Nitric oxide modulates spreading depolarization threshold in the human and rodent cortex

Area of Science:

• Neuroscience
• Pathophysiology
• Biochemistry

Background:

• Prolonged cortical spreading depolarizations (CSDs) are implicated in delayed ischemic neurologic deficits post-subarachnoid hemorrhage (SAH).
• Elevated extracellular potassium and reduced nitric oxide (NO) are observed in SAH.

Purpose of the Study:

• To investigate if altered extracellular composition, specifically low NO levels, increases brain susceptibility to CSDs.
• To determine the role of NO in CSD generation and propagation.

Main Methods:

• In vivo electrophysiology and blood flow studies in rats.
• In vitro analysis of NO levels and electrophysiology in rodent and human brain slices.
• Genetic manipulation of NO synthase in mice.

Main Results:

• Elevated extracellular potassium triggered CSDs in rats.
• CSDs induce NO synthesis; blocking NO synthesis lowered the CSD threshold and caused ischemia.
• Low NO levels increased CSD susceptibility in rat and human slices, dependent on calcium channels and NMDA receptors.
• Endothelial NO synthase deficiency, not neuronal, lowered the CSD threshold.

Conclusions:

• Basal NO production, primarily from endothelial NO synthase, dictates the CSD threshold.
• Reduced NO levels in SAH may increase brain susceptibility to CSDs.
• Therapeutically increasing NO availability could be beneficial for preventing CSD-induced deficits after SAH.