Acute treatment with methotrexate induces hippocampal dysfunction in a mouse model of breast cancer

Yang, Miyoung; Kim, Joong Sun; Kim, Juhwan; Jang, Sungwoong; Kim, Sung Hoon; Kim, Jong Choon; Shin, Taekyun; Wang, Hongbing; Moon, Changjong

doi:10.1016/j.brainresbull.2012.07.003

Cited by 69 publications

(40 citation statements)

References 34 publications

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“…. Evidence of microglial activation has also been detected in the hippocampus and cortex of tumor-bearing rodents (Norden et al, 2014; Pyter et al, 2014; but see Yang et al, 2012). Many of these elevations in neuroinflammatory markers are attenuated by the systemic administration of the anti-inflammatory agent, minocycline (Norden et al, 2014).…”

Section: Rodent Models Of Cancermentioning

confidence: 96%

“…For example, the ability to distinguish between novel and familiar objects is remarkably impaired in tumor-bearing rats and mice (Pyter et al, 2010; Yang et al, 2014). Using a fear-based classical conditioning paradigm, tumor-bearing rats and mice tend to display modest impairments in passive auditory conditioning (Pyter et al, 2010), but not in contextual conditioning (Pyter et al, 2010; Yang et al, 2012). In terms of hippocampal-based learning, rats with tumors make more long-term, reference memory errors in an appetitive radial arm maze task, while working memory remains similar to tumor-free controls.…”

Section: Rodent Models Of Cancermentioning

confidence: 99%

“…Those known to overlap with the hypothesized mechanisms underlying cytokine-induced affective, somatic and cognitive behavior involve: iNOS and COX enzymatic activities, neuronal death, and tryptophan metabolism. Briefly, the negative behavioral consequences of tumors are associated with elevations in iNOS expression among various hypothalamic regions (Wang et al, 2001; Yang et al, 2012) and elevations in cerebral blood vessel expression of COX-1 (Ruud et al, 2013; not COX-2 (Wang et al, 2001). The results from measuring constitutive hippocampal COX-2 expression in tumor-bearing models with affective-like behavior or cognitive impairment are mixed (Yang et al, 2012, 2014).…”

Section: Rodent Models Of Cancermentioning

confidence: 99%

“…Peripheral tumors associated with poor novel object recognition also reduce cell proliferation, neurogenesis, and dendritic length (qualitatively) in the dentate gyrus of the hippocampus (Yang et al, 2014, but see Yang et al, 2012). Growth factors associated with neurogenesis, GMFβ and BDNF, are reduced or remain unaltered in the hippocampus in tumor-bearing rodents that display cognitive impairments or depressive-like behavior (Qi et al, 2009; Pyter et al 2010; Yang et al 2014) Neural redox homeostasis may underlie these changes in brain plasticity as reduced oxidase potential is detected in brains of tumor-bearing mice with depressive-like behavior (Chen et al, 2006; Papiez et al, 2009; Qi et al, 2009), which is reversible with antidepressant treatment (Qi et al, 2009).…”

Section: Rodent Models Of Cancermentioning

confidence: 99%

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Pre-treatment effects of peripheral tumors on brain and behavior: Neuroinflammatory mechanisms in humans and rodents

Schrepf¹,

Lutgendorf²,

Pyter³

2015

Brain, Behavior, and Immunity

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Cancer patients suffer high levels of affective and cognitive disturbances, which have been attributed to diagnosis-related distress, impairment of quality of life, and side effects of primary treatment. An inflammatory microenvironment is also a feature of the vast majority of solid tumors. However, the ability of tumor-associated biological processes to affect the central nervous system (CNS) has only recently been explored in the context of symptoms of depression and cognitive disturbances. In this review, we summarize the burgeoning evidence from rodent cancer models that solid tumors alter neurobiological pathways and subsequent behavioral processes with relevance to affective and cognitive disturbances reported in human cancer populations. We consider, in parallel, the evidence from human clinical cancer research demonstrating that affective and cognitive disturbances are common in some malignancies prior to diagnosis and treatment. We further consider the underlying neurobiological pathways, including altered neuroinflammation, tryptophan metabolism, prostaglandin synthesis and associated neuroanatomical changes, that are most strongly implicated in the rodent literature and supported by analogous evidence from human cancer populations. We focus on the implications of these findings for behavioral researchers and clinicians, with particular emphasis on methodological issues and areas of future research.

