Abstract

Cerebral edema is a common pathological condition associated with a variety of neurological disorders, and its development involves numerous neurobiological mechanisms. This review explores the neurobiological regulatory mechanisms underlying cerebral edema, including the disruption of the blood–brain barrier, inflammatory responses, alterations in vascular permeability, and intracellular edema. We will investigate the formation mechanisms of cerebral edema under different pathological states and discuss potential therapeutic strategies, aiming to provide insights for clinical treatment. Current research highlights the complexity of the interactions between these mechanisms and the need for targeted interventions to mitigate the impact of cerebral edema on patient outcomes. This review aims to synthesize existing knowledge and encourage further exploration in this critical area of neuroscience, ultimately contributing to more effective management of cerebral edema.

1 Introduction

Cerebral edema, defined as the accumulation of excess fluid in the brain tissue, leads to an increase in brain volume and can result in elevated intracranial pressure (ICP) and neurological dysfunction. The pathophysiology of cerebral edema is multifaceted, involving various mechanisms such as cellular fluid transport, inflammatory responses, and neuroregulatory processes. Recent advancements in our understanding of these neurobiological regulatory mechanisms have significantly enhanced our comprehension of underlying causes and potential therapeutic targets of cerebral edema. This review aims to explore the neuroregulatory mechanisms involved in cerebral edema formation and discuss their implications for clinical management and treatment strategies.

The formation of cerebral edema can be categorized into different types, including cytotoxic, vasogenic, and osmotic edema, each with distinct underlying mechanisms. Cytotoxic edema primarily results from cellular injury, leading to the failure of ion pumps and subsequent cellular swelling. Vasogenic edema, on the other hand, occurs due to the disruption of the blood–brain barrier (BBB), allowing plasma proteins and fluid to leak into the extracellular space, thus increasing interstitial fluid volume (Chen S. et al., 2021). Inflammatory processes play a critical role in both cytotoxic and vasogenic edema, as the release of pro-inflammatory cytokines can exacerbate BBB dysfunction and promote fluid accumulation (Wang et al., 2025). Understanding these mechanisms is crucial for developing targeted therapies that can mitigate the effects of cerebral edema and improve patient outcomes.

Recent advances in the signaling pathways involved in cerebral edema formation have opened new avenues for therapeutic interventions. For instance, targeting specific molecules like matrix metalloproteinase-9 (MMP-9) has shown promise in reducing BBB disruption and edema in preclinical models of traumatic brain injury (TBI) (Sunny et al., 2024). Additionally, the use of thrombin inhibitors has been suggested as a strategy to alleviate edema following cortical injuries, underscoring the potential of pharmacological agents to influence the progression of edema development (Singh et al., 2025). Furthermore, the emergence of innovative drug delivery systems, such as nanocarriers, may improve the targeting of therapeutic agents to the inflamed brain, which could enhance the management of cerebral edema (Ollen-Bittle et al., 2024).

In conclusion, cerebral edema remains a significant clinical challenge, with complex neurobiological foundations that require a comprehensive understanding of its regulatory mechanisms. As research continues to demonstrate the intricate interactions between cellular, molecular, and inflammatory factors contributing to edema formation, there is potential for the development of novel therapeutic strategies aimed at improving patient care. This review will serve as a foundation for further exploration into the neuroregulatory mechanisms of cerebral edema and their impact on clinical practice.

2 Types of brain edema2.1 Cytotoxic edema

Cytotoxic Edemais characterized by intracellular swelling of neurons, glia, and endothelial cells due to failure of the ATP-dependent sodium-potassium pump, typically following ischemic or metabolic insults (Manwar et al., 2023). This results in intracellular accumulation of sodium and water. A critical neurochemical event associated with this process is the release of ascorbate, which has been directly observed during glutamate-induced cytotoxic edema (Jin J. et al., 2020). The swelling of astrocytic endfeet is an early event, preceding measurable breakdown of the BBB (Manwar et al., 2023). The aquaporin (AQP) 4 water channel, predominantly located on astrocytic endfeet, plays a pivotal role in facilitating this water influx (Contreras-Zarate et al., 2023). Resolution of cytotoxic edema depends on the restoration of ionic homeostasis. Pharmacological strategies aim to block the initiating cascades; for instance, the anti-epileptic drug topiramate, which inhibits AQP4 function, can reduce radiation-induced astrocytic swelling and cytotoxic edema (Contreras-Zarate et al., 2023). Similarly, genetic knockout or pharmacological inhibition of the sulfonylurea receptor 1 (SUR1), which regulates the SUR1-TRPM4 channel involved in oncotic cell swelling, has been shown to ameliorate cytotoxic edema and improve outcomes in models of sepsis and traumatic brain injury (Moosavi et al., 2016).

