Chemotherapy : neurobiology of cognitive impairment in rats

Chemotherapie bestaat uit een cocktail van cytostatica, middelen die de celdeling remmen of vertragen, en wordt toegepast bij de behandeling voor kanker, vaak in combinatie met chirurgie en bestraling. Hoewel de overlevingskansen sterk worden vergroot met deze behandelmethode, wordt chemotherapie ook geassocieerd met veel bijwerkingen. Een aantal van deze bijwerkingen zijn direct te merken, zoals haaruitval, misselijkheid en gewichtsverlies, en verdwijnen als de behandeling is afgelopen. Maar een bijwerking die vaak pas (laat) na de behandeling opgemerkt en jarenlang aanwezig kan zijn is cognitieve schade. Echter, niet iedereen die behandeld is met chemotherapie heeft last van cognitieve problemen en ook niet iedereen die hier last van heeft, heeft dit in dezelfde mate. Klinische studies laten zien dat ongeveer 17 tot 34% van de behandelde patiënten deze problemen ondervindt en bij de een openbaart dit probleem zich zeer mild, terwijl bij een ander deze problemen dementieachtige verschijnselen kan aannemen. De cognitieve problemen bestaan vooral uit een verslechterd geheugen, meer tijd nodig hebben om informatie te verwerken en verminderde concentratie/ aandacht. Hoewel er al veel klinische studies zijn verricht waarin deze cognitieve problemen zijn onderzocht, is het nog steeds niet duidelijk wat de onderliggende mechanismen zijn. Daarom is in dit proefschrift in een diermodel onderzocht of chemotherapie ook bij ratten cognitieve problemen veroorzaakt en welke processen in de hersenen hiervoor verantwoordelijk zouden kunnen zijn. Voor dit onderzoek werden ratten behandeld met methotrexaat (MTX), een cytostaticum wat veel gebruikt werd in een chemotherapie cocktail voor de behandeling van borstkanker en sterk geassocieerd is met cognitieve problemen. Zie: Samenvatting

Neurobiological basis of chemotherapy-induced cognitive impairment : a review of rodent research

For some cancer survivors chemotherapy treatment is associated with lasting cognitive impairment, long after treatment cessation. Several candidate mechanisms have been suggested, yet clinical research has been unable to clearly tease apart these hypotheses. Rodent research has allowed a systematic study of these underlying mechanisms in the absence of potential patient confounds. Herein, this research is reviewed with emphasis on the role of the blood-brain barrier, neurogenesis, oxidative stress, white matter, immune system/(neuro) inflammation, HPA axis, blood flow, and cancer in chemotherapy-induced cognitive impairment. Furthermore, potential pharmacotherapy and behavioral intervention strategies are reviewed. This paper ends with methodological considerations in study of chemotherapy and cognition.13 page(s

Inhibition of hippocampal cell proliferation by methotrexate in rats is not potentiated by the presence of a tumor

Methotrexate is a widely used cytostatic in chemotherapy cocktails for the treatment of cancer but is associated with cognitive impairment. Previous animal studies indicated that methorexate decreases hippocampal cell proliferation, which might contribute to the observed cognitive impairment. However, clinical studies have shown that cognitive impairment can also be noticed in some cancer patients before any systemic treatment is initiated. We aim in the present study to discern whether hippocampal cell proliferation is negatively affected by tumor growth and if the presence of a tumor amplifies the effects of methotrexate. Buffalo rats were subcutaneously injected with PBS or Morris Hepatoma 7777 cells to induce a tumor. Two weeks after this injection the animals received an intraperitoneal injection of methotrexate or saline. Three weeks later hippocampal cell proliferation was quantified using immunohistochemical staining. Treatment with Morris Hepatoma 7777 cells decreased the number of proliferating cells as compared to control animals. An overall tumor effect was absent mainly because methotrexate treatment significantly decreased cell proliferation with no differences between animals with or without a tumor. Neither methotrexate nor the tumor induced pica behavior. These findings indicate that although the presence of a tumor reduces hippocampal cell proliferation it does not affect the negative effect of methotrexate on this plasticity marker. Since sickness behavior is not induced by methotrexate or tumor presence it does not play a role in the development of cognitive deficits. This study further indicates that the effects of methotrexate on brain and behavior can be studied in healthy animals.

