Cerebral edema is a severe complication of ischemic stroke that leads to increased intracranial pressure, rapid neurological deterioration, and the potential development of cerebral herniation. It is a critical risk factor for poor outcomes following a stroke. For decades, scientists have been working to elucidate the mechanisms of ischemic brain edema formation and to find therapeutic targets. However, current treatments for ischemic brain edema still focus on relieving symptoms rather than aiming to stop the formation and progression of edema.

As a leading provider of stroke research services, Ace Therapeutics is equipped to assist clients in exploring the mechanisms underlying edema formation following cerebral ischemia and reperfusion. We conduct preclinical studies aimed at enhancing the diagnosis and treatment of brain edema after stroke.

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• Brain Edema Measurement Service in Animal Models of Stroke

Mechanisms of Cerebral Edema After Ischemic Stroke

Cerebral edema after an ischemic stroke includes cytotoxic edema, ionic edema, and vasogenic edema. These three processes are closely linked. Cytotoxic edema develops rapidly after a stroke, followed by ionic edema, vasogenic edema, and eventually mixed edema. Cytotoxic and vasogenic edema are interdependent, with the persistence of cytotoxic edema promoting the onset of vasogenic edema, and vice versa.

Fig. 1 Status of the blood–brain barrier at three phases of cerebral edema. (Gu, et al., 2022)

Cytotoxic Edema

Cytotoxic edema is the primary form of edema in the first 24 hours following cerebral ischemia and results from parenchymal injury. Under normal conditions, Na⁺/K⁺-ATPase maintains cellular ionic balance, but ischemia disrupts ATP production, impairing this pump and other transporters. This dysfunction leads to an increase in intracellular Na⁺ and water retention, causing cell swelling without increasing brain tissue volume or intracranial pressure. However, the redistribution of Na+ from the extracellular to intracellular space creates an osmotic gradient that drives water influx from the blood, contributing to brain tissue swelling. Cytotoxic edema primarily affects all brain cells, particularly astrocytes, and compresses extracellular spaces, hindering edema resolution.

Ionic Edema

In addition to the ion transporters and channels normally present in brain cells, ischemic injury induces the expression of other channels that contribute to ionic dysregulation during edema formation. One such example is the SUR1-TRPM4 channel, which is not constitutively expressed but is activated after ischemia. Upon ATP depletion, SUR1-TRPM4 facilitates Na⁺ influx, water retention, and cell swelling, leading to further water and ion leakage from blood vessels and brain swelling. This channel also plays a role in endothelial cell death and vasogenic edema.

Vasogenic Edema

Vasogenic edema is caused by damage to the cerebrovasculature, primarily through the breakdown of the blood-brain barrier (BBB). Sodium transport at the BBB is a key factor in edema formation, with increased BBB permeability to Na⁺ observed within the first 48 hours after cerebral ischemia. This enhanced permeability allows a significant influx of Na⁺ and water into the brain, contributing to both hydrostatic and osmotic extracellular edema. The influx of fluid is mainly driven by the permeability changes to Na⁺, rather than proteins like albumin. The increased sodium transport at the BBB may result from the activity of Na⁺/K⁺-ATPase in capillary endothelial cells, as well as endothelial SUR1-TRPM4 channels that mediate Na⁺ influx and efflux.

Energy deprivation and free radical damage to endothelial cells disrupt the junctions that maintain BBB integrity, increasing paracellular permeability. Proteases, including MMP-2 and MMP-9, play a crucial role in degrading junctional proteins and basement membrane components, further compromising BBB structure. Ablation of MMPs, either by genetic deletion or pharmacological inhibition, can effectively ameliorate BBB disruption and subsequent vasogenic brain edema after ischemic stroke.

Factors Associated With the Formation of Cerebral Edema After Ischemic Stroke

There are many factors that can affect cerebral edema after ischemic stroke, and there are often intricate interactions among them.

Fig. 2 Factors associated with the formation of cerebral edema. (Gu, et al., 2022)

Potential Therapies for Cerebral Edema After Ischemic Stroke

Selecting targets and developing new drugs to prevent and treat cerebral edema based on its underlying molecular mechanisms is currently a major research focus. A significant amount of studies have been conducted to explore these potential therapeutic targets.

It is necessary to find more effective therapeutic targets and conduct further preclinical animal studies in a series of models to study the optimal therapeutic window of various drugs. It is also important to consider that brain edema is caused by multiple mechanisms, and combination therapy may be the most effective treatment strategy.

1. Gu, Y., et al. (2022). Cerebral edema after ischemic stroke: Pathophysiology and underlying mechanisms. Frontiers in neuroscience, 16, 988283.
2. Su, F., & Xu, W. (2020). Enhancing brain plasticity to promote stroke recovery. Frontiers in neurology, 11, 554089.