2.2 Vasogenic edema

Vasogenic Edema arises from increased permeability of the BBB, allowing plasma proteins and fluid to extravasate into the extracellular space. This is often triggered by conditions that impair endothelial integrity, such as hypertension, inflammation, or certain tumors (Li Y. et al., 2023). The disruption is multifocal and initiates around capillaries and venules (Hoffmann et al., 2018). Key mediators include proteolytic enzymes like proteinase-3, which can degrade endothelial junctional proteins (Cummings et al., 2023). In conditions like posterior reversible encephalopathy syndrome, vasogenic edema is a hallmark, believed to stem from endothelial dysfunction and hyperperfusion (Li Y. et al., 2023). Resolution requires restoration of BBB integrity, which involves downregulation of inflammatory mediators and reparative processes in the endothelium. The extent of vasogenic edema can predict subsequent tissue injury, as its volume correlates with final infarct size after ischemia (Hoffmann et al., 2018). It is important to differentiate vasogenic edema from other types using advanced imaging; for example, in cerebral venous thrombosis, vasogenic edema and hemorrhage are more common consequences than true venous infarction (Alajmi et al., 2023).

2.3 Hydrostatic edema

Hydrostatic Edema occurs when increased pressure within the cerebral ventricles forces cerebrospinal fluid across the ventricular ependymal lining into the periventricular white matter. While this classic hydrostatic mechanism is well-established, the provided literature emphasizes that in pathological contexts like post-hemorrhagic ventricular dilatation, periventricular white matter injury involves complex microstructural changes including axonal injury, myelin disruption, and vasogenic edema, rather than pure interstitial fluid accumulation (Isaacs et al., 2022).

2.4 Ionic edema

Ionic Edema represents an intermediate stage in the edema cascade. It is defined by the accumulation of sodium and other ions in the extracellular space due to a compromised BBB ionic gradient, but before the extravasation of large plasma proteins (Biller et al., 2021). This subtype was recently demonstrated in healthy humans following prolonged normobaric hypoxia, where sodium MRI detected sodium ion accumulation in the extracellular space alongside an intact endothelium (Biller et al., 2021). This suggests a transitional state where the BBB may be functionally altered but not fully disrupted. The resolution of ionic edema likely involves the active export of ions from the interstitium, possibly via astrocytic and endothelial ionic pumps, to re-establish the trans-endothelial electrochemical gradient before progression to full vasogenic edema.

3 Causes of brain edema

Brain edema, characterized by the accumulation of excess fluid in the brain, can arise from various pathological conditions. Understanding the causes is crucial for developing effective treatment strategies (Figure 1).

The mechanisms of cerebral edema caused by disruption of the blood–brain barrier under different pathological conditions. (A–I) TBI, stroke, infections, tumors, High-altitude cerebral edema, Anoxic cerebral edema, Cerebral edema associated with hydrocephalus, Hepatic pathology-induced cerebral edema, and Renal pathology-induced cerebral edema disrupting the BBB.

3.1 Traumatic brain injury

TBI is recognized as one of the leading causes of morbidity and mortality worldwide, with a significant impact on public health across all age groups. From infants to the elderly, individuals can sustain TBI due to a variety of incidents, including falls, motor vehicle accidents, sports injuries, and assaults. According to the World Health Organization, TBI affects millions of people globally each year, contributing not only to immediate fatalities but also to long-term disabilities affecting physical, cognitive, and psychosocial domains (Wiles, 2022). The effects of TBI extend beyond the impacted individuals to families and communities, imposing significant economic burdens on healthcare systems and societal structures.

TBI usually originates from a primary injury, directly related to an external blow to the brain. The common symptoms include loss of consciousness, confusion, headache, dizziness, sensory disturbances, and emotional changes. Neurological assessments often reveal a mix of cognitive impairment and motor dysfunction, with some individuals experiencing communication difficulties or altered coordination. The mechanisms behind TBI are complex and involve a cascade of pathological processes. Key mechanisms include inflammatory responses, disruption of the BBB, and excitatory amino acids. Following injury, inflammatory cells infiltrate the brain tissue, releasing cytokines and reactive oxygen species that exacerbate neuronal damage (Kaur and Sharma, 2018). Degradation of the BBB is a critical event that leads to increased permeability, allowing potentially harmful substances to enter the neural tissue and contributing to edema formation (Cash and Theus, 2020). Moreover, the release of excitatory amino acids exacerbates neuronal excitability and cell death, leading to sustained neurological dysfunction (Dorsett et al., 2017).