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Section: Rodent Models Of Cancermentioning

confidence: 96%

Section: Rodent Models Of Cancermentioning

confidence: 99%

Section: Rodent Models Of Cancermentioning

confidence: 99%

Section: Rodent Models Of Cancermentioning

confidence: 99%

See 2 more Smart Citations

Pre-treatment effects of peripheral tumors on brain and behavior: Neuroinflammatory mechanisms in humans and rodents

Schrepf¹,

Lutgendorf²,

Pyter³

2015

Brain, Behavior, and Immunity

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“…First, although previous models have examined the effects of tumor alone [46, 47], chemotherapy [48, 49], peripheral radiation in healthy mice [11], direct immune stimulation [50, 51], and treatment of cancer-related neurological dysfunction [52, 53], none have examined the effects of peripheral radiation in tumor-bearing mice or of immunotherapy in any tumor state. This is not only pertinent to understand given the emerging potential of these therapeutics, but also for the particular insight they may give to the role of the immune system in general.…”

Section: Introductionmentioning

confidence: 99%

Neuroinflammatory and cognitive consequences of combined radiation and immunotherapy in a novel preclinical model

et al. 2016

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BackgroundCancer patients often report behavioral and cognitive changes following cancer treatment. These effects can be seen in patients who have not yet received treatment or have received only peripheral (non-brain) irradiation. Novel treatments combining radiotherapy (RT) and immunotherapy (IT) demonstrate remarkable efficacy with respect to tumor outcomes by enhancing the proinflammatory environment in the tumor. However, a proinflammatory environment in the brain mediates cognitive impairments in other neurological disorders and may affect brain function in cancer patients receiving these novel treatments. Currently, gaps exist as to whether these treatments impact the brain in individuals with or without tumors and with regard to the underlying mechanisms.ResultsCombined treatment with precision RT and checkpoint inhibitor IT achieved control of tumor growth. However, BALB/c mice receiving combined treatment demonstrated changes in measures of anxiety levels, regardless of tumor status. C57BL/6J mice with tumors demonstrated increased anxiety, except following combined treatment. Object recognition memory was impaired in C57BL/6J mice without tumors following combined treatment. All mice with tumors showed impaired object recognition, except those treated with RT alone. Mice with tumors demonstrated impaired amygdala-dependent cued fear memory, while maintaining hippocampus-dependent context fear memory. These behavioral alterations and cognitive impairments were accompanied by increased microglial activation in mice receiving immunotherapy alone or combined with RT. Finally, based on tumor status, there were significant changes in proinflammatory cytokines (IFN-γ, IL-6, IL-5, IL-2, IL-10) and a growth factor (FGF-basic).Materials and MethodsHere we test the hypothesis that IT combined with peripheral RT have detrimental behavioral and cognitive effects as a result of an enhanced proinflammatory environment in the brain. BALB/c mice with or without injected hind flank CT26 colorectal carcinoma or C57BL/6J mice with or without Lewis Lung carcinoma were used for all experiments. Checkpoint inhibitor IT, using an anti-CTLA-4 antibody, and precision CT-guided peripheral RT alone and combined were used to closely model clinical treatment. We assessed behavioral and cognitive performance and investigated the immune environment using immunohistochemistry and multiplex assays to analyze proinflammatory mediators.ConclusionsAlthough combined treatment achieved tumor growth control, it affected the brain and induced changes in measures of anxiety, cognitive impairments, and neuroinflammation.

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Therapeutic Links between Alzheimer’s Disease and Brain Cancer: Drug Discovery Consequences

Kraus

2013

ChemMedChem

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It was recently reported that female survivors of breast cancer have a lower risk of Alzheimer's disease (AD). This observation led to the hypothesis that there is a link between cancer and AD. This Viewpoint provides an analysis of the consequences of this hypothesis, not only from the perspective of drug discovery for new treatments, but above all, the awareness that any AD chemotherapy will require drug administration over longer periods of time before any cognitive effects are observed. Because such drugs will probably act as neuroprotective agents, slowing the progression of AD rather than curing it, they should be prescribed as soon as the first AD symptoms are detected. After a general survey of anticancer drugs that have potential therapeutic value for AD chemotherapy, new drugs that could affect specific signal transduction pathways known to be activated by anticancer drugs are presented, with the unfolding protein response pathway being one of the most relevant biological targets for new AD chemotherapeutic agents.

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Acute treatment with methotrexate induces hippocampal dysfunction in a mouse model of breast cancer

Cited by 69 publications

References 34 publications

Pre-treatment effects of peripheral tumors on brain and behavior: Neuroinflammatory mechanisms in humans and rodents

Pre-treatment effects of peripheral tumors on brain and behavior: Neuroinflammatory mechanisms in humans and rodents

Neuroinflammatory and cognitive consequences of combined radiation and immunotherapy in a novel preclinical model

Therapeutic Links between Alzheimer’s Disease and Brain Cancer: Drug Discovery Consequences

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