Memantine Protects against Paclitaxel-Induced Cognitive Impairment through Modulation of Neurogenesis and Inflammation in Mice

SIMPLE SUMMARY: Chemotherapy-induced cognitive impairment (CICI) is an increasing awareness due to prolonged survival following cancer chemotherapy in cancer patients. Multiple mechanisms have been proposed for CICI induced by various chemotherapeutic agents; however, hippocampal damage and impaired neurogenesis may be one of the mechanisms. The aim of our study was to investigate the interplay between impaired neurogenesis, inflammation, and the symptoms of CICI, including spatial memory dysfunction and mood alteration, in a paclitaxel-treated mice model. In addition, we demonstrated that memantine may serve as a potential therapeutic agent for paclitaxel-induced CICI by modulating neurogenesis and inflammation. However, the treatment regimen may lead to variations in the treatment efficacy, especially in terms of mood dysfunction. Further translational studies may be developed to evaluate the clinical efficacy of memantine in human CICI studies. ABSTRACT: Chemotherapy-induced cognitive impairment (CICI) is an adverse side effect of cancer treatment with increasing awareness. Hippocampal damage and related neurocognitive impairment may mediate the development of CICI, in which altered neurogenesis may play a role. In addition, increased inflammation may be related to chemotherapy-induced hippocampal damage. Memantine, an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist that may enhance neurogenesis and modulate inflammation, may be useful for treating CICI. To test this hypothesis, paclitaxel was administered to eight-week-old male B6 mice to demonstrate the relationship between CICI and impaired neurogenesis, and then, we evaluated the impact of different memantine regimens on neurogenesis and inflammation in this CICI model. The results demonstrated that both the pretreatment and cotreatment regimens with memantine successfully reversed impaired neurogenesis and spatial memory impairment in behavior tests. The pretreatment regimen unsuccessfully inhibited the expression of peripheral and central TNF- [Formula: see text] and IL-1 [Formula: see text] and did not improve the mood alterations following paclitaxel treatment. However, the cotreatment regimen led to a better modulatory effect on inflammation and restoration of mood disturbance. In conclusion, this study illustrated that impaired neurogenesis is one of the mechanisms of paclitaxel-induced CICI. Memantine may serve as a potential treatment for paclitaxel-induced CICI, but different treatment strategies may lead to variations in the treatment efficacy.