Cerebral edema, a significant complication arising from TBI, is characterized by an abnormal accumulation of fluid within the brain parenchyma. Perihemorrhagic edema is common in TBI patients, which can cause increased ICP, hydrocephalus, and even cerebral herniation, which may lead to permanent brain damage and death (Sulhan et al., 2020). The interplay between trauma-induced cellular and molecular alterations promotes edema formation and can severely complicate the clinical management of TBI. Research has indicated that disturbances in water homeostasis in the brain are notably governed by AQPs (Mamtilahun et al., 2019; Czyzewski et al., 2024). Notably, AQP4 has been identified as a pivotal mediator in post-traumatic gliosis and cerebral edema following TBI (Czyzewski et al., 2024). Enhanced AQP4 expression is associated with increased water influx and subsequent edema, while inhibition or dysregulation of AQP4 can help mitigate the extent of edema formation. Additionally, the integrity of the BBB is central to the pathological development of TBI-related edema. Injury to the BBB can lead to neuroinflammation, exacerbating the permeability of the barrier and facilitating the development of edema. Recent studies have elucidated the role of various signaling pathways and inflammatory mediators in the disruption of the BBB following TBI (Lopez et al., 2022), highlighting potential therapeutic targets for intervention. This understanding reinforces the need for ongoing research focusing on the relationship between AQP expression, BBB integrity, and cerebral edema to facilitate the development of innovative strategies aimed at reducing morbidity associated with TBI.

In summary, TBI represents a complicated injury mechanism leading to diverse clinical presentations and multiple pathophysiological processes, including cerebral edema. Understanding the intricate interplay between inflammatory responses, BBB disruption, and the role of AQPs is crucial for developing future therapeutic approaches to mitigate the effects of TBI and improve outcomes for affected individuals. Future studies are warranted to explore targeted interventions that address these pathways to alleviate edema and enhance recovery in TBI patients.

3.2 Stroke

Stroke, a leading cause of death and long-term disability worldwide, can be classified into two major types: ischemic and hemorrhagic strokes. Ischemic stroke, the most common type, occurs when there is a blockage in the blood vessels supplying oxygen and nutrients to the brain. Hemorrhagic stroke, on the other hand, involves bleeding within the brain tissue, either from ruptured arteries or veins. Stroke can lead to severe consequences such as brain edema.

The brain edema plays a crucial role in the development and progression of stroke-related injuries. The neurovascular unit (NVU), which consists of endothelial cells, pericytes, astrocytes, and neurons, plays an essential role in maintaining the integrity of the BBB and regulating the movement of ions, water, and nutrients across it (Figure 2). In ischemic stroke, reduced cerebral blood flow (CBF) leads to changes in NVU transport proteins (e.g., N-methyl-D-aspartate receptors, NMDARs), resulting in increased permeability of the BBB and subsequent brain edema. This process also involves alterations in energy metabolism due to changes in glucose transport proteins (Sifat et al., 2019). As highlighted in recent studies, NMDARs are critical players in the pathophysiology of ischemic stroke. Overactivation of NMDARs during ischemia leads to excessive glutamate release, which triggers calcium overload and neuronal death (Figure 1B; Zong et al., 2022; Yu et al., 2023). Furthermore, the interaction between NMDARs and the NVU exacerbates BBB disruption, contributing to the severity of brain edema through disturb the intercellular tight junctions (Figure 2d; Ge et al., 2020; Yu et al., 2022). Understanding these mechanisms is pivotal for developing targeted therapies aimed at mitigating stroke-induced neurological damage.

