In conclusion, the present study revealed the neuroprotective effect of senegenin in splenectomy-induced cognitive impairment in elderly rats, mediated through inhibition of the inflammation-related TLR4/MyD88/NF-κB and TLR4/TRIF/NF-κB signaling pathways, the downregulation of pro-inflammatory cytokine expression and, ultimately, the suppression of neuroinflammation in the brain. Here, TLR4 is linked to Cognitive impairment.