Methotrexate reduces hippocampal blood vessel density and activates microglia in rats but does not elevate central cytokine release

Seigers, Riejanne; Timmermans, Jessica; Horn, Hans J. van der; Vries, Erik F. J. de; Dierckx, Rudi; Visser, Lydia; Schagen, Sanne B.; Dam, F.S.A.M. van; Koolhaas, Jaap M.; Buwalda, Bauke

doi:10.1016/j.bbr.2009.10.009

Cited by 96 publications

(57 citation statements)

References 39 publications

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“…Progenitor cells in white matter appear to be more sensitive to methotrexate than those in gray matter (Wood et al, 2014), which may help explain why white matter injury tends to be the more common finding in survivors of pediatric ALL. Methotrexate may also increase microglial activation (Seigers et al, 2010;Wood et al, 2014), which is associated with several neurotoxic effects, including oxidative and nitrosative stress (Lull and Block, 2010). These mechanisms would be expected to have diffuse rather than focal effects, which is consistent with our findings.…”

Section: Figsupporting

confidence: 82%

“…This neurotoxicity is often especially debilitating for pediatric cancer survivors due to disruption of vulnerable, developing neural circuitry. Candidate mechanisms for cancer-related cognitive impairment include suppression of neural progenitor proliferation, dysregulation of proinflammatory cytokine cascades, oxidative stress, microvascular damage, and genetic vulnerabilities (Krull et al, 2013a;Monje and Dietrich, 2012;Seigers et al, 2010). Neuroimaging studies indicate that alterations of brain structure and function represent the final common biological pathway resulting in cognitive deficit.…”

Section: Introductionmentioning

confidence: 99%

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Atypical Structural Connectome Organization and Cognitive Impairment in Young Survivors of Acute Lymphoblastic Leukemia

et al. 2016

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Survivors of pediatric acute lymphoblastic leukemia (ALL) are at increased risk for cognitive impairments that disrupt everyday functioning and decrease quality of life. The specific biological mechanisms underlying cognitive impairment following ALL remain largely unclear, but previous studies consistently demonstrate significant white matter pathology. We aimed to extend this literature by examining the organization of the white matter connectome in young patients with a history of ALL treated with chemotherapy only. We applied graph theoretical analysis to diffusion tensor imaging obtained from 31 survivors of ALL age 5-19 years and 39 matched healthy controls. Results indicated significantly lower small-worldness ( p = 0.007) and network clustering coefficient ( p = 0.019), as well as greater cognitive impairment ( p = 0.027) in the ALL group. Regional analysis indicated that clustered connectivity in parietal, frontal, hippocampal, amygdalar, thalamic, and occipital regions was altered in the ALL group. Random forest analysis revealed a model of connectome and demographic variables that could automatically classify survivors of ALL as having cognitive impairment or not (accuracy = 0.89, p < 0.0001). These findings provide further evidence of brain injury in young survivors of ALL, even those without a history of central nervous system (CNS) disease or cranial radiation. Efficiency of local information processing, reorganization of hub connectivity, and cognitive reserve may contribute to cognitive outcome in these children. Certain connectome properties showed U-shaped relationships with cognitive impairment suggesting an optimal range of regional connectivity.

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Section: Figsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Atypical Structural Connectome Organization and Cognitive Impairment in Young Survivors of Acute Lymphoblastic Leukemia

et al. 2016

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“…Possible mechanisms of brain injury following breast cancer chemotherapy (BCC) include direct toxicity to neural progenitor cells (Monje and Dietrich, 2012), elevation of cytokine release and oxidative stress (Conroy, et al, 2013b;Ganz, et al, 2013;Kesler, et al, 2013a;Pomykala, et al, 2013b;Vardy, et al, 2007), DNA damage and epigenetic alterations (Conroy, et al, 2013b), deficient estrogen-related protection of healthy brain cells (Hogervorst, 2013) following chemotherapy-induced menopause (Conroy, et al, 2013a) and altered cerebral blood supply through blood vessel damage (Seigers, et al, 2010) and/or chemotherapy-induced anemia (O'Shaughnessy, 2003). Chemotherapy-related mechanisms interact with other factors including cancer pathogenesis (Kesler, et al, 2011), allostatic load (Miller, et al, 2008) and genetic variations (Ahles and Saykin, 2007).…”

Section: Brain Aging Cancer and Chemotherapymentioning

confidence: 99%

Default mode network as a potential biomarker of chemotherapy-related brain injury