Neurobiological regulatory mechanisms after cerebral edema. (A) Structure of the normal neurovascular unit. The brain capillary is structurally composed of cerebral capillary endothelial cells bound together by tight junctions. Together with neurons (yellow in the image), astrocytes (dark green in the image), (purple in the image), and microglial cells (pale green in the image), they collectively ensure the integrity of the blood–brain barrier. (B) In the early stages of cerebral edema, neuronal damage activates microglia toward the M1 phenotype and induces astrocyte swelling, impairing glutamate uptake. Microglia generate excessive reactive oxygen species, exacerbating oxidative stress. Extracellular glutamate accumulation overstimulates neuronal NMDARs and AMPARs, causing Ca2+ overload and excitotoxicity. Subsequently, astrocytic endfeet retract from endothelial cells (a,b). nNOS-derived NO promotes VEGF synthesis in astrocytes. eNOS-produced NO supports neuronal function (c). Endothelial MMPs degrade extracellular matrix and tight junctions. AQP4 expression is upregulated and undergoes relocalization, facilitating water influx into brain tissue and exacerbating cerebral edema (d). (C) In the late stage of cerebral edema, astrocytes secrete BDNF, which activates neuronal TrkB receptors, promoting neuronal survival, axonal regeneration, and synaptic remodeling (a). Microglia transform into the M2 phenotype. M2 microglia secrete anti-inflammatory cytokines such as TGF-β and IL-10, as well as neurotrophic factors like BDNF, participating in tissue repair and neural regeneration (b). Neutrophils produce iNOS-derived NO, disrupting gap junctions, and release inflammatory mediators (c). Astrocytes secrete VEGF and bFGF, stimulating endothelial proliferation and migration, while TGF-β helps stabilize tight junctions in nascent vessels, contributing to BBB recovery. AQP4 expression is downregulated, reducing water influx into brain tissue, alleviating edema and restoring brain water balance (d). BBB, blood–brain barrier; TNF-α, tumor necrosis factor-α; NMDARs, N-methyl-D-aspartate receptors; MMPs, matrix metalloproteinases; AMPARs, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors; AQP4, aquaporin 4; bFGF, basic fibroblast growth factor; EAAT1/2, excitatory amino acid transporters 1/2.

Studies have highlighted Toll-like receptor 4 as a potential therapeutic target, with its inhibition showing notable benefits in stroked patients. Persistent inflammation mediated by Toll-like receptor 4 can lead to a range of associated diseases, including hydrocephalus and elevated ICP, vasospasm, microthrombosis, and BBB disruption (Shang et al., 2019). In addition to its effects on the BBB, stroke can also impact other aspects of brain function. For example, increased secretion of arginine-vasopressin (AVP) has been observed following stroke, which may contribute to the development of brain edema (Li D. et al., 2021; Cui et al., 2021). Moreover, stroke-induced brain edema has been linked with various diseases such as cerebral infarction and hemorrhage. Therefore, understanding the mechanisms underlying stroke-induced brain edema is crucial for developing effective treatment strategies.

In conclusion, understanding the complex interplay between the NVU, BBB, and cerebral edema in the context of stroke is essential for developing effective therapeutic strategies. Targeting specific components of this pathway, such as Toll-like receptor 4, offers promising avenues for reducing the debilitating effects of stroke and improving patient outcomes.

3.3 Infections

Infection refers to the local tissue and systemic inflammatory response caused by the invasion of pathogens such as bacteria, viruses, fungi, and parasites into the human body. Under normal circumstances, inflammation is a defensive response of the body that can promote tissue repair and functional normalization. Infections increase vascular permeability in the brain, predominantly resulting in vasogenic cerebral edema. The disruption of the BBB due to infection allows plasma constituents and leukocytes to enter the brain parenchyma, exacerbating inflammation and edema formation. Different types of infectious diseases causing brain edema (Table 1; Azevedo-Quintanilha et al., 2019; Krous et al., 2007; Yao et al., 2015; Bharath et al., 2023; Zhao et al., 2021; Song et al., 2016; Davenport et al., 1990; Kidney and Kim, 1998; van der Flier et al., 2005; Lin et al., 2023).

