Amantadine mitigates the cytotoxic and genotoxic effects of doxorubicin in SH-SY5Y cells and reduces its mutagenicity.

Amantadine (AMA) is a useful drug in neuronal disorders, but few studies have been performed to access its toxicological profile. Conversely, doxorubicin (Dox) is a well-known antineoplastic drug that has shown neurotoxic effects leading to cognitive impairment. The aims of this study are to evaluate the cytotoxic, genotoxic, and mutagenic effects of AMA, as well as its possible protective actions against deleterious effects of Dox. The Salmonella/microsome assay was performed to assess mutagenicity while cytotoxicity and genotoxicity were evaluated in SH-SY5Y cells using MTT and comet assays. Possible modulating effects of AMA on the cytotoxicity, genotoxicity, and mutagenicity induced by Dox were evaluated through cotreatment procedures. Amantadine did not induce mutations in the Salmonella/microsome assay and decreased Dox-induced mutagenicity in the TA98 strain. AMA reduced cell viability and induced DNA damage in SH-SY5Y cells. In cotreatment with Dox, AMA attenuated the cytotoxicity of Dox and showed an antigenotoxic effect. In conclusion, AMA does not induce gene mutations, although it has shown a genotoxic effect. Furthermore, AMA decreases frameshift mutations induced by Dox as well as the cytotoxic and genotoxic effects of Dox in SH-SY5Y cells, suggesting that AMA can interfere with Dox mutagenic activity and attenuate its neurotoxic effects.

An update on neurobiological mechanisms involved in the development of chemotherapy-induced cognitive impairment (CICI).

Cancer is the second leading cause of death worldwide despite efforts in early diagnosis of the disease and advances in treatment. The use of drugs that exert toxic effects on tumor cells or chemotherapy is one of the most widely used treatments against cancer. However, its low toxic selectivity affects both healthy cells and cancer cells. It has been reported that chemotherapeutic drugs may generate neurotoxicity that induces deleterious effects of chemotherapy in the central nervous system. In this sense, patients report decreased cognitive abilities, such as memory, learning, and some executive functions after chemotherapy. This chemotherapy-induced cognitive impairment (CICI) develops during treatment and persists even after chemotherapy. Here we present a review of the literature on the main neurobiological mechanisms involved in CICI using a Boolean formula following the steps of the PRISMA guidelines that were used to perform statements searches in various databases. The main mechanisms described in the literature to explain CRCI include direct and indirect mechanisms that induce neurotoxicity by chemotherapeutic agents. Therefore, this review provides a general understanding of the neurobiological mechanisms of CICI and the possible therapeutic targets to prevent it..

Cyclophosphamide and epirubicin induce high apoptosis in microglia cells while epirubicin provokes DNA damage and microglial activation at sub-lethal concentrations.

Chemotherapy Related Cognitive Impairment (CRCI), also called chemobrain, diminishes cancer patient's life quality. Breast cancer (BC) patients have been described to be importantly affected, however, the mechanism leading to CRCI has not been fully elucidated. Recent research proposes microglia as the main architect of CRCI, thus dysregulations in these cells could trigger CRCI. The aim of this research was to evaluate the effects of two drugs commonly used against breast cancer, cyclophosphamide (CTX) and epirubicin (EPI), on the microglia cell line SIM-A9, using the BC cell line, 4T1, as a control. Our results show that CTX and EPI decrease microglia-cell viability and increase cell death on a concentration-dependent manner, being 5 and 2 times more cytotoxic to microglia cell line than to breast cancer 4T1cells, respectively. Both chemotherapies induce cell cycle arrest and a significant increase in p53, p16 and γ-H2AX in breast cancer and microglia cells. Furthermore, mitochondrial membrane potential (ΔΨm) diminishes as cell death increases, and both chemotherapies induce reactive oxygen species (ROS) production on SIM-A9 and 4T1. Moreover, caspase activation increases with treatments and its pharmacological blockade inhibits CTX and EPI induced-cell death. Finally, low concentrations of CTX and EPI induce γ-H2AX, and EPI induces cytokine release, NO production and Iba-1 overexpression. These findings indicate that microglia cells are more sensitive to CTX and EPI than BC cells and undergo DNA damage and cell cycle arrest at very low concentrations, moreover EPI induces microglia activation and a pro-inflammatory profile.

Impaired brain dopamine transporter in chemobrain patients submitted to brain SPECT imaging using the technetium-99m labeled tracer TRODAT-1.

