Pathogenesis of Brain Edema and Investigation into Anti-Edema Drugs

Abstract

Brain edema is a potentially fatal pathological state that occurs after brain injuries such as stroke and head trauma. In the edematous brain, excess accumulation of extracellular fluid results in elevation of intracranial pressure, leading to impaired nerve function. Despite the seriousness of brain edema, only symptomatic treatments to remove edema fluid are currently available. Thus, the development of novel anti-edema drugs is required. The pathogenesis of brain edema is classified as vasogenic or cytotoxic edema. Vasogenic edema is defined as extracellular accumulation of fluid resulting from disruption of the blood-brain barrier (BBB) and extravasations of serum proteins, while cytotoxic edema is characterized by cell swelling caused by intracellular accumulation of fluid. Various experimental animal models are often used to investigate mechanisms underlying brain edema. Many soluble factors and functional molecules have been confirmed to induce BBB disruption or cell swelling and drugs targeted to these factors are expected to have anti-edema effects. In this review, we discuss the mechanisms and involvement of factors that induce brain edema formation, and the possibility of anti-edema drugs targeting them.

Functional kinomics establishes a critical node of volume-sensitive cation-Cl− cotransporter regulation in the mammalian brain

“…Ischemia-induced cytotoxic swelling of BBB endothelial cells and astrocytic end feet disrupts BBB integrity and causes vasogenic cerebral edema515253. We detected less reactive astrocyte formation at AQP4-stained end feet associated with BBB endothelial cells in post-MCAO WNK3 KO brains than in WNK3 WT brains.…”

Attenuation of Blood-Brain Barrier Breakdown and Hyperpermeability by Calpain Inhibition

“…Various mediators of inflammation are shown to modulate BBB breakdown and permeability in a variety of pathologies (3). Blood-brain barrier breakdown and the associated hyperpermeability is the leading cause of brain edema and elevated intracranial pressure followed by decreased perfusion pressure leading to poor clinical outcomes in traumatic brain injury (TBI) (4).…”

Traumatic brain injury- Possible beneficial effect of omentum

“…As earlier reported [1], vasogenic edema produced by hypothermia normally reaches its maximal effect on the third day after hypothermic application. When the animals in the 1991 study were sacrificed 72 hours later, (3 days) following hypothermic application, no sign of vasogenic edema was reported.…”

“…The intracellular water content in a cytotoxic neuron is not the early problem following a TBI, but it is vasogenic edema in the brain tissue that is the main problem following a TBI. It has been claimed that the breakage of capillaries in the BBB occurs as early as four to six hours after a TBI and progresses over the next seven days being maximal two to three days after a TBI [1]. Unfortunately, various efforts to treat the results of the ruptured BBB vessels in the first few days following a TBI have not proven successful.…”