Infectious diseasePrimary associated pathogenKey pathogenic mechanisms and pathological featuresReferencesMalariaPlasmodium berghei ANKA (experimental model)1. BBB disruption, astrocyte swelling, adhesion and accumulation of leukocytes in cerebral vessels, and a pro-inflammatory response are key factors.
2. Deficiency of integrin αDβ2 attenuates BBB disruption and cerebral edema.Azevedo-Quintanilha et al. (2019)Viral meningitisVarious viruses (e.g., enterovirus, HHV-6)Even clinically mild viral (lymphocytic) meningitis can cause severe diffuse cerebral edema, brain herniation, and neurogenic pulmonary edema in young children.Krous et al. (2007)Influenza virus (H1N1)Infection increases BBB permeability and causes brain edema, associated with overexpression of inflammatory mediators such as endothelin-1, inducible nitric oxide synthase, and TNF-α.Yao et al. (2015)SARS-CoV-2 (Omicron BA.2)Infection in children can cause acute fulminant cerebral edema, often accompanied by shock and multi-organ failure; pathophysiology may be related to a significant systemic hyperinflammatory response.Lin et al. (2023)Ameba infectionsNaegleria fowleriCauses Primary Amebic Meningoencephalitis; neuroimaging may show a nonspecific pattern of diffuse cerebral edema.Kidney and Kim (1998)Acanthamoeba spp.Causes Granulomatous Amebic Encephalitis; neuroimaging often shows focal enhancing lesions.Bacterial meningitisPneumococcusIn an experimental model, VEGF levels in CSF were elevated and correlated with brain edema.van der Flier et al. (2005)Mycoplasma/ureaplasma infectionMycoplasma hominis, Ureaplasma spp.Causes disseminated infection in immunocompromised patients, leading to nonhepatic hyperammonemia syndrome, which can result in severe cerebral edema and refractory status epilepticus.Bharath et al. (2023)Other bacterial infectionsLeptospira spp.Patients with severe infection and multisystem involvement may develop cerebral edema during treatment for acute renal failure (e.g., hemodialysis or hemofiltration).Davenport et al. (1990)Mycobacterium tuberculosisCauses adrenal insufficiency, which can precipitate an adrenal crisis under stress, leading to diluted hyponatremia and severe cerebral edema.Zhao et al. (2021)Infection as a predisposing factorPreexisting systemic inflammation/infectionCan significantly facilitate the development of cerebral edema upon subsequent exposure to short-term severe hypoxia (e.g., high altitude). The mechanism involves inflammatory signaling upregulating the expression and function of the brain water channel AQP4.Song et al. (2016)

Infectious diseases causing brain edema.

Infections are among the most common complications following ischemic stroke, further complicating patient outcomes. Post-stroke infections can significantly impact stroke prognosis by aggravating neuroinflammation. Peripheral inflammatory signals have been shown to communicate with the central nervous system (CNS), exacerbating neural inflammatory responses. The lipopolysaccharide-induced ischemic brain injury infection model led to an excessive inflammatory response, which consequently increased the infarct volume and edema degree 24 h after middle cerebral artery occlusion (Wang et al., 2019). Plasmodium infection can induce reversible brain swelling through disrupting BBB (Jin et al., 2022). This finding highlights the potential for parasitic infections to directly influence cerebral edema development. In C57BL/6 mice infected with toxoplasma gondii, vasogenic edema was observed. Treatment with a viral vector expressing vascular endothelial growth factor (VEGF) showed improvements in lymphatic drainage in infected mice (Kovacs et al., 2024). However, this treatment did not result in increased clearance of edematous fluid from the brain, suggesting complex interactions between infection, vascular responses, and edema resolution.

3.4 Tumors

Cerebral edema associated with brain tumors is a very common occurrence, including primary and metastatic tumors. Leakage of plasma across the vessel wall into the parenchyma through the disruption of the BBB, causes edema around the brain tumor, also known as brain tumor-related edema (Esquenazi et al., 2017; Solar et al., 2022). Since the brain is enclosed within the skull, an increase in ICP due to tumor growth or edema is initially countered by compensatory mechanisms such as cerebrospinal fluid displacement, reduced CBF, and alterations in brain parenchyma shape. However, as the tumor progresses, these compensatory mechanisms weaken, leading to a dramatic rise in ICP (Sorribes et al., 2019). The high ICP can paradoxically inhibit the production and circulation of CSF, potentially leading to the accumulation of toxic proteins, solutes, pro-inflammatory cytokines, and chemokines, exacerbating glioma progression (Ma et al., 2019). Furthermore, the expression of AQPs plays a pivotal role in gliomas. On the one hand, elevated AQP1 expression contributes to increased angiogenesis in astrocytoma, enhancing tumor growth and spread. In human glioblastoma, the disruption of BBB is significantly correlated with the increased AQP4 expression, particularly extended isoform of AQP4 protein (Valente et al., 2022). On the other hand, AQP5 accelerates glioma cell proliferation, migration, and reduces apoptosis via modulation of the EGFR/ERK/p38 MAPK signaling pathway, while AQP8 may also promote astrocytoma proliferation and migration (Zhou et al., 2022), enhancing infiltration into surrounding brain tissue.

