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  • Functional and structural MRI is a strong tool to


    Functional and structural MRI is a strong tool to demonstrate brains in cancer survivors are different from brains of people not treated with chemotherapeutic agents or healthy people with no cancer, especially in the case patient who did not show big differences on neuropsychological tests compared to her healthy monozygotic twin, but had self-reported cognitive impairment [29]. Such changes indicate that cancer survivors who had chemotherapy have to activate more areas in the Glpbio Omadacycline and make more efforts to maintain the ability of work, even if they show a normal aspect in neuropsychological tests [30]. PET scanning also revealed abnormal glucose metabolism in brain of cancer survivors who had undergone chemotherapy [31,32]. Better understanding of the molecular mechanisms of CICI is important to reduce or even prevent cognitive dysfunction after cancer treatment, with the goal of improving the quality of life of survivors without changing chemotherapeutic efficacy. This is particularly the case for those child patients and adult patients who live longer. However, the mechanisms of CICI still are not fully understood. A complication of CICI is that it is multifactorial in origin, and it shares similar appearances and causes with depression, anxiety and fatigue, which are commonly associated with cancer treatment and cancer per se [5,33]. Lack of education and aging could be other confounders [34,35]. Neuronal activity is often altered by chemotherapy [36,37]. Neuronal apoptosis was observed in correlation with cognitive impairments associated with traumatic brain injury, aging, several neurodegenerative disease and chemotherapy [2,38,39]. NMDA receptor antagonists, such as memantine, could reverse the cognitive deficits and protect memory functions by blocking NMDA receptors during chemotherapy treatment [40,41]. Co-administration of the anti-cancer drug, methotrexate, with the NMDA receptor antagonist dextromethorphan reduced the severity of seizures [42]. However, these antagonists can themselves cause significant side effects [43]. As noted above, neuronal death, which underlies CICI symptoms, occurs even though many FDA-approved anti-cancer drugs cannot cross the BBB. Recent studies suggested that decreased integrity of the BBB, low availability of DNA and neural repair processes, decreased antioxidant levels and increased oxidative stress, hormone changes and immune system responses contribute to neurotoxicity, and eventual neuronal death with subsequent cognitive impairments following chemotherapy [2,3,5,44]. The candidate mechanisms are shown in Fig. 1. In this current review paper, we summarize recent important candidate mechanisms of CICI mentioned above, especially cytokines and oxidative stress. We attempt to build a fuller picture of mechanisms of CICI, and thereby for future studies and clinical treatments designed to improve the quality of life of cancer survivors without interference of chemotherapeutic efficacy.
    Chemotherapy-induced disruption of BBB integrity increases BBB permeability and brain vulnerability Some commonly used chemotherapeutic agents lead to significantly increased cell death and decreased cell division in multiple areas in brain of mice. CNS progenitor cells and non-dividing oligodendrocytes are more vulnerable to carmustine (BCNU), cisplatin and cytarabine than multiple cancer cell lines [45]. BBB permeability increased after treatment with irinotecan [46]. Dysfunction of the BBB has been recognized in several neurological disorders and many neurodegenerative diseases, including Parkinson's disease (PD) and Alzheimer's disease (AD), both with associated pro-inflammatory states [[47], [48], [49], [50]]. Abnormal BBB integrity leads to direct or indirect neurotoxicity. Furthermore, some chemotherapeutic agents [51], such as BCNU, paclitaxel and 5-fluorouracil, reportedly were detected in low, non-therapeutic concentrations in brains of rodents or primates [52], and these drug levels could potentially contribute to direct harmful effects to the parenchyma. Docetaxel (DTX) led to impaired novel object recognition (NOR) memory of mice in post-treatment behavioral tests, and this drug was detected in brain that demonstrated astrocyte activation [53].