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1.
Proc Natl Acad Sci U S A ; 118(20)2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-33972444

RESUMO

In mammalian cells, cyanide is viewed as a cytotoxic agent, which exerts its effects through inhibition of mitochondrial Complex IV (Cytochrome C oxidase [CCOx]). However, the current report demonstrates that cyanide's effect on CCOx is biphasic; low (nanomolar to low-micromolar) concentrations stimulate CCOx activity, while higher (high-micromolar) concentrations produce the "classic" inhibitory effect. Low concentrations of cyanide stimulated mitochondrial electron transport and elevated intracellular adenosine triphosphate (ATP), resulting in the stimulation of cell proliferation. The stimulatory effect of cyanide on CCOx was associated with the removal of the constitutive, inhibitory glutathionylation on its catalytic 30- and 57-kDa subunits. Transfer of diluted Pseudomonas aeruginosa (a cyanide-producing bacterium) supernatants to mammalian cells stimulated cellular bioenergetics, while concentrated supernatants were inhibitory. These effects were absent with supernatants from mutant Pseudomonas lacking its cyanide-producing enzyme. These results raise the possibility that cyanide at low, endogenous levels serves regulatory purposes in mammals. Indeed, the expression of six putative mammalian cyanide-producing and/or -metabolizing enzymes was confirmed in HepG2 cells; one of them (myeloperoxidase) showed a biphasic regulation after cyanide exposure. Cyanide shares features with "classical" mammalian gasotransmitters NO, CO, and H2S and may be considered the fourth mammalian gasotransmitter.


Assuntos
Cianetos/farmacologia , Complexo IV da Cadeia de Transporte de Elétrons/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Cianetos/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/fisiologia , Células HCT116 , Células HT29 , Humanos , Mitocôndrias/metabolismo
2.
J Neurophysiol ; 122(3): 1123-1135, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31291154

RESUMO

The nearly axiomatic idea that de novo protein synthesis is necessary for long-term memory consolidation is based heavily on behavioral studies using translational inhibitors such as anisomycin. Although inhibiting protein synthesis has been shown to disrupt the expression of memory, translational inhibitors also have been found to profoundly disrupt basic neurobiological functions, including the suppression of ongoing neural activity in vivo. In the present study, using transverse hippocampal brain slices, we monitored the passive and active membrane properties of hippocampal CA1 pyramidal neurons using intracellular whole cell recordings during a brief ~30-min exposure to fast-bath-perfused anisomycin. Anisomycin suppressed protein synthesis to 46% of control levels as measured using incorporation of radiolabeled amino acids and autoradiography. During its application, anisomycin caused a significant depolarization of the membrane potential, without any changes in apparent input resistance or membrane time constant. Anisomycin-treated neurons also showed significant decreases in firing frequencies and spike amplitudes, and showed increases in spike width across spike trains, without changes in spike threshold. Because these changes indicated a loss of cellular energetics contributing to maintenance of ionic gradients across the membrane, we confirmed that anisomycin impaired mitochondrial function by reduced staining with 2,3,5-triphenyltetrazolium chloride and also impaired cytochrome c oxidase (complex IV) activity as indicated through high-resolution respirometry. These findings emphasize that anisomycin-induced alterations in neural activity and metabolism are a likely consequence of cell-wide translational inhibition. Critical reevaluation of studies using translational inhibitors to promote the protein synthesis dependent idea of long-term memory is absolutely necessary.NEW & NOTEWORTHY Memory consolidation is thought to be dependent on the synthesis of new proteins because translational inhibitors produce amnesia when administered just after learning. However, these agents also disrupt basic neurobiological functions. We show that blocking protein synthesis disrupts basic membrane properties of hippocampal neurons that correspond to induced disruptions of mitochondrial function. It is likely that translational inhibitors cause amnesia through their disruption of neural activity as a result of dysfunction of intracellular energetics.


Assuntos
Anisomicina/farmacologia , Região CA1 Hipocampal/efeitos dos fármacos , Complexo IV da Cadeia de Transporte de Elétrons/efeitos dos fármacos , Potenciais da Membrana/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Biossíntese de Proteínas/efeitos dos fármacos , Inibidores da Síntese de Proteínas/farmacologia , Células Piramidais/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Animais , Memória de Longo Prazo/efeitos dos fármacos , Ratos
3.
Curr Genet ; 65(6): 1347-1353, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31172256

RESUMO

The respiratory chain has been proposed as an attractive target for the development of new therapies to tackle human fungal pathogens. This arises from the presence of fungal-specific electron transport chain components and links between respiration and the control of virulence traits in several pathogenic species. However, as the physiological roles of mitochondria remain largely undetermined with respect to pathogenesis, its value as a potential new drug target remains to be determined. The use of respiration inhibitors as fungicides is well developed but has been hampered by the emergence of rapid resistance to current inhibitors. In addition, recent data suggest that adaptation of the human fungal pathogen, Candida albicans, to respiration inhibitors can enhance virulence traits such as yeast-to-hypha transition and cell wall organisation. We conclude that although respiration holds promise as a target for the development of new therapies to treat human fungal infections, we require a more detailed understanding of the role that mitochondria play in stress adaption and virulence.