Additionally, gliomas alterations the BBB integrity, increased permeability, and impaired endothelial barrier functions further contribute to brain tumor-related epilepsy (Groblewska and Mroczko, 2021). Such as Piezo1, a calcium-permeable transmembrane ion channel protein, is upregulated in glioblastomas. Piezo1 promotes Ca2+ influx into vascular endothelial cells, activating calcium-dependent calpains. Calpains further degrade tight junctions between vascular endothelial cells, increasing vascular permeability and exacerbating brain edema (Qu et al., 2020). The relationship between brain tumors and brain edema is complex, driven by alterations in ICP dynamics, vascular changes, and disruptions in the function of essential fluid transport mechanisms.

3.5 High-altitude cerebral edema

High-altitude cerebral edema (HACE) is a severe neurological disorder occurring above 2,500 m, affecting millions of residents and visitors annually (Cai et al., 2026). As the end-stage manifestation of acute mountain sickness, HACE is characterized by life-threatening encephalopathy with symptoms including severe headache, ataxia, altered mental status, and impaired cognitive and motor functions (Zhou et al., 2017; Han et al., 2026). Current theory posits that AMS and HACE represent a continuum of neurological dysfunction. Imaging studies have not only confirmed cerebral edema in HACE patients but also suggest that some individuals with AMS may exhibit mild cytotoxic edema in specific brain regions, which could represent an early stage or parallel process to the more severe vasogenic edema observed in HACE (Gatterer et al., 2024).

The primary pathophysiological trigger is hypobaric hypoxia, which initiates a cascade of molecular events leading to cerebral edema (Li et al., 2025). HACE involves vasogenic and cytotoxic edema, driven by BBB disruption via hypoxia-induced upregulation of CAV-1 and degradation of claudin-5 (Wang X. et al., 2022; Xue et al., 2022; Zuo et al., 2025). Furthermore, oxidative stress activates inflammatory pathways through NF-κB and the NOD-like receptor thermal protein domain-associated protein 3 inflammasome. The activated microglia exacerbate BBB damage and contribute to the inflammatory milieu (Wang X. et al., 2022). Concurrently, cytotoxic edema arises from direct cellular dysfunction. Studies reveal that hypoxia induces metabolic disturbances, including glucose metabolic reprogramming and mitochondrial dysfunction, amplifying injury through the opening of the mitochondrial permeability transition pore and the release of apoptotic factors (Han et al., 2024). Single-cell analyses have identified dysregulated oxidative phosphorylation and ribosomal stress in oligodendrocytes and neurons, promoting apoptosis and contributing to edema (Lv et al., 2025). These processes are amplified by a robust neuroinflammatory response mediated by pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6, and the activation of pathways involving HIF-1α and NF-κB (Li et al., 2025; Zhou et al., 2017; Shi et al., 2020). Thus, HACE pathophysiology is a complex interplay between increased cerebrovascular permeability and direct cellular edema, driven by hypoxia-induced metabolic, inflammatory, and vascular insults.

3.6 Anoxic cerebral edema

Anoxic cerebral edema, one of the main causes of neurological disability and mortality, results from severe oxygen deficiency due to events like cardiac arrest or high-altitude exposure (Hanning et al., 2016). The main manifestations include increased ICP, neurological deficits, and, in severe cases, brain herniation. The underlying mechanisms involve a complex interplay leading to both cytotoxic and vasogenic edema. One contributing theory is the “tight-fit” hypothesis, which posits that individuals with less compliant cerebrospinal fluid systems (e.g., smaller ventricles) experience a greater rise in ICP for a given increase in brain volume due to hypoxic swelling (Wilson and Milledge, 2008). While some experimental models suggest that the formation of this type of edema may not initially involve increased permeability of the BBB to large proteins like horseradish peroxidase (Ushijima et al., 1984), other pathways are critically involved.

Recent research has significantly advanced the understanding of the role of neuroinflammation and stress responses in the pathogenesis of anoxic cerebral edema. Systemic pro-inflammatory priming is a key facilitator. Experimental evidence demonstrates that a pre-existing inflammatory state, when combined with acute hypoxia can trigger edema via TLR4/corticotropin-releasing hormone receptor 1 signaling, activating NF-κB/MAPK pathways and upregulating AQP4 expression and increased water permeability in astrocytes (Song et al., 2016). Furthermore, hypoxia itself can elevate plasma levels of pro-inflammatory cytokines (e.g., TNF-α, IL-1β, IL-6) and corticotropin-releasing hormone (Song et al., 2016). Conversely, prophylactic administration of anti-inflammatory and antioxidant agents, such as p-coumaric acid, has been shown to exert protective effects against anoxic cerebral edema in mice. This protection is mediated by reducing oxidative stress, dampening inflammation, enhancing BBBintegrity, and improving Na+-K+-ATPase activity (Li et al., 2019). These findings collectively underscore central roles for inflammatory cascades and cellular stress in driving the molecular and cellular events that culminate in hypoxic brain swelling.

