Chemotherapy-Induced Cognitive Impairment Is Associated with Increased Inflammation and Oxidative Damage in the Hippocampus

Bagnall-Moreau, Ciara; Chaudhry, Sovira; Salas-Ramirez, Kaliris Y.; Ahles, Tim A.; Hubbard, Karen

doi:10.1007/s12035-019-1589-z

Cited by 82 publications

(53 citation statements)

References 48 publications

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“…The absence of inflammation after chemotherapy reported here is supported by other preclinical studies ( 39 , 40 ). Nonetheless, some studies have shown that chemotherapy increases inflammatory cytokines in blood and brain tissue ( 18 , 19 , 41 – 43 ). As each of these animal studies used different chemotherapeutic agents, doses, or treatment regimens, it is possible the role of inflammation on chemobrain may be specific to chemotherapy type or magnitude of exposure.…”

Section: Discussionmentioning

confidence: 99%

“…These findings also indicate that while aspirin may have therapeutic utility for the prevention of tumor-induced cognitive impairment ( 11 ), aspirin is unlikely to show benefit in targeting paclitaxel-induced chemobrain. It will be important to determine the potential use of aspirin to target chemobrain symptoms induced by other chemotherapeutic agents and dosing schedules that have been shown to increase inflammatory cytokines ( 19 , 41 – 43 ).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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Inflammation has been proposed to play a causal role in chemobrain which—if true—would represent an opportunity to repurpose existing anti-inflammatory drugs for the prevention and treatment of chemobrain. Here, we show that the chemoagent paclitaxel induces memory impairment and anhedonia in mice within 24 h of treatment cessation, but inflammation is not present until 2 weeks after treatment. We find no evidence of brain inflammation as measured by cytokine analysis at any time point. Furthermore, treating with aspirin to block inflammation did not affect paclitaxel-induced memory impairment. These findings suggest that inflammation may not be responsible for memory impairment induced by paclitaxel. These results contrast with recent findings of a causal role for inflammation in cancer-induced memory deficits in mice that were prevented by treatment with oral aspirin, suggesting that cognitive impairment in cancer patients undergoing treatment may arise from multiple convergent mechanisms.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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“…Despite the very low penetrance of CYP or ADR across the blood brain barrier (BBB), acute CYP or ADR treatments negatively impacted hippocampal cell proliferation and increased cell death demonstrating the extreme sensitivity of the CNS to chemotherapy [32, 51]. In rodents, combined ADR and CYP treatment impaired contextual fear conditioning memory and passive avoidance tasks and, elevated oxidative stress and inflammation [13, 35]. These studies suggest that exposure of the brain parenchyma to even low levels of drug may be sufficient to disrupt sensitive, rapidly dividing cells in neurogenic regions and elevate neuroinflammation long after cessation of chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

Attenuation of neuroinflammation reverses Adriamycin-induced cognitive impairments

Allen

Apodaca

Syage

et al. 2019

acta neuropathol commun

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Numerous clinical studies have established the debilitating neurocognitive side effects of chemotherapy in the treatment of breast cancer, often referred as chemobrain. We hypothesize that cognitive impairments are associated with elevated microglial inflammation in the brain. Thus, either elimination of microglia or restoration of microglial function could ameliorate cognitive dysfunction. Using a rodent model of chronic Adriamycin (ADR) treatment, a commonly used breast cancer chemotherapy, we evaluated two strategies to ameliorate chemobrain: 1) microglia depletion using the colony stimulating factor-1 receptor (CSF1R) inhibitor PLX5622 and 2) human induced pluripotent stem cell-derived microglia (iMG)-derived extracellular vesicle (EV) treatment. In strategy 1 mice received ADR once weekly for 4 weeks and were then administered CSF1R inhibitor (PLX5622) starting 72 h post-ADR treatment. ADR-treated animals given a normal diet exhibited significant behavioral deficits and increased microglial activation 4–6 weeks later. PLX5622-treated mice exhibited no ADR-related cognitive deficits and near complete depletion of IBA-1 and CD68+ microglia in the brain. Cytokine and RNA sequencing analysis for inflammation pathways validated these findings. In strategy 2, 1 week after the last ADR treatment, mice received retro-orbital vein injections of iMG-EV (once weekly for 4 weeks) and 1 week later, mice underwent behavior testing. ADR-treated mice receiving EV showed nearly complete restoration of cognitive function and significant reductions in microglial activation as compared to untreated ADR mice. Our data demonstrate that ADR treatment elevates CNS inflammation that is linked to cognitive dysfunction and that attenuation of neuroinflammation reverses the adverse neurocognitive effects of chemotherapy.

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“…A previous study suggested that oxidative stress is highly connected with reduced cognition, including declined psychomotor speed, mental flexibility, and attention in patients with type 2 diabetes [37]. Oxidative damage in the hippocampus is also implicated in chemotherapy-induced cognitive impairment [38]. Besides, oxidative stress could mediate inflammation and apoptosis in hippocampus, which promote hippocampal lesions [39].…”

Section: Discussionmentioning

confidence: 99%

Exogenous hydrogen sulfide alleviates surgery-induced neuroinflammatory cognitive impairment in adult mice by inhibiting NO signaling

Yin

Shun-li

2020

BMC Anesthesiol

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Background: To investigate the effect and mechanisms of exogenous hydrogen sulfide in surgery-induced neuroinflammatory cognitive dysfunction. Methods: C57BL/6 J male mice (n = 140) were used and randomly divided into seven groups: the sham group, surgery group, GYY4137 group, L-NAME group, surgery+GYY4137 group, surgery +L-NAME group, and surgery+GYY4137 + L-NAME group. After the interventions, open field tests (OFT) and the Morris water maze (MWM) test were conducted to evaluate learning and memory abilities in the mice. ELISAs, nitrate reductase assays, and Western blots (WB) were conducted to evaluate interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), nitric oxide (NO), inducible nitric oxide synthase (iNOS), malondialdehyde (MDA), and antioxidant enzyme superoxide dismutase (SOD) levels. Furthermore, the expression level of microglial marker ionized calcium binding adaptor molecule 1 (IBA) in the hippocampal CA1 and CA3 areas was detected by an immunohistochemical (IHC) assay and apoptotic cells were observed using terminal deoxynucleotidyl transferase dUTP end-labeling (TUNEL) staining kits. Results: We found that surgery induced neuroinflammatory cognitive dysfunction, oxidative stress, microglial activation, and cell apoptosis in the hippocampus. Moreover, following surgery, NO and iNOS levels were elevated in the hippocampus. Notably, all the effects caused by surgery were reversed by the H 2 S donor GYY4137 or the iNOS inhibitor N(gamma)-nitro-L-arginine methyl ester (L-NAME). However, the combined application of GYY4137 and L-NAME was not superior to treatment with either agent alone and the effect of GYY4137 was similar to that of L-NAME. Conclusion: The long-acting hydrogen sulfide donor GYY4137 had an ability to reversed the cognitive deficits and inflammation caused by carotid artery exposure surgery. This implies that NO signaling pathways might participate in this process. These results indicate that exogenous H 2 S may be a promising therapy for POCD.

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Chemotherapy-Induced Cognitive Impairment Is Associated with Increased Inflammation and Oxidative Damage in the Hippocampus

Cited by 82 publications

References 48 publications

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

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

Attenuation of neuroinflammation reverses Adriamycin-induced cognitive impairments

Exogenous hydrogen sulfide alleviates surgery-induced neuroinflammatory cognitive impairment in adult mice by inhibiting NO signaling

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