Purpose Chemotherapy-related cognitive impairment (CRCI) is commonly reported following the administration of chemotherapeutic agents and comprises a wide variety of neurological problems. No effective treatments for CRCI are currently available. Here we examined the mechanisms involving cisplatin-induced hippocampal damage following cisplatin administration in a rat model and in cultured rat hippocampal neurons and neural stem/progenitor cells (NSCs). We also assessed the protective effects of the antioxidant, N-acetylcysteine in mitigating these damages. Experimental design Adult male rats received 6 mg/kg cisplatin in the acute studies. In chronic studies, rats received 5 mg/kg cisplatin or saline injections once per week for 4 weeks. N-acetylcysteine (250 mg/kg/day) or saline was administered for five consecutive days during cisplatin treatment. Cognitive testing was performed 5 weeks after treatment cessation. Cisplatin-treated cultured hippocampal neurons and NSCs were examined for changes in mitochondrial function, oxidative stress production, caspase-9 activation, and neuronal dendritic spine density. Results Acute cisplatin treatment reduced dendritic branching and spine density, and induced mitochondrial degradation. Rats receiving the chronic cisplatin regimen showed impaired performance in contextual fear conditioning, context object discrimination, and novel object recognition tasks compared to controls. Cisplatin induced mitochondrial DNA damage, impaired respiratory activity, increased oxidative stress, and activated caspase-9 in cultured hippocampal neurons and NSCs. N-acetylcysteine treatment prevented free radical production, ameliorated apoptotic cellular death and dendritic spine loss, and partially reversed the cisplatin-induced cognitive impairments. Conclusions Our results suggest that mitochondrial dysfunction and increased oxidative stress are involved in cisplatin-induced cognitive impairments. Therapeutic agents, such as N-acetylcysteine, may be effective in mitigating the deleterious effects of cisplatin.

Mitochondrial dysfunction is a hallmark of cancer biology. Tumor mitochondrial metabolism is characterized by an abnormal ability to function in scarce oxygen conditions through glycolysis (the Warburg effect), and accumulation of mitochondrial DNA defects are present in both hereditary neoplasia and sporadic cancers. Mitochondrial Lon is a major regulator of mitochondrial metabolism and the mitochondrial response to free radical damage, and plays an essential role in the maintenance and repair of mitochondrial DNA. Despite these critical cellular functions of Lon, very little has been reported regarding its role in glioma. Lon expression in gliomas and its relevance with patient survival was examined using published databases and human tissue sections. The effect of Lon in glioma biology was investigated through siRNA targeting Lon. We also tested the in vitro antitumor activity of Lon inhibitor, CC4, in the glioma cell lines D-54 and U-251. High Lon expression was associated with high glioma tumor grade and poor patient survival. While Lon expression was elevated in response to a variety of stimuli, Lon knockdown in glioma cell lines decreased cell viability under normal conditions, and dramatically impaired glioma cell survival under hypoxic conditions. Furthermore, the Lon inhibitor, CC4, efficiently prohibited glioma cell proliferation and synergistically enhanced the therapeutic efficacy of the chemotherapeutic agents, temozolomide (TMZ) and cisplatin. We demonstrate that Lon plays a key role in glioma cell hypoxic survival and mitochondrial respiration, and propose Lon as a promising therapeutic target in the treatment of malignant gliomas.

Adaptive homeostasis is defined as the transient expansion or contraction of the homeostatic range following exposure to subtoxic, non-damaging, signaling molecules or events, or the removal or cessation of such molecules or events (). Adaptive homeostasis allows us to transiently adapt (and then de-adapt) to fluctuating levels of internal and external stressors. The ability to cope with transient changes in internal and external environmental stress, however, diminishes with age. Declining adaptive homeostasis may make older people more susceptible to many diseases. Chronic oxidative stress and defective protein homeostasis (proteostasis) are two major factors associated with the etiology of age-related disorders. In the present paper, we review the contribution of impaired responses to oxidative stress and defective adaptive homeostasis in the development of age-associated diseases.

Cancer survivors diagnosed during infancy and adolescence may be at risk for chemotherapy-related cognitive impairments (CRCI), however the effects of pediatric chemotherapy treatment on adulthood cognitive function are not well understood. Impairments in memory, attention and executive function affect 15–50% of childhood leukemia survivors related to methotrexate exposure. Systemic cisplatin is used to treat a variety of childhood and adult cancers, yet the risk and extent of cognitive impairment due to platinum-based chemotherapy in pediatric patients is unknown. Systemic cisplatin penetrates the CNS, induces hippocampal synaptic damage, and leads to neuronal and neural stem/progenitor cell (NSC) loss. Survivors of non-leukemic cancers may be at risk for significant cognitive impairment related to cisplatin-driven neurotoxicity. We sought to examine the long-term effects of systemic cisplatin administration on cognitive function when administered during infancy and adolescence in a rat model. We performed cognitive testing in adult rats exposed to systemic cisplatin during either infancy or adolescence. Rats treated as adolescents showed significantly poor retrieval of a novel object as compared to controls. Further, cisplatin-treated infants and adolescents showed poor contextual discrimination as compared to controls, and an impaired response to cued fear conditioning. Ultimately, systemic cisplatin exposure resulted in more profound impairments in cognitive function in rats treated during adolescence than in those treated during infancy. Further, exposure to cisplatin during adolescence affected both hippocampus and amygdala dependent cognitive function, suggesting a more global cognitive dysfunction at this age.

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