New Insights on Mechanisms and Therapeutic Targets of Cerebral Edema

Abstract

Cerebral Edema (CE) is the final common pathway of brain death. In severe neurological disease, neuronal cell damage first contributes to tissue edema, and then Increased Intracranial Pressure (ICP) occurs, which results in diminishing cerebral perfusion pressure. In turn, anoxic brain injury brought on by decreased cerebral perfusion pressure eventually results in neuronal cell impairment, creating a vicious cycle. Traditionally, CE is understood to be tightly linked to elevated ICP, which ultimately generates cerebral hernia and is therefore regarded as a risk factor for mortality. Intracranial hypertension and brain edema are two serious neurological disorders that are commonly treated with mannitol. However, mannitol usage should be monitored since inappropriate utilization of the substance could conversely have negative effects on CE patients. CE is thought to be related to bloodbrain barrier dysfunction. Nonetheless, a fluid clearance mechanism called the glial-lymphatic or glymphatic system was updated. This pathway facilitates the transport of cerebrospinal fluid (CSF) into the brain along arterial perivascular spaces and later into the brain interstitium. After removing solutes from the neuropil into meningeal and cervical lymphatic drainage arteries, the route then directs flows into the venous perivascular and perineuronal regions. Remarkably, the dual function of the glymphatic system was observed to protect the brain from further exacerbated damage. From our point of view, future studies ought to concentrate on the management of CE based on numerous targets of the updated glymphatic system. Further clinical trials are encouraged to apply these agents to the clinic as soon as possible.

Keywords: Cerebral edema; blood-brain barrier; glymphatic system; intracranial pressure; mannitol.; meningeal lymphatic vessels.

Fig. (1)

The paradoxical functions played by neuroinflammatory pathways. At different stages of cerebral ischemia, different phenotypes of microglia play different roles. Left: In the early phase of cerebral ischemia, M1 phenotype microglia produce proinflammatory cytokines that mediate the development of vasogenic edema. Right: In the subacute phase of cerebral ischemia, M2 phenotype microglia are activated to exert anti-inflammatory properties, which are manifested by the release of various cytokines that act on various cells in the brain tissue, such as neural precursor cells and astrocytes, to accelerate inflammation reduction and repair the blood-brain barrier.

Fig. (2)

The position of different types of channels in water and ion transport and related potential targets for drug action. (A) SUR1 consists of two interacting transmembrane structural domains (TMD1 and TMD2). Four SUR1 subunits combine with four TRPM4 subunits to form a functional SUR1-TRPM4 octamer. SUR1-TRPM4 channels mediate the entry of Na⁺, K⁺, and Cl^- into the cell. The interaction of AQP4 and the SUR1-TRPM4 channel facilitates the penetration of water molecules into the cell. (B) WNK3 activates NKCC1 by phosphorylating the upstream regulator SPAK, promoting the transport of ions which are translocated into the cell. This function is inhibited by NKCC 1 inhibitors. The combination of NKCC1 with AQP4 accelerates the infiltration of excitatory amino acids, the production of NO, and the release of inflammatory cytokines. (Abbreviations: AQP4, aquaporin-4; NKCC 1, Na⁺–K⁺–2Cl^- cotransporter 1; NO, nitric oxide; SUR1, sulfonylurea receptor 1; TRPM4, transient receptor potential melatonin 4; TMD, transmembrane structural domains).