Abstract:

Stroke is a major cause of mortality and permanent disability. The onset of stroke is followed by life-threatening pathophysiological responses including brain edema, elevation of intracranial pressure, disruption of blood-brain barrier (BBB), brain infarct and permanent tissue damage. Brain edema develops due to accumulation of water in intracellular and extracellular compartments of the brain, which causes an increase in brain volume and elevation of intracranial pressure. Compression of the brain tissue has an impact on cerebral blood flow which results in secondary brain injury. Often, clinical presentation of stroke is accompanied by hyponatremia caused either by the syndrome of inappropriate release of antidiuretic hormone (SIADH) or cerebral salt wasting (CSW). SIADH is the result of uncontrolled secretion of antidiuretic hormone (ADH) also called arginine-vasopressin (AVP). AVP acts on V1a and V2 receptors triggering vasoconstriction, platelet aggregation, and water retention followed by hypervolemic or normovolemic hyponatremia and low plasma osmolality. Current therapeutic applications against brain edema (such as decompression craniotomy or hypertonic saline) do not fully address complications caused by SIADH or CSW.  Therefore, new research approaches are required to identify and target precise causes of stroke-induced brain edema. Many studies report that AVP receptors (V1a and V2) mediate cascades of events that result in vasoconstriction, platelet aggregation, water retention, and hyponatremia. V1a receptors are found primarily in vascular smooth muscle cells and platelets, and activation of V1a receptors by AVP induces vasoconstriction and platelet aggregation. Therefore, blocking of V1a receptors after ischemic brain injury may potentially prevent vasoconstriction and clot formation, which may also improve regional cerebral blood flow (rCBF), and lower the magnitude of brain edema. V2 receptors are localized in the collecting ducts of the kidneys, and activation of V2 receptors by AVP leads to increased water reabsorption and reduction of plasma sodium and osmolality. Pharmacological inhibition of V2 receptors has been shown to increase water secretion (aquaresis) in the kidneys, raising sodium concentration in the blood and thus may help control brain edema.