correlated with infarct size, PID suppression by anesthesia was not protective in the absence of reperfusion. PIDs persisted up to 36 hours after transient occlusions. These results differ markedly from the one previous report of such monitoring in awake Sprague-Dawley rats, which found an extended biphasic PID time course during 24 hours after both permanent and transient filament occlusions. PID occurrence closely reflects the time course of infarct progression in the respective models, and may be more useful than absolute PID number as an index of ongoing pathology.

Spreading depolarizations trigger caveolin‐1–dependent endothelial transcytosis

“…Importantly, in our experiments where only a small number of CSDs were induced over one hour, BBB opening was transient, with spontaneous recovery within 48 hours. In the injured brain, recurrent CSDs continue to develop for many hours and even days after the initial insult (Hartings et al, 2003; Kudo et al, 2016), which might explain the longer-lasting BBB opening after brain injury. Since CSDs originating in injured brain often propagate into the normal tissue, they may explain the BBB opening in surrounding non-injured brain as well (Lapilover et al, 2012; Stoll et al, 2009).…”

Substrain- and sex-dependent differences in stroke vulnerability in C57BL/6 mice

“…It must be noted that such measurements in anesthetized animals at a single early time point do not provide information about the time course of CBF change and infarct progression over the hours during which final infarct distribution is determined. 58 Also, we detected no evidence in any animal for the expected perfusion responses that accompany peri-infarct depolarizations, 59 suggesting that these may have been suppressed by anesthesia either directly 60,61 or via indirect physiological effects such as hyperglycemia, 62,63 which was not assessed. Comprehensive comparisons of the time course of perfusion changes and infarct progression across substrains would provide more insight into the mechanisms underlying substrain differences.…”

Comparative distribution ofArcadlin/Protocadherin‐8mRNA in the intact and ischemic brains of adult mice

“…Cerebral ischemia generates spreading depolarization and the induction of c‐fos and c‐jun family genes in the neocortex (An et al., 1993; Blumenfeld et al., 1992; Kudo et al., 2016; Nedergaard & Hansen, 1993). The results of the present study confirmed increased c‐Fos expression in the ipsilateral cortex.…”