Abstract
RationaleChemotherapy-induced cognitive impairment, also known as ‘chemobrain’, is now widely recognized as a frequent adverse side effect of cancer treatment that often persists into survivorship. There are no drugs available to prevent or treat chemotherapy-induced cognitive deficits. The aim of this study was to establish a mouse model of cisplatin-induced cognitive deficits and to determine the potential preventive effects of the anti-diabetic drug metformin.ResultsTreatment of C57/BL6J mice with cisplatin (cumulative dose 34.5mg/kg) impaired performance in the novel object and place recognition task as well as in the social discrimination task indicating cognitive deficits. Co-administration of metformin prevented these cisplatin-induced cognitive impairments. At the structural level, we demonstrate that cisplatin reduces coherency of white matter fibers in the cingulate cortex. Moreover, the number of dendritic spines and neuronal arborizations as quantified on Golgi-stained brains was reduced after cisplatin treatment. Co-administration of metformin prevented all of these structural abnormalities in cisplatin-treated mice. In contrast to what has been reported in other models of chemobrain, we do not have evidence for persistent microglial or astrocyte activation in the brains of cisplatin-treated mice. Finally, we show that co-administration of metformin also protects against cisplatin-induced peripheral neuropathy.ConclusionIn summary, we show here for the first time that treatment of mice with cisplatin induces cognitive deficits that are associated with structural abnormalities in the brain. Moreover, we present the first evidence that the widely used and safe anti-diabetic drug metformin protects against these deleterious effects of cancer treatment. In view of the ongoing clinical trials to examine the potential efficacy of metformin as add-on therapy in patients treated for cancer, these findings should allow rapid clinical translation.
Highlights
Thanks to the increased efficacy of cancer therapy there are nearly 14 million cancer survivors in the United States alone[1]
We demonstrate that cisplatin reduces coherency of white matter fibers in the cingulate cortex
The number of dendritic spines and neuronal arborizations as quantified on Golgi-stained brains was reduced after cisplatin treatment
Summary
Thanks to the increased efficacy of cancer therapy there are nearly 14 million cancer survivors in the United States alone[1]. Chemotherapy-induced cognitive impairment, known as chemobrain, is a common negative side effect of cancer treatment that is frequently reported by patients treated for tumors outside the central nervous system. These cognitive deficits often last long into survivorship and negatively impact quality of life[2,3,4,5,6,7]. There are a few studies indicating that cisplatin treatment reduces cognitive function in juvenile rats and adult mice[26,27,28,29] These earlier studies did not examine the effects of cisplatin on brain structure
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