Aquaporin4 Knockout Aggravates Early Brain Injury Following Subarachnoid Hemorrhage Through Impairment of the Glymphatic System in Rat Brain

The Glymphatic System: A Novel Therapeutic Target for Stroke Treatment

“…Currently, there is no effective intervention for preventing secondary neuropathological damage and improving the prognosis of SAH patients. Impaired CSF circulation along periarterial influx routes has been indicated in rodent models and gyrencephalic non-human primate model of SAH and has shed new light on translational therapeutic strategies ( Gaberel et al, 2014 ; Goulay et al, 2017 ; Golanov et al, 2018 ; Liu et al, 2020a , b ; Figure 1B ). Following SAH, blood components particularly fibrin and fibrinogen deposit in PVS, which led to occlusion and dysfunction of the GS, ultimately worsening cerebral ischemia and edema ( Goulay et al, 2017 ).…”

“…Some other studies reported the neuroprotective role of AQP4 in early brain injury (EBI) following SAH. Given that AQP4 facilitated ISF transport in the brain parenchyma to eliminate the toxic factors, AQP4 knockout has been shown to aggravate EBI following SAH through impairment of the GS ( Liu et al, 2020a , b ). Pu et al (2019) also demonstrated that the perivascular polarity of AQP4 decreased after SAH, which resulted in accumulations of tau proteins and CD3 + , CD4 + , and CD8 + cells, and led to a series of pathological changes, including microvascular spasm, activation of glial cells, neuroinflammation, and neuronal apoptosis ( El Amki et al, 2018 ).…”

“…One potential explanation for the controversial role of AQP4 in SAH is that the expression of AQP4 in the influx and efflux routes of the GS is different. After SAH, astrocytes surrounding the arteries were activated to increase the expression of AQP4; however, the expression of AQP4 around the veins changed slightly ( Liu et al, 2020b ). Therefore, the inflow of CSF from periarterial space (PAS) increased highly due to the enhanced level of AQP4, and the ISF volume expanded owing to the unchanged expression of AQP4 around the veins.…”

Glymphatic System in the Central Nervous System, a Novel Therapeutic Direction Against Brain Edema After Stroke

“…After using deferoxamine to reduce the iron concentration around the hematoma, the expression of AQP4 decreases, and brain edema is reduced in the model of experimental intracerebral hemorrhage (ICH; Qing et al, 2009 ). AQP4 knockout mice in the SAH model, which was established using the endovascular perforation method, showed impaired transport of ISF and increased water content in the brain (Liu et al, 2020 ). The contradictions between the two studies may be related to the difference in SAH models, or it may mean that AQP4 has a biphasic effect after a hemorrhagic stroke.…”

The Involvement of Aquaporin-4 in the Interstitial Fluid Drainage Impairment Following Subarachnoid Hemorrhage

“…The ISF carrying various waste proteins and metabolic products is cleared out of the brain through the paravenous space (PVS; Iliff et al, 2013). Our previous study showed that Aqp4 knockout aggravated the loss of neurons in the hippocampus and the BBB disruption after SAH (Liu et al, 2020). However, the potential injury mechanism and relationship with the GS are yet to be clarified.…”