3.7 Cerebral edema associated with hydrocephalus

Hydrocephalus-related brain edema coexists with primary CNS injury, and the relationship is not a simple causal one. Instead, they exacerbate each other through two parallel and interwoven pathways: choroid plexus immune activation and compartmentalization disorder of the subarachnoid space. On one hand, intraventricular hemorrhage or pathogen-associated molecular patterns can be recognized by Toll-like receptors on choroid plexus epithelial cells, triggering a nuclear factor kappa B-dependent inflammatory cascade. The upregulation of this pathway directly enhances the expression and phosphorylation of NKCC1, shifting the choroid plexus from ‘secretory homeostasis’ to a hyper-secretory state (Courtney et al., 2025). The increased cerebrospinal fluid production rate elevates intraventricular hydrostatic pressure, which is reversely transmitted to the periventricular white matter spaces, hindering the reflux of interstitial fluid toward the ventricles. This forms the hydrodynamic basis for interstitial edema. Since this type of edema is not accompanied by widespread BBBdisruption, it often appears as smooth periventricular T2 hyperintensity on imaging. On the other hand, the subarachnoid space is not homogeneous. The perivascular subarachnoid space along major arterial trunks is responsible for directional cerebrospinal fluid transport under physiological conditions. In patients with idiopathic normal pressure hydrocephalus, this structure exhibits characteristic phenotypes of enlarged area and prolonged first-pass time of tracers, indicating widened perivascular spaces but significantly reduced anterograde transport efficiency (Eide and Ringstad, 2024). The specific mechanisms—whether due to changes in membrane permeability, weakened vascular pulsation driving force, or compensatory remodeling after chronic inefficient transport—require further investigation.

In hydrocephalus associated cerebral edema, dysfunction of the glymphatic drainage system plays a key role. The glymphatic system is a recently defined brain-wide perivascular network responsible for the exchange between CSF and interstitial fluid and facilitates the clearance of brain metabolic waste (Lv et al., 2021). This system consists of a periarterial CSF influx pathway, convective transport mediated by AQP4 water channels on astrocytic endfeet, and a perivenous efflux pathway, and is closely connected to the meningeal lymphatic system. In various neurological disorders including hydrocephalus, glymphatic system function is disrupted (Al Masri et al., 2024). In hydrocephalus, obstruction of CSF circulation pathways can lead to periventricular interstitial edema, which essentially represents the backflow of CSF into the brain parenchyma through the ependyma (Milhorat, 1992). The glymphatic system, as a core pathway for brain ISF drainage, directly exacerbates such edema when its function is impaired. Studies indicate that in idiopathic normal pressure hydrocephalus, significant glymphatic dysregulation exists, manifested as impaired CSF dynamics and delayed clearance of metabolic waste (Al Masri et al., 2024). Furthermore, in cerebral edema and chronic hydrocephalus following subarachnoid hemorrhage, glymphatic-meningeal lymphatic function is also impaired and is closely associated with elevated extrinsic coagulation pathway factors and inflammatory cytokines (Fang et al., 2024). The AQP4 water channel is a central regulator of glymphatic function (Lv et al., 2021). Its dysfunction is a key link connecting cerebral edema and glymphatic system disruption. In cerebral edema, the functional state of AQP4 determines the direction of water transport: AQP4 deletion aggravates vasogenic edema but alleviates cytotoxic edema. In hydrocephalus, maladaptive changes in AQP4 may further impair glymphatic drainage, and targeting the regulation of AQP4 channels has emerged as a promising therapeutic strategy (Filippidis et al., 2016). For example, in subarachnoid hemorrhage models, the use of tissue plasminogen activator has been shown to alleviate neuroinflammation and cerebral edema, with a potential mechanism possibly involving the restoration of glymphatic-meningeal lymphatic function (Fang et al., 2024).

