Glucose Modulation of Spreading Depression Susceptibility

Abstract

Spreading depression of Leão is an intense spreading depolarization (SD) wave associated with massive transmembrane ionic, water, and neurotransmitter shifts. Spreading depolarization underlies migraine aura, and occurs in brain injury, making it a potential therapeutic target. While susceptibility to SD can be modulated pharmacologically, much less is known about modulation by systemic physiological factors, such as the glycemic state. In this study, we systematically examined modulation of SD susceptibility by blood glucose in anesthetized rats under full physiological monitoring. Hyperglycemia and hypoglycemia were induced by insulin or dextrose infusion (blood glucose B40 and 400 mg/dL, respectively). Spreading depolarizations were evoked by direct cortical electrical stimulation to determine the intensity threshold, or by continuous topical KCl application to determine SD frequency. Hyperglycemia elevated the electrical SD threshold and reduced the frequency of KCl-induced SDs, without significantly affecting other SD properties. In contrast, hypoglycemia significantly prolonged individual and cumulative SD durations, but did not alter the electrical SD threshold, or SD frequency, amplitude or propagation speed. These data show that increased cerebral glucose availability makes the tissue resistant to SD.

Advancing age and ischemia elevate the electric threshold to elicit spreading depolarization in the cerebral cortex of young adult rats

“…As such, high concentration of blood glucose (23-24 mmol/l) was shown to make the tissue resistant to SD in rats. 22 Yet, our data on blood glucose level indicated normoglycemic conditions (blood glucose concentration around 9-11 mmol/l) in all age groups and revealed no difference between baseline and late ischemia. Therefore, we suspect that factors other than the availability of glucose must determine the ischemia-related inhibition of SD elicitation as seen here.…”

Supply-Demand Mismatch Transients in Susceptible Peri-infarct Hot Zones Explain the Origins of Spreading Injury Depolarizations

“…The mechanism appears to involve increased regional O 2 availability in penumbra thereby preventing the ripples of oxygenation from dipping below the depolarization threshold. Along the same lines, higher glucose availability may render hot zones less susceptible to depolarization (Hoffmann et al, 2013) as PID occurrence is inversely related to blood glucose (Nedergaard and Astrup, 1986; Strong et al, 2000). This is an important consideration for the optimal target range for blood glucose in clinical trials of tight euglycemic control in acute stroke.…”

Spreading Depolarization-Induced Adenosine Accumulation Reflects Metabolic Status In Vitro and In Vivo

“…The observation that hypoglycemia prolongs DC shift durations is well established. 35,36 Presumably, substrate deficiency limits energy production below that required for [K + ] o clearance by Na + /K + ATPase and thus delays cellular repolarization. 38 Previous authors have demonstrated that SD itself depletes glucose levels, which require 25 to 30 minutes to recover.…”