Pharmacological inhibition of TLR4-NF-κB signaling by TAK-242 attenuates hydrocephalus after intraventricular hemorrhage

Compelling evidence has confirmed that inflammatory pathways involving TLR4-regulated cytokines and immune cells are vitally important for the pathogenesis of posthemorrhagic hydrocephalus (PHH), hinting that pharmacological prevention of PHH is feasible. TAK-242, as a toll-like receptor 4 (TLR4) inhibitor, down regulates TLR4-induced inflammatory responses and becomes a potent and novel therapeutic drug candidate for PHH. In the present study, we investigate whether TAK-242 protects against hydrocephalus and improves the prognosis of intraventricular hemorrhage (IVH). We also explore the possible role of TAK-242 for the regulation of TLR4-NF-kappa B signaling pathway. A model of PHH was conducted in 6-week-old Male Sprague-Dawley (SD) rats. The rats were divided into four main groups, including the sham, IVH + vehicle, IVH + TAK-242 and IVH groups. Magnetic resonance imaging (MRI) was applied to measure the lateral ventricle volume. Western blot (WB) and immunofluorescence (IF) were applied to detect the expression of TLR4, NF-kappa B, fibronectin and laminin. A combined scoring system and Morris water maze were employed to evaluate neurological functions after IVH. We found that IVH induced heightened activation of TLR4-NF-kappa B signaling pathway. We observed the increased lateral ventricular volume, elevation of NF-kappa B in choroid plexus, as well as fibronectin and laminin in the subarachnoid space (SAS) and ventricular wall after IVH. Obviously, TAK-242 treatment effectively inhibited the up regulation of NF-kappa B, fibronectin, laminin and significantly alleviated ventriculomegaly after IVH. Importantly, TAK-242 improved neurocognitive deficits after PHH. In conclusion, TAK-242 attenuated IVH-induced hydrocephalus and improved the prognosis of PHH. The underlying mechanism involved the TAK-242-mediated downregulation of TLR4-NF-kappa B signaling pathway.

Automated summary

This study found that the use of TLR4 inhibitor TAK-242 can effectively prevent the occurrence of posthemorrhagic hydrocephalus and improve the prognosis. Its mechanism of action involves the regulation of the TLR4-NF-κB signaling pathway.