How does hyperglycemia (elevated blood glucose) impair the blood-brain barrier (BBB) and contribute to cerebral edema?

From the Guidelines

Elevated blood glucose impairs the blood-brain barrier (BBB) and increases cerebral edema through several interconnected mechanisms, including oxidative stress, inflammation, and osmotic effects, which ultimately lead to increased morbidity, mortality, and decreased quality of life in patients with brain injuries, stroke, or other neurological conditions. The detrimental effects of hyperglycemia are not clearly understood but include increasing tissue acidosis secondary to anaerobic glycolysis, lactic acidosis, and free radical production 1. Hyperglycemia also may affect the blood–brain barrier and the development of brain edema 1 and may be associated with an increased risk of hemorrhagic transformation of the infarction 1. Some key points to consider include:

• Hyperglycemia will be detected on admission in approximately one third of patients with stroke 1
• Clinical studies demonstrate that the presence of hyperglycemia is associated with poor outcomes after ischemic stroke, including among patients treated with thrombolytic agents 1
• A history of diabetes mellitus also is associated with a poorer outcome after stroke 1
• The goals of management of brain edema are to reduce intracranial pressure, maintain adequate cerebral perfusion to avoid worsening of the brain ischemia, and prevent secondary brain injury from herniation among those patients with very large infarctions of the cerebral hemisphere 1
• Prevention measures that might decrease the risk of cerebral edema in high-risk patients are gradual replacement of sodium and water deficits in patients who are hyperosmolar and the addition of dextrose to the hydrating solution once blood glucose reaches 250 mg/dl 1 Therefore, strict glucose control is essential in patients with brain injuries, stroke, or other neurological conditions to prevent worsening brain damage and improve outcomes.

From the Research

Hyperglycemia and Blood-Brain Barrier Impairment

• Hyperglycemia can impair the blood-brain barrier (BBB) and contribute to cerebral edema, as seen in cases of hyperglycemic crises 2.
• The mechanisms underlying hyperglycemia's effects on the BBB involve changes in ion and water transport, including increased abundance and activity of Na+-K+-2Cl- cotransport (NKCC) and Na+/H+ exchange 1 (NHE1) 3.
• Hyperglycemia can also lead to the disruption of tight junctions and the activation of various kinases, such as serum-glucocorticoid regulated kinase 1 (SGK1) and protein kinase C beta II (PKCβII), which can further impair the BBB 3.

Cerebral Edema and Hyperglycemia

• Cerebral edema is a rare but potentially devastating complication of hyperglycemic crises, and can be exacerbated by overly-aggressive fluid resuscitation and rapid correction of hyperglycemia and hyperosmolarity 2.
• Hyperglycemia can increase the permeability of the BBB, leading to the extravasation of fluids and ions into the brain and contributing to edema formation 4, 5.
• The development of cerebral edema in hyperglycemic patients may be influenced by factors such as the severity and duration of hyperglycemia, as well as the presence of other comorbidities or insults to the brain 4, 6.

Molecular Mechanisms

• The receptor for advanced glycation end products (RAGE) may play a role in the development of BBB damage and cerebral edema in hyperglycemic patients, by transporting amyloid-beta (Aβ) from the blood into the brain and promoting oxidative stress and inflammation 4.
• Hyperglycemia can also lead to changes in the expression and activity of various proteins involved in the maintenance of the BBB, including claudin, occludin, and zonula occludens-1 5.
• The activation of neuroinflammatory pathways, including the suppression of microglial cells and the increased infiltration of neutrophils, may also contribute to the detrimental effects of hyperglycemia on the BBB and cerebral edema 5.