Effect of Early Inhibition of Toll-Like Receptor 4 on Hippocampal Plasticity in a Neonatal Rat Model of Hypoxic-Ischemic Brain Damage.

Abstract

Hippocampal plasticity is closely related to physiological brain functions such as learning and memory. However, the effect of toll-like receptor 4 (TLR4) activation on hippocampal plasticity after neonatal hypoxic-ischaemic brain damage (HIBD) remains unclear. In our study, seven-day-old rat pups were randomly categorised into three groups: control, hypoxic-ischemia (HI), and HI + TAK-242 (TAK-242). The pups were ligated in the left common carotid artery and then subjected to hypoxia to establish the neonatal HIBD model.The expression of the TLR4 in the left hippocampus of the HI group was increased compared to the control group, while TAK-242 reduced the expression level at 3 days after HIBD. Additionally, TAK-242 reversed the increased Zea-Longa score, increased the left/right hippocampal weight ratio, and increased the number of Nissl-positive neurons in the hippocampal CA1 region compared to HI group at 3 days after HIBD. Pre-injection of TAK-242 alleviated the decrease in PSD95, Aggrecan and NR1, BDNF, CREB, and pCREB expression in the hippocampus at 24 h after HIBD. It also alleviated the decrease in PSD95, BDNF, and NR2A/NR1 expression in the hippocampus at 7 days after HIBD. Furthermore, Pre-injection of TAK-242 alleviated the decrease in NR2A/NR1 expression at 21 days after HIBD. Finally,TAK-242 increased the percentage of third-grade dendritic mushroom spines processes in the basal and apical segments of neurons in the hippocampal CA1 region at 21 days after HIBD.Therefore, we conclude that preinhibition of TLR4 prior to neonatal HIBD improved the plasticity of the hippocampus.