Kesler

2014

Neurobiology of Aging

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Chronic medical conditions and/or their treatments may interact with aging to alter or even accelerate brain senescence. Adult onset cancer, for example, is a disease associated with advanced aging and emerging evidence suggests a profile of subtle but diffuse brain injury following cancer chemotherapy. Breast cancer is currently the primary model for studying these “chemobrain” effects. Given the widespread changes to brain structure and function as well as the common impairment of integrated cognitive skills observed following breast cancer chemotherapy, it is likely that large-scale brain networks are involved. Default mode network (DMN) is a strong candidate considering its preferential vulnerability to aging and sensitivity to toxicity and disease states. Additionally, chemotherapy is associated with several physiologic effects including increased inflammation and oxidative stress that are believed to elevate toxicity in the DMN. Biomarkers of DMN connectivity could aid in the development of treatments for chemotherapy-related cognitive decline. For example, certain nutritional interventions could potentially reduce the metabolic changes (e.g. amyloid beta toxicity) associated with DMN disruption.

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“…Evaluations of neuroinflammation and neurogenic markers are common endpoints in studies of cellular changes associated with chemotherapy-related neurotoxicity and/or cognitive deficits in rodents (reviewed in Seigers and Fardell, 2011) and frequently employ the same cell markers used in our study. For instance, activated microglia have been evaluated in chemotherapy-treated mice using the markers ED1 (Christie et al, 2012; Acharya et al, 2015) and Iba1 (Seigers et al, 2010; Seigers et al, 2016), and GFAP has been used as a marker of astroglial reaction in rodent models of chemotherapy-related neurotoxicity and/or cognitive deficits (Dietrich et al, 2006; Fardell et al, 2014; Acharya et al, 2015). DCX has been used as a marker of neural progenitor cells in the hippocampus, in combination with markers of proliferation or apoptosis, to assess the effects of chemotherapeutic agents on neurogenesis (Dietrich et al, 2006; Yang et al, 2010; Mustafa et al, 2008; Christie et al, 2012; Seigers et al, 2016).…”

Section: Resultsmentioning

confidence: 99%

Minocycline, a putative neuroprotectant, co-administered with doxorubicin-cyclophosphamide chemotherapy in a xenograft model of triple-negative breast cancer

Himmel

Lustberg

DeVries

et al. 2016

Experimental and Toxicologic Pathology

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Minocycline is purported to have neuroprotective properties in experimental models of some human neurologic diseases, and has therefore been identified as a putative neuroprotectant for chemotherapy-induced cognitive impairment (CICI) in breast cancer patients. However, because its mechanism of action is believed to be mediated through anti-inflammatory, anti-apoptotic, and anti-oxidant pathways, co-administration of minocycline with chemotherapeutic agents has the potential to reduce the efficacy of anticancer drugs. The objective of this study is to evaluate the effect of minocycline on the activity of the AC chemotherapeutic regimen (Adriamycin [doxorubicin], Cytoxan [cyclophosphamide]) in in vitro and in vivo models of triple-negative breast cancer (TNBC). Clonogenic and methylthiazol tetrazolium (MTT) assays were used to assess survival and viability in two TNBC cell lines treated with increasing concentrations of AC in the presence or absence of minocycline. Biomarkers of apoptosis, cell stress, and DNA damage were evaluated by western blot. The in vivo effects of AC and minocycline, each alone and in combination, were assessed in a xenograft model of TNBC in female athymic nude mice by weekly tumor volume measurement, body and organ weight measurement, and histopathology. Apoptosis and proliferation were characterized by immunohistochemistry in the xenografts tumors. Brains from tumor-bearing mice were evaluated for microglial activation, glial scars, and the proportion of neural progenitor cells. Data from these in vitro and in vivo studies demonstrate that minocycline does not diminish the cytotoxic and tumor-suppressive effects of this chemotherapeutic drug combination in TNBC cells. Moreover, minocycline appeared to prevent the reduction in doublecortin-positive neural progenitor cells observed in AC-treated mice. We posit that minocycline may be useful clinically for its reported neuroprotective activity in breast cancer patients receiving AC without loss of chemotherapeutic efficacy.

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Methotrexate reduces hippocampal blood vessel density and activates microglia in rats but does not elevate central cytokine release

Cited by 96 publications

References 39 publications

Atypical Structural Connectome Organization and Cognitive Impairment in Young Survivors of Acute Lymphoblastic Leukemia

Atypical Structural Connectome Organization and Cognitive Impairment in Young Survivors of Acute Lymphoblastic Leukemia

Default mode network as a potential biomarker of chemotherapy-related brain injury

Minocycline, a putative neuroprotectant, co-administered with doxorubicin-cyclophosphamide chemotherapy in a xenograft model of triple-negative breast cancer

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