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Tumor Discovery The mechanism of cancer-related cognitive decline

can lead to abnormal angiogenesis and other pathogenic are important for myelin formation and neuroplasticity;
changes that can disrupt the integrity and physiological the myelinated axons constitute the white matter of the
function of the BBB. BBB dysfunction can also exacerbate brain [47,51] . Furthermore, 5-fluorouracil is associated
the pathological protein deposition in the brain tissue and with reduced myelination of the corpus callosum and
aggravate cognitive impairment. dysregulated expression of oligodendrocyte transcription
factor 2 in rats . The number of oligodendrocytes and their
[52]
3. Antitumor therapy-related neuronal progenitor cells in the white matter, volume of the corpus
damage callosum, and myelin basic protein decreased significantly
in a rat cancer model after 6 and 16 months of treatment
3.1. Chemotherapy with methotrexate . This suggests that the toxic effects of
[53]
The adverse effects of cancer chemotherapies often manifest chemotherapy agents are associated with myelin formation
as peripheral neuropathy, ototoxicity, pulmonary fibrosis, and white matter abnormalities in the brain regions related
as well as abnormalities in hepatic and renal functions . to cognition. In addition, the toxic effects of these drugs may
[43]
Recently, there have been several reports on chemotherapy- also lead to increased necrosis and apoptosis and reduced
induced cognitive impairment (CICI), and some scholars proliferation of the hippocampal neurons, interfering with
refer this impairment of attention, memory, learning and the neurogenesis in the hippocampus and other regions,
language function, and other cognitive domains to as which in turn affects learning and memory [54,55] . Moreover,
[44]
“chemo brain” or “chemo fog” . CICI can occur both during chemotherapy drugs promote the release of inflammatory
or several years after chemotherapy [6,45] . A nationwide factors in the peripheral blood, which subsequently cross
longitudinal cohort study in China showed that patients with the BBB or induce the release of inflammatory factors in
stage I-IIIC breast cancer exhibit significant impairment the CNS. This causes cognitive impairment by mediating
in multiple cognitive domains, including memory, neuroimmune inflammatory responses and affecting
attention, and executive functions, within 6 months after epigenetic modifications. Doxorubicin can increase the
chemotherapy . There is a dose-response relationship levels of inflammatory factors and TNF-α in the peripheral
[46]
between chemotherapy drugs and cognitive function. blood; the latter crosses the BBB through receptor-
Collins et al. performed neuropsychological tests in 60 mediated endocytosis and accumulates in the brain tissue,
[47]
postoperative patients with early-stage breast cancer before causing oxidative and nitrosative damage to important
chemotherapy and at the end of each chemotherapy cycle. biomolecules, mitochondrial dysfunction, and neuronal
They found that the cognitive function of the patients apoptosis [56,57] . On the other hand, chemotherapy drugs can
undergoing chemotherapy declined progressively during activate the microglia to release pro-inflammatory factors,
the course (i.e., as the doses of chemotherapy drugs such as IL-6 and TNF-α, or alter the interaction between
increased). Although there are a variety of chemotherapy astrocytes and oligodendrocytes, inhibit hippocampal
drugs, the cognitive and neurological effects of only a neurogenesis and myelin plasticity in white matter, and
selection of drugs have been reported, mainly alkylating interfere with neurotransmission and axon formation, thus
agents (cyclophosphamide), antimetabolites (methotrexate resulting in cognitive impairment [58-60] . Animal experiments
and 5-fluorouracil), cytotoxic antibiotics (doxorubicin), showed that the levels of inflammatory mediators, such
antimicrotubule agents (paclitaxel and docetaxel), as IL-1β, TNF-α, and cyclooxygenase-2, increased
monoclonal antibodies (trastuzumab and rituximab), and significantly and the level of the anti-inflammatory
[48]
immune checkpoint inhibitors . The specific etiology and factor IL-10 decreased in rats 4 weeks after 5-fluorouracil

pathogenesis of CICI remain unclear. Based on the available injection . Lyon et al. suggested that inflammatory
[61]
[52]
research evidence, the hypothesized pathogenesis involves factors might induce DNA methylation mediated by protein
multiple dimensions, mainly direct neurotoxic effects of enhancer of zeste 2 (an important DNA repair enzyme) and
drugs, immune dysfunction, oxidative stress response, chromosomal instability (telomere shortening), causing
and altered cerebral blood flow [48,49] . The transport of cell death or abnormal gene expression, ultimately leading
cisplatin, a commonly used chemotherapy agent for lung to CICI. Oxidative stress caused by an imbalance between
cancer, across the BBB is mediated by the copper uptake the generation of reactive oxygen species (including free
protein copper transporter 1, which, in turn, induces brain radicals and peroxides) and the biological antioxidant
network abnormalities, impaired glucose metabolism, defense system is considered another potential pathogenic
and cognitive impairment . Animal studies have shown mechanism of CICI. Animal experiments showed that
[50]
that systemically administered chemotherapy drugs, such doxorubicin treatment increased the sensitivity of calcium-
as cisplatin and carmustine, act on the CNS progenitor mediated brain mitochondrial permeability transition pore
cells, whose proliferation produces oligodendrocytes that in rats and the mitochondrial membrane permeability,

Volume 1 Issue 1 (2022) 4 https://doi.org/10.36922/td.v1i1.46