Assuntos
Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Antifúngicos/uso terapêutico , Candida albicans/crescimento & desenvolvimento , Candida albicans/patogenicidade , Quimioterapia Combinada , Complexo I de Transporte de Elétrons/efeitos dos fármacos , Complexo I de Transporte de Elétrons/metabolismo , Complexo II de Transporte de Elétrons/efeitos dos fármacos , Complexo II de Transporte de Elétrons/metabolismo , Complexo III da Cadeia de Transporte de Elétrons/efeitos dos fármacos , Complexo III da Cadeia de Transporte de Elétrons/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/efeitos dos fármacos , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Fungos/efeitos dos fármacos , Fungos/metabolismo , Fungos/patogenicidade , Humanos , Mitocôndrias/metabolismo , Micoses/tratamento farmacológico , Oxirredutases/efeitos dos fármacos , Oxirredutases/metabolismo , Virulência/efeitos dos fármacos
4.
Artigo em Inglês | MEDLINE | ID: mdl-28760899

RESUMO

We deleted subunits I (cydA) and II (cydB) of the Mycobacterium tuberculosis cytochrome bd menaquinol oxidase. The resulting ΔcydA and ΔcydAB mutants were hypersusceptible to compounds targeting the mycobacterial bc1 menaquinol-cytochrome c oxidoreductase and exhibited bioenergetic profiles indistinguishable from strains deficient in the ABC-type transporter, CydDC, predicted to be essential for cytochrome bd assembly. These results confirm CydAB and CydDC as potential targets for drugs aimed at inhibiting a terminal respiratory oxidase implicated in pathogenesis.


Assuntos
Citocromos c/efeitos dos fármacos , Complexo IV da Cadeia de Transporte de Elétrons/efeitos dos fármacos , Complexo IV da Cadeia de Transporte de Elétrons/genética , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Antituberculosos/farmacologia , Descoberta de Drogas , Genoma Bacteriano/genética , Testes de Sensibilidade Microbiana , Fosforilação Oxidativa/efeitos dos fármacos , Oxigênio/metabolismo , Consumo de Oxigênio/genética , Deleção de Sequência/genética
5.
Am J Physiol Heart Circ Physiol ; 312(3): H446-H458, 2017 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-28011589

RESUMO

Nanomaterial production is expanding as new industrial and consumer applications are introduced. Nevertheless, the impacts of exposure to these compounds are not fully realized. The present study was designed to determine whether gestational nano-sized titanium dioxide exposure impacts cardiac and metabolic function of developing progeny. Pregnant Sprague-Dawley rats were exposed to nano-aerosols (~10 mg/m3, 130- to 150-nm count median aerodynamic diameter) for 7-8 nonconsecutive days, beginning at gestational day 5-6 Physiological and bioenergetic effects on heart function and cardiomyocytes across three time points, fetal (gestational day 20), neonatal (4-10 days), and young adult (6-12 wk), were evaluated. Functional analysis utilizing echocardiography, speckle-tracking based strain, and cardiomyocyte contractility, coupled with mitochondrial energetics, revealed effects of nano-exposure. Maternal exposed progeny demonstrated a decrease in E- and A-wave velocities, with a 15% higher E-to-A ratio than controls. Myocytes isolated from exposed animals exhibited ~30% decrease in total contractility, departure velocity, and area of contraction. Bioenergetic analysis revealed a significant increase in proton leak across all ages, accompanied by decreases in metabolic function, including basal respiration, maximal respiration, and spare capacity. Finally, electron transport chain complex I and IV activities were negatively impacted in the exposed group, which may be linked to a metabolic shift. Molecular data suggest that an increase in fatty acid metabolism, uncoupling, and cellular stress proteins may be associated with functional deficits of the heart. In conclusion, gestational nano-exposure significantly impairs the functional capabilities of the heart through cardiomyocyte impairment, which is associated with mitochondrial dysfunction.NEW & NOTEWORTHY Cardiac function is evaluated, for the first time, in progeny following maternal nanomaterial inhalation. The findings indicate that exposure to nano-sized titanium dioxide (nano-TiO2) during gestation negatively impacts cardiac function and mitochondrial respiration and bioenergetics. We conclude that maternal nano-TiO2 inhalation contributes to adverse cardiovascular health effects, lasting into adulthood.


