Fully of FDA approved anti
Fully 50% of FDA-approved anti-cancer drugs are ROS-generating agents , and ROS can compromise the BBB by triggering several pathways, including oxidative stress . Increased BBB permeability and disruption allow peripheral toxins and inflammatory mediators able to go into Omadacycline chemicals easier, especially allow those pro-inflammatory cytokines generated by chemotherapy targeted tissues . Cytokine enters brain by receptor mediated-endocytosis or passive diffusion through the leaky regions of BBB since some pro-inflammatory cytokines disrupt the tight junction of BBB [47,52,55,56], eliciting glia activation and local inflammatory response in brain as a consequence.
Transmembrane protein toll-like receptor 4 (TLR4) is a possible factor influencing on BBB integrity after chemotherapy treatment. Evidence showed TLR4 is involved in chemotherapy-induced gut toxicity (GIGT), and there might be a linkage between GIGT and chemobrain [46,52]. The activation of TLR4 produces pro-inflammatory cytokines and chemokines, as well as leads to activation of intracellular NF-κB . Activation of astrocytes in CNS of WT mice is decreased by the absence of the TLR4 gene after treatment with irinotecan, indicating a role for TLR4 signaling in chemotherapy-induced neuro-inflammation and neurotoxicity .
Multidrug resistance protein (MDR1), also known as permeability glycoprotein (P-pg), and multidrug resistance-associated protein-1 (MRP1) are involved in the neurotoxicity and cognitive impairment after chemotherapy. Elevated expression of MRP1 in heart of doxorubicin (Dox)-treated mice protects heart from induced oxidative stress . Dox also elevated MRP1 activity in mice brain with elevated oxidative stress . Delivery of anti-depression drugs could be improved by decreasing the efflux function and expression of MDR1 . Meanwhile, expression of these proteins could be associated with polymorphism of multidrug resistance genes, implying the level of drugs pumped out of cells and brains could be different in various genotypes [61,62]. However, association between MDR1 polymorphism and clinical response was not found in chemotherapy-treated Hodgkin's lymphoma patients . Knockout of multidrug resistant genes makes mice more sensitive to the anti-cancer drug vincristine . Therefore, expression of these multidrug proteins at the BBB controls the level of chemotherapeutic drugs in brain and contributes to the prevention of their deleterious impacts on CNS. Drugs or other toxins could cross BBB with a harmful level and lead to cognitive impairment as a consequence if the polymorphism of the MRP-1 genes decrease the protein function or those proteins are damaged by oxidative stress from the periphery.
DNA damage and associated deficits of DNA repair are linked with CICI DNA damage and deficits of DNA repair systems also are known to be linked with cognitive deficits. Radiotherapy and some classes of chemotherapeutic drugs, such as alkylating or antibiotic agents, operate primarily by damaging the DNA of cancer cells, inducing apoptotic processes [65,66]. Oxidative stress is a main cause of DNA damage in brain cells . Chemotherapy often is associated with ROS/RNS production and oxidative stress, which cause further DNA damage in tissues [14,68]. Moreover, the complex process of normal DNA replication is frequently subject to mistakes and mutations, and such damage requires an efficient repair process that can repair the damaged DNA or lead to cell death via apoptosis. The failure of the regular DNA repair process can lead to irreparable modifications, such as double-strands breaks, mismatches and DNA crosslinks that can result in cell death or oncogene activation or inactivation of tumor suppressor genes leading to cancer . Several lines of evidence correlate oxidative DNA damage, mainly associated with the normal aging process, and/or alterations in DNA repair system with neurodegeneration and cognitive impairment . For these reasons, patients with genetic deficits in DNA repair systems might be subject to an increased risk to develop both cancer and neurodegenerative disorders characterized by cognitive impairment [71,72]. Regarding CICI, patients with alleles associated with less efficient DNA repair systems conceivably might be more inclined to show cognitive impairment before or after chemotherapeutic treatment.