Pharmacological Inhibition of TLR4-NF-κB Signaling by TAK-242 Attenuates Hydrocephalus after Intraventricular Hemorrhage

Abstract

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 4 receptor (TLR4) inhibitor, downregulates 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-κB signaling pathway. A model of PHH was conducted in 6-week-old Male Sprague-Dawley rats. The rats were divided into four main groups, including the sham, IVH+ vehicle, IVH+ TAK-242 and IVH groups. Magnetic resonance imaging was applied to measure the lateral ventricle volume. Western blot (WB) and immunofluorescence (IF) were applied to detect the expression of TLR4, NF-κB, 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-κB signaling pathway. We observed the increased lateral ventricular volume, elevation of NF-κB 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-κB, 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-κB signaling pathway.