Abstract
Objective This study explored the potential therapeutic effect and possible mechanism of Kai-Xin-San (KXS) on doxorubicin-induced cognitive impairment in 4T1 breast cancer mice. Methods A model of chemotherapy-induced cognitive impairment (CICI) was established with the injection of doxorubicin (DOX, 5 mg/kg) at a 7-day interval in a 4T1 breast cancer mouse. KXS was given (1 g/kg) daily by gavage over three weeks starting at the first week while giving DOX. The Morris water maze task was performed to measure the CICI-like behaviors. Oxidative stress markers in the hippocampus, inflammatory cytokines in the serum and hippocampus, Nissl staining, immunofluorescence staining, and analysis for Glial fibrillary acidic protein and ionized calcium-binding adapter molecule 1 of the hippocampus were examined to explore the effect and mechanism of KXS on DOX-induced CICI. Meanwhile, tumor growth and survival time were tested in this study. Results CICI-like behaviors induced by DOX occurred earlier and were severer than the cognitive impairment induced by the tumor, and the effect of KXS on improving the cognitive impairment was obvious. KXS protected against DOX-induced neuroinflammation by decreasing levels of proinflammatory cytokines interleukin-6, interleukin-12p70, and tumor necrosis factor-alpha in both serum and brain and interleukin-1β in the brain, increasing the anti-inflammatory cytokines interleukin-4 in the serum and interleukin-10 in the hippocampus, and inhibiting the astrocytic hyperplasia and microglial polarization in the hippocampus. KXS reduced neural degeneration and protected against DOX-induced oxidative stress according to decreased malondialdehyde level, increased glutathione level, and enhanced activities of superoxide dismutase, catalase, and glutathione peroxidase. Moreover, KXS recovered the lost body weights after DOX administration and prolonged the survival times of mice. Conclusions KXS may attenuate DOX-induced cognitive impairment by regulating inflammatory responses and reducing oxidative stress and neural degeneration. These findings also presented the role of KXS in improving the quality of life and prolonging survival time in breast cancer mice that received chemotherapy.
Highlights
Great advancements in therapeutic methods have increased, chemotherapy is still the vital treatment for breast cancer [1]
Doxorubicin (DOX), a typical chemotherapeutic agent known for Evidence-Based Complementary and Alternative Medicine producing reactive oxygen species (ROS) and inducing oxidative stress in the tumor or even the whole body [5], is used commonly in adjuvant and neoadjuvant chemotherapy treatment for breast cancer [1]
DOX poorly crosses the blood-brain barrier (BBB), more and more experimental pieces of evidence show that DOX may cause many impaired cognitive functions [8, 9], which are observed in clinical studies [10]
Summary
Great advancements in therapeutic methods have increased, chemotherapy is still the vital treatment for breast cancer [1]. Chemotherapy-induced cognitive impairment (CICI), one of the most serious adverse effects caused by chemotherapeutic treatments, has been observed in 69–78% of breast cancer patients [2], presenting as cognitive dysfunctions in memory, concentration, reasoning, and executive function during or following treatment [3], which affect the long-term quality of life or even result in the deaths of patients [4]. E resulting neuroinflammation and oxidative stress can trigger apoptotic cell death and cause neurobehavioral alterations [7, 14] These studies suggested that neuroinflammation, oxidative stress, and damages to neuronal structure and function might play a key role in DOX-induced cognitive dysfunction, definite and effective intervenes are still lacking
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