Persisting Depletion of Brain Glucose following Cortical Spreading Depression, despite Apparent Hyperaemia: Evidence for Risk of an Adverse Effect of Leão's Spreading Depression

Abstract

Rapid sampling microdialysis (rsMD) directed towards the cerebral cortex has allowed identification of a combined time-series signature for glucose and lactate that characterizes peri-infarct depolarization in experimental focal ischaemia, but no comparable data exist for 'classical' cortical spreading depression (CSD) associated with hyperaemia in the normally perfused brain. Here, we examined the rsMD responses of dialysate glucose and lactate to five hyperaemic spreading depressions induced with intracortical microinjections, typically of 1 mol/L KCl, in open-skull preparations in five cats under chloralose anaesthesia. Depolarization was verified with microelectrodes, and laser speckle flowmetry was used to examine propagation of the events and perfusion responses near the MD probe. Ten minutes after depolarization, dialysate glucose fell and lactate rose by 28% and 58% respectively. There was no recovery of dialysate glucose 30 mins after depolarization. Mean baseline indicative cerebral blood flow was 25.5±4.1 mL/100 g/min and mean maximum hyperaemic increase was by 29.6 ± 6 mL/100 g/min; hyperaemia remained present 30 mins after CSD. As CSD events are repetitive, frequent, and often clustered temporally in human acute brain injury, these results indicate a high risk of depletion of extracellular glucose in association with depolarization events of a pattern previously thought to be largely benign.

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

“…Thus, these metabolic signals are concordant, and our data support the conclusion that there is a vulnerable period marked by metabolic depletion after SD. 4 We suggest that, like glucose, adenosine signals appear to be sensitive to deteriorations of energy status in compromised tissue, and could serve as a useful prognostic marker under certain conditions. Adenosine in Stroke Linked to Spreading Depolarizations We observed adenosine peaks in association with depolarizations around the perimeter of focal strokes ( Figure 6).…”

Clinical Relevance of Cortical Spreading Depression in Neurological Disorders: Migraine, Malignant Stroke, Subarachnoid and Intracranial Hemorrhage, and Traumatic Brain Injury

“…In a study combining focal ischemia with CSDs evoked in normal brain outside the penumbra, Busch et al (1996) were able to show directly that acceleration of infarct growth is related to the number of induced events spreading into the penumbra and there believed to take on the characteristics and pathogenicity of PIDs. The basis for this relationship may lie in the imbalance between metabolic workload and delivery of oxygen and glucose: metabolic workload is abnormally high because of restoration of cell membrane ion gradients after depolarization events, leading to depletion of the tissue glucose pool (Nedergaard and Astrup, 1986;Hopwood et al, 2005;Hashemi et al, 2009;Feuerstein et al, 2010) and insufficient oxygen delivery to the tissue . On the other hand, oxygen and glucose supply is reduced due to microvascular constriction in response to the depolarization (Dreier et al, 1998;Strong et al, 2007;Luckl et al, 2009).…”

“…CSD may underlie such microdialysis markers of disturbed metabolism (Parkin et al, 2005;Hartings et al, 2008), as PIDs cause cumulative depletion of glucose and accumulation of lactate (Hopwood et al, 2005). CSD is also associated with increased glucose utilization in experimental TBI (Sunami et al, 1989) and, when recurrent, progressively depletes glucose even in the healthy brain (Hashemi et al, 2009). Stepwise depletion of brain glucose in association with individual depolarizations has now been shown in patients with acute ischemic or traumatic brain injury (Feuerstein et al, 2010).…”

Glucose Modulation of Spreading Depression Susceptibility

“…Spreading depolarization rapidly stimulates glucose consumption, leading to a lasting depletion of tissue glucose, and hypoglycemia delays SD recovery, suggesting that glucose is an important immediate source of energy required to restore the transmembrane ionic gradients after SD. [7][8][9] Indeed, hyperglycemia suppresses peri-infarct SDs. [10][11][12] However, it is not clear whether this is because of improved energy status in ischemic penumbra stabilizing the polarization state, or because tissue glucose availability directly modulates SD susceptibility.…”