TRPV4 antagonism attenuates TLR4–NLRP3-mediated neuroinflammation and oxidative stress in cingulate cortex neurons in a genetic rat model of hydrocephalus

Hydrocephalus is characterized by pathological ventricular expansion and periventricular tissue damage, although the molecular mechanisms governing parenchymal injury in this condition remain unclear. Surgical interventions, such as cerebrospinal fluid (CSF) shunting are the standard of care; however, high complication rates underscore the urgent need to understand the underlying pathophysiology and develop targeted pharmacological therapies. Current therapeutic studies focus on reducing CSF secretion, but whether these interventions directly protect brain parenchyma is unknown. Here, using the Tmem 67 –/– rat model of congenital hydrocephalus, we identified a distinct mechano-inflammatory axis driving cortical neurodegeneration. We found that ventricular distension was accompanied by increased activation of Toll-like receptor 4 (TLR4) and NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasomes in cingulate cortex (CgCt) neurons adjacent to the corpus callosum. Inflammatory signaling was localized within neuronal populations, although non-neuronal inflammatory involvement was also observed in the CgCt. Neuronal inflammation was accompanied by mitochondrial oxidative stress-associated signaling in the CgCt and lipid peroxidation, culminating in hypertrophy, and apoptosis. Treatment with transient receptor potential vanilloid 4 (TRPV4) antagonist RN1734 significantly reduced TLR4 and NLRP3 inflammasome expression and lipid peroxidation, although it did not- fully rescue neuronal hypertrophy. Therefore, these findings suggest that TRPV4 antagonism may attenuate hydrocephalus-associated inflammation within cortical tissue by reducing pathological CSF production while simultaneously attenuating downstream inflammatory and oxidative signaling within CgCt.