Short CommunicationIncreased glucose availability does not restore prolonged spreading depression durations in hypotensive rats without brain injury
Introduction
Cortical spreading depression (CSD) is associated with a marked surge in O2 and glucose utilization in both normal and ischemic brain. Indeed, severe hypoxia or hypoglycemia can delay the recovery of CSD, and even precipitate persistent depolarization, indicating that maintenance and restoration of membrane ionic gradients are dependent on cellular energy status (Gido et al., 1993). Because of this, the prolonged durations of peri-infarct depolarization (PID) waves in ischemic penumbra have been explained by O2 and glucose shortage. This was further supported by the observation that PIDs become indistinguishable from CSD waves as they propagate into the surrounding non-ischemic brain.
Consistent with this notion, we recently showed that CSD duration is inversely related to cerebral perfusion pressure in rats, so that systemic hypotension significantly prolonged the slow potential shift and delayed CSD recovery (Sukhotinsky et al., 2008, Sukhotinsky et al., 2010). However, systemic hyperoxia did not restore prolonged CSD durations in hypotensive rats despite restored tissue pO2, suggesting that the inverse relationship between cerebral perfusion pressure and CSD duration is independent of cortical O2 availability and oxidative phosphorylation (Sukhotinsky et al., 2010). Because glycolysis is rapidly stimulated during CSD (Csiba et al., 1985, Hashemi et al., 2009, Shinohara et al., 1979), glucose may be a more relevant and immediate energy source impacting restoration of membrane ionic gradients, and may become rate-limiting during CSD. We, therefore, tested whether prolonged CSD durations in hypotensive rats can be reversed by increasing tissue glucose availability.
Section snippets
General surgical preparation
National and institutional guidelines for animal care and use for research purposes were strictly followed, and study protocol was approved by the institutional review board. Rats (Sprague–Dawley, male, 275–400 g) were fasted overnight, anesthetized with urethane (1.3–1.5 g/kg, intraperitoneal), and intubated for mechanical ventilation (70% N2O/30% O2 during preparation, room air during the experiment; SAR-830, CWE, PA, USA). Femoral vein and artery were cannulated for infusions, continuous mean
Results
Systemic physiological parameters were within previously reported normal limits in normotensive, normoglycemic, anesthetized rats (Fig. 1). Hypotension by controlled exsanguination was associated with mild metabolic acidosis and reduction of paO2 within physiological limits, neither of which were altered by subsequent hyperglycemia. Blood glucose showed a small but steady increase during the course of each experiment, presumably related to anesthesia and surgery. Dextrose infusion raised blood
Discussion
We showed that, despite a significant increase in tissue glucose availability, hyperglycemia does not restore the delayed CSD recovery during hypotension. Taken together with our previous demonstration that increasing O2 availability by normobaric hyperoxia is also ineffective (Sukhotinsky et al., 2008, Sukhotinsky et al., 2010), and that the magnitude of hypotension sufficient to prolong CSDs causes only mild hypoperfusion (i.e., 10–30% decrease in resting CBF), these data do not support the
Disclosure/conflict of interest
Authors do not have any financial conflicts of interest to declare.
Acknowledgments
This work was supported by the National Institute of Health (NS061505, NS055104), Deutsche Forschungsgemeinschaft (HO4211/1-1) and the American Heart Association (10SDG2610275). We would like to thank Dr. Brian Healy of the MGH Biostatistics Center for his critical insights during data analysis.
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