Disease Research (CNDR). Written informed consent was obtained from all subjects. The cases used in this study are summarized in Supplemental Table 3. RNA-seq data. All original RNA-seq data were previously deposited in the NCBI's Gene Expression Omnibus database (GEO GSE101689).
Cognitive impairment termed chemobrain is a common neurotoxicity associated with chemotherapy treatment, affecting an estimated 78% of patients. Prompted by the hypothesis that neuronal mitochondrial dysfunction underlies chemotherapy-induced cognitive impairment (CICI), we explored the efficacy of administering the small molecule pifithrin (PFT)-µ, an inhibitor of mitochondrial p53 accumulation, in preventing CICI. Male C57BL/6J mice injected with cisplatin +/− PFT-µ for two 5-day cycles were assessed for cognitive function using novel object/place recognition and alternation in a Y-maze. Cisplatin impaired performance in the novel object/place recognition and Y-maze tests. PFT-µ treatment prevented CICI and associated cisplatin-induced changes in coherency of myelin basic protein fibers in the cingular cortex and loss of doublecortin+ cells in the subventricular zone and hippocampal dentate gyrus. Mechanistically, cisplatin decreased spare respirator capacity of brain synaptosomes and caused abnormal mitochondrial morphology, which was counteracted by PFT-µ administration. Notably, increased mitochondrial p53 did not lead to cerebral caspase-3 activation or cytochrome-c release. Furthermore, PFT-µ administration did not impair the anticancer efficacy of cisplatin and radiotherapy in tumor-bearing mice. Our results supported the hypothesis that neuronal mitochondrial dysfunction induced by mitochondrial p53 accumulation is an underlying cause of CICI, and that PFT-µ may offer a tractable therapeutic strategy to limit this common side-effect of many types of chemotherapy.
While chemotherapeutic agents have yielded relative success in the treatment of cancer, patients are often plagued with unwanted and even debilitating side-effects from the treatment which can lead to dose reduction or even cessation of treatment. Common side effects (symptoms) of chemotherapy include (i) cognitive deficiencies such as problems with attention, memory and executive functioning; (ii) fatigue and motivational deficit; and (iii) neuropathy. These symptoms often develop during treatment but can remain even after cessation of chemotherapy, severely impacting long-term quality of life. Little is known about the underlying mechanisms responsible for the development of these behavioral toxicities, however, neuroinflammation is widely considered to be one of the major mechanisms responsible for chemotherapy-induced symptoms. Here, we critically assess what is known in regards to the role of neuroinflammation in chemotherapy-induced symptoms. We also argue that, based on the available evidence, neuroinflammation is unlikely the only mechanism involved in the pathogenesis of chemotherapy-induced behavioral toxicities. We evaluate two other putative candidate mechanisms. To this end we discuss the mediating role of damage-associated molecular patterns (DAMPs) activated in response to chemotherapy-induced cellular damage. We also review the literature with respect to possible alternative mechanisms such as a chemotherapy-induced change in the bioenergetic status of the tissue involving changes in mitochondrial function in relation to chemotherapy-induced behavioral toxicities. Understanding the mechanisms that underlie the emergence of fatigue, neuropathy, and cognitive difficulties is vital to better treatment and long-term survival of cancer patients.
Cognitive impairments are a common side effect of chemotherapy that often persists long after treatment completion. There are no FDA-approved interventions to treat these cognitive deficits also called ‘chemobrain’. We hypothesized that nasal administration of mesenchymal stem cells (MSC) reverses chemobrain. To test this hypothesis, we used a mouse model of cognitive deficits induced by cisplatin that we recently developed. Mice were treated with two cycles of cisplatin followed by nasal administration of MSC. Cisplatin treatment induced deficits in the puzzle box, novel object/place recognition and Y-maze tests, indicating cognitive impairment. Nasal MSC treatment fully reversed these cognitive deficits in males and females. MSC also reversed the cisplatin-induced damage to cortical myelin. Resting state functional MRI and connectome analysis revealed a decrease in characteristic path length after cisplatin, while MSC treatment increased path length in cisplatin-treated mice. MSCs enter the brain but did not survive longer than 12-72 hrs, indicating that they do not replace damaged tissue. RNA-sequencing analysis identified mitochondrial oxidative phosphorylation as a top pathway activated by MSC administration to cisplatin-treated mice. Consistently, MSC treatment restored the cisplatin-induced mitochondrial dysfunction and structural abnormalities in brain synaptosomes. Nasal administration of MSC did not interfere with the peripheral anti-tumor effect of cisplatin. In conclusion, nasal administration of MSC may represent a powerful, non-invasive, and safe regenerative treatment for resolution of chemobrain.
Mesenchymal stem cells (MSCs) transfer healthy mitochondria to damaged acceptor cells via actin-based intercellular structures. In this study, we tested the hypothesis that MSCs transfer mitochondria to neural stem cells (NSCs) to protect NSCs against the neurotoxic effects of cisplatin treatment. Our results show that MSCs donate mitochondria to NSCs damaged in vitro by cisplatin. Transfer of healthy MSC-derived mitochondria decreases cisplatin-induced NSC death. Moreover, mitochondrial transfer from MSCs to NSCs reverses the cisplatin-induced decrease in mitochondrial membrane potential. Blocking the formation of actin-based intercellular structures inhibited the transfer of mitochondria to NSCs and abrogated the positive effects of MSCs on NSC survival. Conversely, overexpression of the mitochondrial motor protein Rho-GTPase 1 (Miro1) in MSCs increased mitochondrial transfer and further improved survival of cisplatin-treated NSCs.In vivo, MSC administration prevented the loss of DCX+ neural progenitor cells in the subventricular zone and hippocampal dentate gyrus which occurs as a result of cisplatin treatment. We propose mitochondrial transfer as one of the mechanisms via which MSCs exert their therapeutic regenerative effects after cisplatin treatment.Electronic supplementary materialThe online version of this article (10.1186/s40478-018-0644-8) contains supplementary material, which is available to authorized users.
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