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

Abstract

Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. AbstractMethotrexate (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. A dose-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.

Effects of chemotherapeutic agents 5-fluorouracil and methotrexate alone and combined in a mouse model of learning and memory

“…In previous studies, these doses of methotrexate alone disrupted conditioned taste aversion, conditioned emotional responses, spatial memory, and novel object recognition (Madhyastha et al 2002;Seigers et al 2008;Yanovski et al 1989) but failed to alter responding in a different conditioned taste aversion assay and a Pavlovian appetitive conditioning assay (Stock et al 1995). The doses of 3.2-32 mg/kg methotrexate used in mice and rats fall within the predicted 8-42-mg/kg-scaled mouse doses as determined from the range of clinical doses used to treat breast cancer in humans (40 mg/m 2 ) according to pharmacokinetic studies (Lobo and Balthasar 2003;Ohdo et al 1997;Peters et al 1993).…”

“…Recent studies have implicated hippocampal deficits in rodents treated with chemotherapeutic agents, although the results of these studies are also mixed. In the Morris water maze and the novel object recognition task, rats treated with methotrexate showed deficits correlated with decreased hippocampal cell proliferation, suggesting impairments of spatial memory and comparator functions of the hippocampus, respectively (Seigers et al 2008). However, repeated injections of cyclophosphamide or 5-fluorouracil caused transient enhancements of both memory and hippocampal synaptic plasticity in spatial learning tasks (Lee et al 2006) but produced transient memory deficits in a mouse step-down inhibitory avoidanceconditioning task (Reiriz et al 2006).…”

“…However, repeated injections of cyclophosphamide or 5-fluorouracil caused transient enhancements of both memory and hippocampal synaptic plasticity in spatial learning tasks (Lee et al 2006) but produced transient memory deficits in a mouse step-down inhibitory avoidanceconditioning task (Reiriz et al 2006). The susceptibility of neural cells to chemotherapeutic agents is supported by in vitro studies that demonstrate increased cell death and decreased cell division in the subventricular zone, in the dentate gyrus of the hippocampus, and in the corpus callosum of mice and rats even at doses below those used in standard chemotherapeutic clinical regimens (Dietrich et al 2006;Mignone and Weber 2006;Seigers et al 2008). The observation that chemotherapeutic agents are more toxic to hippocampal cells than to cancer cell lines suggests that learning and memory deficits might be detected at doses below those normally used in chemotherapeutic regimens.…”

Global and focal brain volume in long-term breast cancer survivors exposed to adjuvant chemotherapy

“…Since both cyclophosphamide and 5-fluorouracil continue to be implemented in current regimens, and these agents, as well as many other commonly used agents are independently associated with structural brain changes in animals [24,25], our study results might also apply to contemporary regimens.…”

Effects of Lycopene Alone or Combined with Melatonin on Methotrexate-Induced Nephrotoxicity in Rats

“…Methotrexate (Mtx), an antifolate, is used as an anti-cancer drug in higher doses such as lymphoma, breast carcinoma, sarcoma, breast cancer (Choudhury et al, 2000;Miyazaki et al, 2003;Seigers et al, 2008;Findlay et al, 2008;D'Adamo, 2011) and also in lower doses in the treatment of rheumatic diseases, psoriasis, refractory inflammatory bowel disease since it has immunosuppressant effect (Peters et al, 2000;Gisondi and Girolomoni, 2007;Renna, 2014).…”