Assuntos
Metabolismo Energético/efeitos dos fármacos , Coração/diagnóstico por imagem , Miocárdio/patologia , Nanoestruturas/toxicidade , Efeitos Tardios da Exposição Pré-Natal/patologia , Envelhecimento , Animais , Ecocardiografia , Complexo I de Transporte de Elétrons/efeitos dos fármacos , Complexo I de Transporte de Elétrons/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/efeitos dos fármacos , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Feminino , Cardiopatias/induzido quimicamente , Cardiopatias/diagnóstico por imagem , Cardiopatias/patologia , Testes de Função Cardíaca , Contração Miocárdica/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Gravidez , Ratos , Ratos Sprague-Dawley , Titânio/toxicidade
6.
Microb Pathog ; 107: 349-353, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28414167

RESUMO

It has long been recognized that there are several infectious diseases linked to the impairment of enzymatic complexes of the mitochondrial respiratory chain, with consequent production of reactive oxygen species (ROS), that contribute to disease pathogenesis. In this study, we determined whether the inhibition on mitochondrial respiratory chain might be considered a pathway involved in the production of ROS in gills of Rhamdia quelen experimentally infected by P. aeruginosa. The animals were divided into two groups with six fish each: uninfected (the negative control group) and infected (the positive control group). On day 7 post-infection (PI), animals were euthanized and the gills were collected to assess the activities of complexes I-III, II and IV of the respiratory chain, as well as ROS levels. The activities of complexes I-III, II and IV of the respiratory chain in gills decreased, while the ROS levels increased in infected compared to uninfected animals. Moreover, a significant negative correlation was found between enzymatic activity of the complexes I-III and IV related to ROS levels in P. aeruginosa infected animals, corroborating to our hypothesis that inhibition on complexes of respiratory chain leads to ROS formation. Also, microscopic severe gill damage and destruction of primary and secondary lamellae were observed in infected animals, with the presence of hyperplasia, leukocytic infiltration and telangiectasia. In summary, we have demonstrated, for the first time, that experimental infection by P. aeruginosa inhibits the activities of mitochondrial complexes of respiratory chain and, consequently, impairs the cellular energy homeostasis. Moreover, the inhibition on mitochondrial complexes I-III and IV are linked to the ROS production, contributing to disease pathogenesis.


Assuntos
Peixes-Gato/metabolismo , Transporte de Elétrons/efeitos dos fármacos , Doenças dos Peixes/microbiologia , Brânquias/metabolismo , Mitocôndrias/metabolismo , Pseudomonas aeruginosa/patogenicidade , Espécies Reativas de Oxigênio/antagonistas & inibidores , Animais , Citocromo-c Peroxidase , Modelos Animais de Doenças , Complexo I de Transporte de Elétrons/efeitos dos fármacos , Complexo IV da Cadeia de Transporte de Elétrons/efeitos dos fármacos , Doenças dos Peixes/patologia , Brânquias/enzimologia , Brânquias/patologia , Mitocôndrias/efeitos dos fármacos , Quinona Redutases , Espécies Reativas de Oxigênio/metabolismo
7.
Am J Physiol Endocrinol Metab ; 311(5): E836-E849, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-27677502

