Metformin Prevents Cisplatin-Induced Cognitive Impairment and Brain Damage in Mice

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.

Brain structure and function in patients with ovarian cancer treated with first-line chemotherapy: a pilot study

“…Recent studies have documented that chemotherapy can disrupt hippocampal neurogenesis (Dietrich et al 2006), and is associated with alterations in white matter integrity (Inagaki et al 2007; Deprez et al 2013). Recent rodent studies have shown that cisplatin inhibits neurogenesis and disrupts cognitive function (Manohar et al 2014; Vichaya et al 2015), and that metformin may prevent cisplatin-related central neurotoxicity (Zhou et al 2016). Additional studies addressing the neurotoxicity of specific chemotherapeutic agents would contribute to our understanding of the underlying mechanisms, and the development of preventive interventions.…”

Pifithrin-μ Prevents Cisplatin-Induced Chemobrain by Preserving Neuronal Mitochondrial Function

“…All behavioral assays were performed in a blinded setup. NOPR was performed as we have previously described [2]. In brief, mice were transferred to a testing arena (46.99 cm × 25.4 cm) containing two identical objects placed against one side of the arena for 5 min (training phase) and then returned to their home cages for 30 min.…”

“…The integrity of the neurogenic stem cell niche is crucial for adequate cognitive function [27], [28]; we have found that cisplatin reduces white-matter integrity as analyzed at the level of the coherency of myelin basic protein (MBP) fibers in the cingulate cortex [2]. We therefore performed fixation and immunostaining of neuronal precursors in the subventricular zone (SVZ) and dentate gyrus (DG), as previously described [3].…”

“…Advances in the efficacy of cancer treatment have led to a sharp increase in the number of cancer survivors, which has reached nearly 15 million in the United States alone[1], [2]. However, in many cases cancer treatment is associated with severe neurotoxic side effects, including fatigue, peripheral pain [3], paresthesia, and cognitive deficits, that can persist long after completion of treatment [4].…”

“…We recently showed that cisplatin-induced cognitive impairment in mice was associated with increased coherency of white-matter structures and sharp decrease in the number of neuronal dendritic spines and arborizations [2]. …”