Abstract
The chemotherapeutic agent paclitaxel is widely used for cancer treatment. Paclitaxel treatment impairs learning and memory function, a side effect that reduces the quality of life of cancer survivors. However, the neural mechanisms underlying paclitaxel-induced impairment of learning and memory remain unclear. Paclitaxel treatment leads to proinflammatory factor release and neuronal apoptosis. Thus, we hypothesized that paclitaxel impairs learning and memory function through proinflammatory factor-induced neuronal apoptosis. Neuronal apoptosis was assessed by TUNEL assay in the hippocampus. Protein expression levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in the hippocampus tissue were analyzed by Western blot assay. Spatial learning and memory function were determined by using the Morris water maze (MWM) test. Paclitaxel treatment significantly increased the escape latencies and decreased the number of crossing in the MWM test. Furthermore, paclitaxel significantly increased the number of TUNEL-positive neurons in the hippocampus. Also, paclitaxel treatment increased the expression levels of TNF-α and IL-1β in the hippocampus tissue. In addition, the TNF-α synthesis inhibitor thalidomide significantly attenuated the number of paclitaxel-induced TUNEL-positive neurons in the hippocampus and restored the impaired spatial learning and memory function in paclitaxel-treated rats. These data suggest that TNF-α is critically involved in the paclitaxel-induced impairment of learning and memory function.
Highlights
The chemotherapeutic agent paclitaxel is widely used to treat patients with breast, ovarian, and lung cancers [1,2,3,4,5]
This study demonstrated that chronic systemic administration of paclitaxel impaired spatial learning and memory function through tumor necrosis factor-α (TNF-α)
We found that inhibition of TNF-α synthesis restored the impaired learning and memory function in paclitaxel-treated rats
Summary
The chemotherapeutic agent paclitaxel is widely used to treat patients with breast, ovarian, and lung cancers [1,2,3,4,5]. The mechanisms underlying paclitaxel-induced neurological dysfunction remain unclear. Paclitaxel induces apoptosis in neurons through a mechanism distinct from that of nonneuronal cells [19]. In this regard, paclitaxel induces apoptosis through endoplasmic reticulum stress [20]. The mechanisms underlying the neurotoxicity of paclitaxel on hippocampus neurons are not clear. TNF-α preferentially binds to TNFR1 which contains a death-effector domain to induce caspase-8 cleavage and apoptosis [31, 32]. We hypothesized that neuronal apoptosis caused by proinflammatory factors contributes to paclitaxelinduced impairment of neurological function
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