RESUMO

Alcohol ingestion decreases postexercise rates of muscle protein synthesis, but the mechanism(s) (e.g., increased protein breakdown) underlying this observation is unknown. Autophagy is an intracellular "recycling" system required for homeostatic substrate and organelle turnover; its dysregulation may provoke apoptosis and lead to muscle atrophy. We investigated the acute effects of alcohol ingestion on autophagic cell signaling responses to a bout of concurrent (combined resistance- and endurance-based) exercise. In a randomized crossover design, eight physically active males completed three experimental trials of concurrent exercise with either postexercise ingestion of alcohol and carbohydrate (12 ± 2 standard drinks; ALC-CHO), energy-matched alcohol and protein (ALC-PRO), or protein (PRO) only. Muscle biopsies were taken at rest and 2 and 8 h postexercise. Select autophagy-related gene (Atg) proteins decreased compared with rest with ALC-CHO (P < 0.05) but not ALC-PRO. There were parallel increases (P < 0.05) in p62 and PINK1 commensurate with a reduction in BNIP3 content, indicating a diminished capacity for mitochondria-specific autophagy (mitophagy) when alcohol and carbohydrate were coingested. DNA fragmentation increased in both alcohol conditions (P < 0.05); however, nuclear AIF accumulation preceded this apoptotic response with ALC-CHO only (P < 0.05). In contrast, increases in the nuclear content of p53, TFEB, and PGC-1α in ALC-PRO were accompanied by markers of mitochondrial biogenesis at the transcriptional (Tfam, SCO2, and NRF-1) and translational (COX-IV, ATPAF1, and VDAC1) level (P < 0.05). We conclude that alcohol ingestion following exercise triggers apoptosis, whereas the anabolic properties of protein coingestion may stimulate mitochondrial biogenesis to protect cellular homeostasis.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Depressores do Sistema Nervoso Central/farmacologia , Carboidratos da Dieta/farmacologia , Proteínas Alimentares/farmacologia , Etanol/farmacologia , Exercício Físico/fisiologia , Fibras Musculares Esqueléticas/efeitos dos fármacos , Adolescente , Adulto , Consumo de Bebidas Alcoólicas , Apoptose/fisiologia , Autofagia/fisiologia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/efeitos dos fármacos , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Proteínas de Transporte/efeitos dos fármacos , Proteínas de Transporte/metabolismo , Estudos Cross-Over , Fragmentação do DNA/efeitos dos fármacos , Proteínas de Ligação a DNA/efeitos dos fármacos , Proteínas de Ligação a DNA/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/efeitos dos fármacos , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Voluntários Saudáveis , Humanos , Masculino , Proteínas de Membrana/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Proteínas Mitocondriais/efeitos dos fármacos , Proteínas Mitocondriais/metabolismo , ATPases Mitocondriais Próton-Translocadoras/efeitos dos fármacos , ATPases Mitocondriais Próton-Translocadoras/metabolismo , Mitofagia/efeitos dos fármacos , Mitofagia/fisiologia , Chaperonas Moleculares/efeitos dos fármacos , Chaperonas Moleculares/metabolismo , Fibras Musculares Esqueléticas/fisiologia , Fator 1 Nuclear Respiratório/efeitos dos fármacos , Fator 1 Nuclear Respiratório/metabolismo , Biogênese de Organelas , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Proteínas Quinases/efeitos dos fármacos , Proteínas Quinases/metabolismo , Proteínas Proto-Oncogênicas/efeitos dos fármacos , Proteínas Proto-Oncogênicas/metabolismo , Proteínas de Ligação a RNA/efeitos dos fármacos , Proteínas de Ligação a RNA/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/efeitos dos fármacos , Fatores de Transcrição/metabolismo , Proteína Supressora de Tumor p53/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Canal de Ânion 1 Dependente de Voltagem/efeitos dos fármacos , Canal de Ânion 1 Dependente de Voltagem/metabolismo , Adulto Jovem
8.
Cancer ; 122(6): 946-53, 2016 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-26762648

RESUMO

BACKGROUND: Impaired cardiac function in doxorubicin-treated childhood cancer survivors is partly mediated by the disruption of mitochondrial energy production. Doxorubicin intercalates into mitochondrial DNA (mtDNA) and disrupts genes encoding for polypeptides that make adenosine triphosphate. METHODS: This cross-sectional study examined mtDNA copy numbers per cell and oxidative phosphorylation (OXPHOS) in peripheral blood mononuclear cells (PBMCs) in 64 childhood survivors of high-risk acute lymphoblastic leukemia (ALL) who had been treated on Dana-Farber Cancer Institute childhood ALL protocols and had received doxorubicin alone (42%) or doxorubicin with the cardioprotectant dexrazoxane (58%). The number of mtDNA copies per cell and the OXPHOS enzyme activity of nicotinamide adenine dinucleotide dehydrogenase (complex I [CI]) and cytochrome c oxidase (complex IV [CIV]) were measured with quantitative real-time polymerase chain reaction immunoassays and thin-layer chromatography, respectively. RESULTS: At a median follow-up of 7.8 years after treatment, the median number of mtDNA copies per cell for patients treated with doxorubicin alone (1106.3) was significantly higher than the median number for those who had also received dexrazoxane (310.5; P = .001). No significant differences were detected between the groups for CI or CIV activity. CONCLUSIONS: Doxorubicin-treated survivors had an increased number of PBMC mtDNA copies per cell, and concomitant use of dexrazoxane was associated with a lower number of mtDNA copies per cell. Because of a possible compensatory increase in mtDNA copies per cell to maintain mitochondrial function in the setting of mitochondrial dysfunction, overall OXPHOS activity was not different between the groups. The long-term sustainability of this compensatory response in these survivors at risk for cardiac dysfunction over their lifespan is concerning.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cardiotônicos/uso terapêutico , Variações do Número de Cópias de DNA/efeitos dos fármacos , DNA Mitocondrial/efeitos dos fármacos , Dexrazoxano/uso terapêutico , Doxorrubicina/efeitos adversos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Mitocôndrias Cardíacas/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Antibióticos Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Pré-Escolar , Cromatografia em Camada Fina , Estudos Transversais , Doxorrubicina/administração & dosagem , Complexo I de Transporte de Elétrons/efeitos dos fármacos , Complexo I de Transporte de Elétrons/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/efeitos dos fármacos , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Feminino , Seguimentos , Humanos , Lactente , Leucócitos Mononucleares/enzimologia , Masculino , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/genética , Oxirredução , Fosforilação , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Reação em Cadeia da Polimerase em Tempo Real , Fatores Sexuais , Sobreviventes
9.
J Bioenerg Biomembr ; 48(5): 483-491, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27787743

