Proinflammatory Factors Mediate Paclitaxel-Induced Impairment of Learning and Memory

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.

The Anti-Inflammatory Drug Aspirin Does Not Protect Against Chemotherapy-Induced Memory Impairment by Paclitaxel in Mice

“…The current findings offer important insights into correlative evidence that cognitive impairment and mood-related symptoms are associated with elevated inflammatory markers in clinical (6,34) and preclinical studies of cancer treatment (19,48). This study confirms recent findings that paclitaxel is able to cross the blood brain barrier in the absence of cancer (35), raising the possibility of direct cytotoxic effects of paclitaxel on cells of the brain.…”

“…This study confirms recent findings that paclitaxel is able to cross the blood brain barrier in the absence of cancer (35), raising the possibility of direct cytotoxic effects of paclitaxel on cells of the brain. Recent studies support this assertion with evidence that chemotherapy drugs induce apoptosis in neurons, reduce neurogenesis and synaptic integrity, and cause mitochondrial dysfunction (19,40,42,48,49). Additionally, the downregulation of vesicular zinc in the hippocampus has also been shown to mediate the effect of paclitaxel on hippocampal neurogenesis (36).…”

“…Both tests are sensitive and well-validated methods, where depression-like behavior in rodents is indicated by reduced consumption of sucrose solution or increased immobility during the forced swim test (25,26). Paclitaxel reduced sucrose preference, which reached significance based on multiple comparisons on days [17][18][19] (F (19,540) = 3.17, p < 0.0001) ( Figure 1D) but did not change forced swim test immobility ( Figure 1E) (p > 0.05). Reduced sucrose preference could indicate depression-like behavior, or may be attributable to chemotherapy-induced changes in taste perception, which would not impact behavior in the forced swim test.…”

“…Such a hypothesis is plausible given the known relationship between peripheral inflammation, brain inflammation and disturbances in cognitive function, mood and behavior in non-cancer contexts (10)(11)(12)(13)(14)(15)(16). Given that numerous studies have identified an increase in proinflammatory cytokines in response to chemotherapy, it is not surprising that inflammation would be considered a candidate mechanism (17)(18)(19).…”

Ameliorative effect of gallic acid in paclitaxel-induced neuropathic pain in mice

“…The relevance of humans pathology is similar to that of complex regional pain syndrome (CRPS) [59,60]. PT causes neuroinflammation and neurodegeneration via accumulation of intracellular calcium (Ca 2+ ) ion concentrations [61–62,63,64], release of inflammatory cytokines [11], and alteration of neuronal microtubulin & myelin proteins [65,66]. In addition, PT also alters the neurovascular system leading to enhance the neuropathic pain symptoms [67].…”