Targeting TRPV4 to restore glymphatic system function and alleviate cerebral edema in ischemic stroke

Jun 7, 2025Brain pathology (Zurich, Switzerland)

Using TRPV4 to improve brain fluid clearance and reduce swelling after stroke

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Abstract

Inhibition of significantly improved function and reduced cerebral edema in a mouse model of ischemic stroke.

Cerebral edema and glymphatic system dysfunction were observed in mice after middle cerebral artery occlusion and reperfusion.
Increased expression of TRPV4 and decreased levels of β-dystroglycan were found in the ischemic penumbra.
Inhibiting TRPV4 with HC067047 restored aquaporin-4 polarization and increased β-dystroglycan expression.
HC067047 treatment led to reduced expression of matrix metalloproteinase-9 and RhoA.
Neurological recovery was enhanced following TRPV4 inhibition, indicating potential therapeutic benefits.

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Emerging studies underscore the pivotal role of (GS) dysfunction in the pathogenesis of cerebral edema following brain injury. The transient receptor potential vanilloid 4 () channels have been implicated in modulating the polarization of aquaporin-4 (), a key protein involved in GS function. This study investigates the potential of targeting TRPV4 to alleviate GS dysfunction and reduce cerebral edema following ischemic stroke. TRPV4 inhibitor HC067047 or a vehicle was administered via lateral ventricle cannulation in a mouse model of middle cerebral artery occlusion and reperfusion (MCAO/R). The function of the GS was assessed through tracer injection experiments, including in vivo transcranial imaging, ex vivo brain tissue and section analysis, and fluorescence retention in deep cervical lymph nodes (dCLNs). Cerebral edema was quantified using magnetic resonance imaging. AQP4 polarization and β-dystroglycan (β-DG) expression were evaluated by immunofluorescence. Western blotting was employed to measure protein levels of β-DG, matrix metalloproteinase-9 (MMP9), and Ras homolog family member A (RhoA). Long-term neurological outcomes were assessed via behavioral testing. MCAO/R mice exhibited significant GS dysfunction, cerebral edema, and disrupted AQP4 polarization. Additionally, β-DG expression was markedly reduced, while TRPV4 expression was elevated in the ischemic penumbra. Western blotting revealed increased expression of MMP9 and RhoA. The inhibition of TRPV4 by HC067047 significantly improved GS function, reduced cerebral edema, and enhanced neurological recovery. Mechanistically, HC067047 partially restored AQP4 polarization, upregulated β-DG expression, and suppressed the expression of MMP9 and RhoA. These findings highlight the therapeutic potential of TRPV4 inhibition in ischemic stroke by restoring GS function, mitigating cerebral edema, and promoting neurological recovery, thereby positioning TRPV4 as a promising target for future interventions.

Key numbers

significantly higher

Increase in survival rate

Compared to vehicle control group

significantly increased

Reduction in cerebral edema

Measured via MRI metrics

significantly increased

Glymphatic influx improvement

Assessed through transcranial imaging

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Targeting TRPV4 to restore glymphatic system function and alleviate cerebral edema in ischemic stroke

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