PURPOSE: "Chemobrain" is a medical secondary effect of cancer chemotherapy treatment characterized by a general decline in cognition affecting visual and verbal memory, attention, complex problem-solving skills, and motor function. Dopamine (DA) central nervous system neurotransmitters serve an important role in cognition, and changes in DA could potentially explain impaired cognition associated with chemotherapy. Therefore, our objective was to assess in vivo dopaminergic dysfunction in the central nervous system (CNS) of a group of female breast cancer survivors with cognitive impairment following chemotherapy. METHODS: Twenty-eight women reporting chemobrain were recruited for this study and compared to 22 healthy reference women. Striatal dopamine transporter (DAT) binding ratio was determined by 99mTc-TRODAT-1 (a highly selective radiotracer for DAT in the dorsal striatum) single-photon emission computed tomography and a quantitative evaluation was obtained by DatQUANT™ software (GE Healthcare). The DAT binding ratio (BRDAT) in the patient and control groups was compared using the Student's t test, a multivariate analysis of variance (MANOVA) was used to compare age, years of schooling and BRDAT. The relationship between continuous variables, such as cognitive impairment and BRDAT was assessed using Pearson correlation test. RESULTS: There was a difference in BRDAT between the chemobrain patients and control group. Patients had statistically significant (p < 0.05) lower concentrations of the radiopharmaceutical in the striatum. CONCLUSIONS: We identified a significant dopaminergic decrease in all regions of the dorsal striatum within the patients reporting cognitive dysfunction after chemotherapy. Therefore, our results indicate a possible role of dopamine transporter in the physiopathology of chemobrain, even out of the acute phase of symptoms.

Doxorrubicina e chemobrain - Estudos experimentais para a avaliação dos déficits cognitivos pós-quimioterapia / Doxorubicin and chemobrain - Experimental studies for the assessment of the cognitive deficits after chemotherapy

A doxorrubicina (DOX), um agente interativo da topoisomerase, é comumente utilizada no tratamento de vários tipos de câncer sólidos e hematológicos. Esta droga é conhecida por causar prejuízos cognitivos em indivíduos submetidos à quimioterapia de longo prazo (déficits também chamados de chemobrain). Frente à relativa inexistência de estratégias preventivas ou terapêuticas eficazes para evitar o desenvolvimento do chemobrain, modelos experimentais in vitro e in vivo têm sido empregados na busca da compreensão dos mecanismos subjacentes a tal fenômeno.  A presente revisão visa a apresentar estudos envolvendo a administração de DOX, como base para o possível entendimento dos processos que conduzem aos prejuízos cognitivos induzidos pela quimioterapia.(AU)

Doxorubicin (DOX), a topoisomerase interactive agent, is commonly used to treat several types of solid and hematological cancers. This drug is known to cause cognitive impairments in individuals submitted to long-term chemotherapy (deficits also called as chemobrain). Given the relative absence of effective preventive or therapeutic strategies to avoid the development of chemobrain, in vitro and in vivo experimental models have been employed in the search for an understanding of the mechanisms underlying such phenomena. The present review aims to present studies involving the administration of DOX, as a basis for the possible comprehension of the processes leading to the cognitive impairments induced by chemotherapy.(AU)

Doxorrubicina e chemobrain - Estudos experimentais para a avaliação dos déficits cognitivos pós-quimioterapia / Doxorubicin and chemobrain - Experimental studies for the assessment of the cognitive deficits after chemotherapy

A doxorrubicina (DOX), um agente interativo da topoisomerase, é comumente utilizada no tratamento de vários tipos de câncer sólidos e hematológicos. Esta droga é conhecida por causar prejuízos cognitivos em indivíduos submetidos à quimioterapia de longo prazo (déficits também chamados de chemobrain). Frente à relativa inexistência de estratégias preventivas ou terapêuticas eficazes para evitar o desenvolvimento do chemobrain, modelos experimentais in vitro e in vivo têm sido empregados na busca da compreensão dos mecanismos subjacentes a tal fenômeno.  A presente revisão visa a apresentar estudos envolvendo a administração de DOX, como base para o possível entendimento dos processos que conduzem aos prejuízos cognitivos induzidos pela quimioterapia.

Doxorubicin (DOX), a topoisomerase interactive agent, is commonly used to treat several types of solid and hematological cancers. This drug is known to cause cognitive impairments in individuals submitted to long-term chemotherapy (deficits also called as chemobrain). Given the relative absence of effective preventive or therapeutic strategies to avoid the development of chemobrain, in vitro and in vivo experimental models have been employed in the search for an understanding of the mechanisms underlying such phenomena. The present review aims to present studies involving the administration of DOX, as a basis for the possible comprehension of the processes leading to the cognitive impairments induced by chemotherapy.