TLR4 inhibition ameliorates mesencephalic substantia nigra injury in neonatal rats exposed to lipopolysaccharide via regulation of neuro-immunity

Dopaminergic neurons play a key role in motor function of the extrapyramidal system. Previous studies have shown that septic neonates may have cognitive dysfunction in later life. Toll-like Receptor 4 (TLR4) is a transmembrane protein which is widely distributed in nerve cells. Its activation will activate the innate immune system through increasing an intracellular signaling pathway NF-κB and inflammatory cytokine production. Here, One-day-old rats were exposed to lipopolysaccharide (LPS, 1 mg/kg) as a sepsis model. We pre-treat neonatal rats with TAK-242, a TLR4 Inhibitor, 1 day and 1 h before LPS injection to observe the neuroprotective effects on dopaminergic neurons of inhibition TLR4 in septic neonatal rats. The number of dopaminergic neurons in the mesencephalic substantia nigra in septic brain was significantly reduced. Meanwhile, the number of activated microglia was increased. Additionally, the total number of lattice in the open field test of septic rats was less than that of control rats at the age of postnatal day 80 (PND80), the total time of septic rats to catch the rope in the grip traction test was less than the control rats at the age of PND80, and the septic rats were easier to slide down in the slopes experiment. However, TAK-242 administration significantly ameliorated LPS-induced dopaminergic neurons loss, prevented microglia activation, and improved behavioral test results of septic rats. We also found that TLR4 inhibition decreased the LPS-induced high expressions of NF-κB p65 and IL-1β of microglia. In conclusion, TLR4 inhibition showed neuroprotective effects on septic neonatal rats via regulation of neuro-immunity.