Long-lasting suppression of hippocampal cell proliferation and impaired cognitive performance by methotrexate in the rat

Methotrexate (MTX) is a cytostatic agent widely used in combination with other agents as adjuvant chemotherapy for breast cancer and is associated with cognitive impairment as a long-term side effect in some cancer patients. This paper aimed to identify a neurobiological mechanism possibly responsible for this cognitive impairment using an animal model. The first study explored the hypothesis that MTX reduces neuronal cell proliferation. Adose-dependent long-lasting decrease in hippocampal cell proliferation was shown with Ki-67 immunocytochemistry, following a single intravenous injection of MTX (37.5–300 mg/kg). Animals treated with MTX also showed a dose-dependent transient decrease in body weight gain. In the second study, the effect of MTX (250 mg/kg) on two spatial learning tasks was examined. Animals treated with MTX learned the Morris water maze task adequately; however, these animals showed a longer latency time to cross the platform location in the probe trial, reflecting an impairment of spatial memory function. In the novel object recognition task, animals treated with MTX failed to distinguish a novel object from a familiar one, indicating a decrease in the comparator function of the hippocampus. Our studies indicated that, in the rat, MTX has a dose-dependent negative effect on hippocampal cell proliferation, and on cognitive behavior. These findings suggest that adverse effects of certain cytotoxic agents on hippocampal cell proliferation may have a potential contributory role in cognitive impairment observed in humans after chemotherapy.

Methotrexate decreases hippocampal cell proliferation and induces memory deficits in rats

Methotrexate (MTX) is a cytostatic agent used in adjuvant chemotherapy for treatment of breast cancer and is associated with cognitive impairment in a subgroup of patients. The aim of this paper is to test whether MTX can rapidly affect various brain structures resulting in decreased hippocampal cell proliferation and white matter damage. We also studied whether cell death occurs in the hippocampus following MTX. All these processes may contribute to the memory deficits reported in patients. The first study explored the effect of an intravenously injected high-dose MTX (250 mg/kg) on hippocampal cell proliferation, white matter, and cell death. Proliferation was not significantly decreased 1 day after administration of MTX, although a high individual variation was seen. However, 7 days after MTX treatment hippocampal cell proliferation was significantly lower compared to control animals. White matter density was decreased in the lateral corpus callosum of animals treated with MTX, 1 day, 1 week, and 3 weeks after treatment. MTX did not induce hippocampal cell death at any of the time intervals after treatment. The second study examined the effect of MTX on memory by subjecting animals to a learning task directly followed with MTX treatment. In both learning tasks, memory was impaired in treated animals. In the Morris water maze, animals treated with MTX spent significantly less time in the correct quadrant compared to control animals during the probe trial which was performed 1 week after training and treatment. In contextual fear conditioning, animals treated with MTX showed significantly less freezing behavior compared to control animals, 4 weeks after training and treatment. These studies suggest that the negative effect of MTX on hippocampal cell proliferation and white matter density may be part of the mechanisms underlying the cognitive impairment observed as side effect after cytotoxic treatment in humans.

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

Methotrexate is a cytostatic drug applied in adjuvant chemotherapy and associated with cognitive impairment in part of the cancer patients. In this paper we studied in rats whether a reduction in blood supply to the brain or neuroinflammation are possible mediators of this cognitive dysfunctionality. Methotrexate reduced hippocampal blood vessel density 1 week and 3 weeks after treatment as measured immunohistochemically with an endothelial barrier antigen. Since reduced brain vascularization may relate to lowered central glucose metabolism [18F]FDG PET was performed. Methotrexate reduced tracer uptake in the hippocampal region 1 week after treatment, which was not seen 3 weeks after treatment. Neuroinflammatory processes were explored via a number of methods: a microglia immunohistochemical marker was applied to hippocampal sections, [11C]PK11195 PET was performed, and cytokine levels in plasma and homogenized hippocampal tissue were measured. Methotrexate activated microglia in the hippocampus 1 week and 3 weeks after treatment. PET analysis, however, did not show an increase in hippocampal tracer uptake and the multiplex analysis of various cytokines showed that hippocampal cytokine levels were not increased after methotrexate administration. Methotrexate did reduce plasma cytokine levels indicating a suppression of peripheral immune functioning. Methotrexate reduces hippocampal blood vessel density, indicative of a reduced brain glucose metabolism, which may contribute to the cognitive impairment following methotrexate administration. Although methotrexate activates microglia activation in the hippocampus, no effects were seen in [11C]PK11195 tracer uptake or hippocampal cytokine levels. This suggests that the microglial activation in this study is not a marker for neuroinflammation.