The impact of anesthetics and hyperoxia on cortical spreading depression

Abstract

Cortical spreading depression (CSD), a transient neuronal and glial depolarization that propagates slowly across the cerebral cortex, is the putative electrophysiological event underlying migraine aura. It negatively impacts tissue injury during stroke, cerebral contusion and intracranial hemorrhage. Susceptibility to CSD has been assessed in several experimental animal models in vivo, such as after topical KCl application or cathodal stimulation. Various combinations of anesthetics and ambient conditions have been used by different laboratories making comparisons problematic and differences in data difficult to reconcile. We systematically studied CSD susceptibility comparing commonly used experimental anesthetics (isoflurane, alpha-chloralose, and urethane) with or without N(2)O or normobaric hyperoxia (100% O(2) inhalation). The frequency of evoked CSDs, and their propagation speed, duration, and amplitude were recorded during 2 h topical KCl (1 M) application. We found that N(2)O reduced CSD frequency when combined with isoflurane or urethane, but not alpha-chloralose; N(2)O also decreased CSD propagation speed and duration. Urethane anesthesia was associated with the highest CSD frequency that was comparable to pentobarbital. Inhalation of 100% O(2) did not alter CSD frequency, propagation speed or duration in combination with any of the anesthetics tested. Our data show anesthetic modulation of CSD susceptibility in an experimental model of human disease, underscoring the importance of proper study design for hypothesis testing as well as for comparing results between studies.

Figure 1. The impact of anesthetics and inspired gas mixture on CSD susceptibility

Representative 30 minute DC potential recordings from parietal cortex (A), and average CSD frequencies (B) during 2h topical KCl application (1M) to occipital cortex. Data are mean ± SD. Calibration scales indicate 10 min and 20 mV. Error bars refer to first and second hour data combined. *: p<0.05, urethane vs. isoflurane (groups I–III combined). †: p<0.05, group II vs. I and III within isoflurane. ‡: p<0.05, isoflurane vs. urethane and α-chloralose within II. §: p<0.05, urethane vs. isoflurane and α-chloralose within I. #: p=0.05, group II vs. I within urethane.

Figure 1. The impact of anesthetics and inspired gas mixture on CSD susceptibility

Representative 30 minute DC potential recordings from parietal cortex (A), and average CSD frequencies (B) during 2h topical KCl application (1M) to occipital cortex. Data are mean ± SD. Calibration scales indicate 10 min and 20 mV. Error bars refer to first and second hour data combined. *: p<0.05, urethane vs. isoflurane (groups I–III combined). †: p<0.05, group II vs. I and III within isoflurane. ‡: p<0.05, isoflurane vs. urethane and α-chloralose within II. §: p<0.05, urethane vs. isoflurane and α-chloralose within I. #: p=0.05, group II vs. I within urethane.

Figure 2. The impact of anesthetics and inspired gas mixture on CSD duration and propagation speed

Representative DC potential shifts simultaneously recorded from parietal and frontal cortex using two microelectrodes (ME1 and ME2, respectively). Vertical lines mark the onset of each DC shift. The first 2–3 CSDs are shown after initial topical KCl (1M) application (arrowhead) to demonstrate the decrease in the duration and propagation speed (i.e., longer DC shift latency between ME1 and ME2) of the second and third CSDs, observed regardless of the type of anesthetic or ventilation gas. The variability in the latency between ME1 and ME2 among rats is due to variation in the distance between ME1 and ME2 in each experiment; this distance was measured in each experiment and propagation speeds calculated accordingly. Calibration scales indicate 2 min and 20 mV.