3.8 Hepatic pathology-induced cerebral edema

Hepatic pathology, particularly in the context of acute or chronic liver failure, is a primary instigator of cerebral edema, a severe and often fatal neurological complication. The compromised liver fails to adequately detoxify the bloodstream, leading to the systemic accumulation of neurotoxic substances (Kaler, 2016). This toxic milieu is further exacerbated by systemic inflammatory responses originating from the injured liver; for instance, conditions like metabolic dysfunction-associated steatohepatitis are characterized by the release of pro-inflammatory mediators such as periostin, which can disseminate via circulation and potentially impact distant organs including the brain (Xie et al., 2024). Furthermore, the gut-liver axis plays a critical role, as hepatic dysfunction alters bile acid metabolism and compromises intestinal barrier integrity, facilitating the translocation of bacterial products like lipopolysaccharide into the portal circulation (Barretto et al., 2021; Luo et al., 2025). These circulating toxins and inflammatory signals collectively assault the CNS, setting the stage for edema formation.

The liver’s inability to clear ammonia leads to hyperammonemia, which disrupts cerebral amino acid metabolism and osmotic regulation within astrocytes (Ajoolabady et al., 2023). Concurrently, alterations in aromatic amino acid metabolism contribute to the synthesis of false neurotransmitters, disrupting normal neuronal function. These metabolic insults converge to destabilize the BBB and induce astrocyte swelling, the hallmark of cytotoxic edema (Ibrahim et al., 2018). At a cellular level, similar pathogenic processes observed in hepatic cells, such as endoplasmic reticulum stress and iron overload-induced ferroptosis, may have parallels in neural cells, promoting oxidative stress and cell death that exacerbate edema (Guo J. et al., 2021; Ajoolabady et al., 2023; Liu et al., 2025). The activation of stress-response pathways like KEAP1-NRF2 in hepatocytes under pathological conditions suggests a systemic redox imbalance that could similarly affect the vulnerable brain parenchyma (Liang et al., 2026).

Severe hepatic pathologies, including advanced cirrhosis or acute failure, can lead to cardiopulmonary complications and hemodynamic instability, resulting in cerebral hypoperfusion and hypoxia (Malka-Markovitz et al., 2025). This hypoxia disrupts cellular energy metabolism, leading to ionic pump failure, intracellular sodium and water accumulation, and subsequent swelling of neuronal and glial cells. Moreover, intravital imaging studies in steatohepatitis models reveal a dynamic, pathological microenvironment with immune cell activation and cluster formation, which in the brain could correlate with neuroinflammatory responses that worsen hypoxic injury and edema (Wang et al., 2021). The interplay between systemic inflammation from liver disease, endothelial dysfunction, and reduced oxygen delivery creates a vicious cycle that amplifies hypoxic brain damage.

3.9 Renal pathology-induced cerebral edema

Renal pathology can significantly influence cerebral edema through systemic metabolic disturbances. Severe kidney disease, particularly acute or chronic renal failure, impairs the body’s ability to excrete metabolic waste products and maintain electrolyte and acid–base homeostasis. This results in the accumulation of uremic toxins, hyperkalemia, and metabolic acidosis. These systemic alterations compromise CNS function, leading to cellular swelling.

The mechanisms by which renal pathology leads to cerebral edema are multifaceted, involving direct metabolic pathways and secondary inflammatory responses. Firstly, kidney failure causes profound metabolic and excretory changes. The retention of urea and other nitrogenous wastes contributes to osmotic imbalances. Similar to how hepatic dysfunction alters metabolite profiles (Guo J. et al., 2021), renal failure disrupts the systemic balance of solutes, creating an osmotic gradient that favors water movement into brain cells. Furthermore, impaired renal excretion leads to the accumulation of cytokines and inflammatory mediators, fostering a state of systemic inflammation. This inflammation is a key driver of endothelial dysfunction, as observed in various hepatic pathologies (Xie et al., 2024; Zhang H. et al., 2024). Systemic inflammation can weaken the BBB, a critical finding in studies of other organ-related encephalopathies (Lagana et al., 2020).

Secondly, the direct pathway to cerebral edema involves BBB disruption and cellular swelling. Uremic toxins and inflammatory cytokines can directly activate endothelial cells and pericytes, compromising tight junction integrity. Subsequently, astrocytes, which play a crucial role in brain ion and water homeostasis, undergo swelling. This systemic disturbances trigger neuroinflammation and oxidative stress, leading to glial cell injury and swelling (Ajoolabady et al., 2023; Wang C. Y. et al., 2022). Thus, renal failure creates a cascade from systemic solute imbalance and inflammation to direct BBB injury and cellular edema in the brain.

4 Neurological regulatory mechanisms

The brain employs several regulatory mechanisms to maintain hom