Hydrocephalus is mostly  recognized by enlargement of the fluid filled ventricles within the brain. As cerebrospinal fluid (CSF) accumulates, however, the expanding ventricles also place substantial mechanical stress on the surrounding brain tissue. Current treatment is predominantly surgical, making the development of complementary pharmacological approaches an important research goal.

Our laboratory has been investigating TRPV4 (Transient Receptor Potential Vanilloid 4), a mechanosensitive ion channel involved in CSF regulation. Previous work demonstrated that blocking TRPV4 with the antagonist RN1734 reduces ventriculomegaly in the Tmem67^−/− genetic rat model of congenital hydrocephalus, in part through effects on ion transport and CSF secretion by the choroid plexus. 

This study focused on the pericallosal cingulate cortex and surrounding periventricular structures. Hydrocephalic animals showed severe ventricular enlargement together with compression of white matter tracts, altered cortical organization, and enlarged neuronal cell bodies.

We then investigated inflammatory signaling. Two molecules were of particular interest: TLR4, an innate immune pattern recognition receptor, and NLRP3, an important component of the inflammasome. Hydrocephalic animals exhibited substantially increased TLR4, NLRP3, and cleaved Caspase-1-associated inflammatory signaling within the cingulate cortex. Much of this inflammatory signal was localized to neurons, although non-neuronal inflammatory involvement was also detected. Inflammation was accompanied by another important pathological process: oxidative stress. Hydrocephalic animals showed increased mitochondrial oxidative stress-associated fluorescence and increased 4-hydroxynonenal (4-HNE), a marker of lipid peroxidation. Neurons were also markedly enlarged, and neuronal apoptosis was substantially increased, these observations indicate that hydrocephalus involves much more than abnormal CSF accumulation, as ventricular enlargement is accompanied by a complex pattern of structural injury, inflammatory signaling, oxidative stress, and neuronal damage.

What happened after TRPV4 antagonism?

Treatment with RN1734 attenuated several components of this pathology. TLR4-, NLRP3-, and cleaved Caspase-1-associated neuronal inflammatory signaling decreased following treatment. RN1734 also reduced oxidative stress-associated signaling, lipid peroxidation, and neuronal apoptosis.

Why is this important?

Our findings encourage a broader view of hydrocephalus. Treating ventricular enlargement is clearly important, but protecting the surrounding brain tissue may be equally important for improving neurological outcomes. The current study cannot definitively determine whether RN1734 acts directly on cortical cells or whether the improvement in brain pathology occurs primarily because reduced ventricular enlargement decreases mechanical stress. This remains an important mechanistic question. Nevertheless, our results demonstrate that TRPV4 antagonism is associated not only with reduced ventricular pathology but also with attenuation of inflammatory, oxidative, and apoptotic changes within the hydrocephalic cortex.

https://doi.org/10.1186/s12974-026-04031-7    Full Article  Link