RESUMO

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxicated mice have been widely used to model the loss of dopaminergic neurons. As this treatment leads to basal ganglia degeneration, it was proposed that MPTP mice could be used as a model of Leigh syndrome. However, this mitochondrial pathology is biochemically characterized by a respiratory chain dysfunction. To determine if MPTP can affect in vivo mitochondria function, we measured the activities of mitochondrial respiratory chain complexes in several tissues. Our results show that MPTP affects mainly mitochondrial respiratory chain complex IV, as found in Leigh Syndrome, confirming that acute MPTP intoxicated mice are a good model of Leigh Syndrome.


Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/efeitos adversos , Modelos Animais de Doenças , Transporte de Elétrons/efeitos dos fármacos , Doença de Leigh/induzido quimicamente , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/administração & dosagem , Animais , Complexo IV da Cadeia de Transporte de Elétrons/efeitos dos fármacos , Intoxicação por MPTP , Camundongos , Mitocôndrias/metabolismo
10.
Toxicol Ind Health ; 31(12): 1325-33, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23843224

RESUMO

The present study is an unsubstantiated qualitative assessment of the abused drugs-tramadol and clonazepam. The aim of this study is to evaluate whether the effects of tramadol, clonazepam, and their combination on mitochondrial electron transport chain (ETC) complexes were influential at therapeutic or at progressively increasing doses. The study comprised of a total of 70 healthy male rats, aged 3 months. According to the drug intake regimen, animals were divided into seven groups: control, tramadol therapeutic, clonazepam therapeutic, combination therapeutic, tramadol abuse, clonazepam abuse, and combination abuse group. At the end of the experiment, brain mitochondrial ETC complexes (I, II, III, and IV) were evaluated. Histopathological examinations were also performed on brain tissues. The results showed that groups that received tramadol (therapeutic and abuse) suffered from weight loss. Tramadol abuse group and combination abuse group showed significant decrease in the activities of I, III, and IV complexes but not in the activity of complex II. In conclusion, tramadol but not clonazepam has been found to partially inhibit the activities of respiratory chain complexes I, III, and IV but not the activity of complex II and such inhibition occurred only at doses that exceeded the maximum recommended adult human daily therapeutic doses. This result explains the clinical and histopathological effects of tramadol, such as seizures and red neurons (marker for apoptosis), respectively.


Assuntos
Modelos Animais de Doenças , Complexo III da Cadeia de Transporte de Elétrons/efeitos dos fármacos , Complexo IV da Cadeia de Transporte de Elétrons/efeitos dos fármacos , Complexo I de Transporte de Elétrons/efeitos dos fármacos , Síndromes Neurotóxicas/enzimologia , Transtornos Relacionados ao Uso de Opioides/enzimologia , Tramadol/intoxicação , Analgésicos Opioides/intoxicação , Animais , Anticonvulsivantes/intoxicação , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Encéfalo/patologia , Clonazepam/intoxicação , Complexo I de Transporte de Elétrons/antagonistas & inibidores , Complexo I de Transporte de Elétrons/metabolismo , Complexo II de Transporte de Elétrons/efeitos dos fármacos , Complexo II de Transporte de Elétrons/metabolismo , Complexo III da Cadeia de Transporte de Elétrons/antagonistas & inibidores , Complexo III da Cadeia de Transporte de Elétrons/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/antagonistas & inibidores , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/enzimologia , Proteínas do Tecido Nervoso/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/enzimologia , Neurônios/patologia , Síndromes Neurotóxicas/complicações , Síndromes Neurotóxicas/patologia , Transtornos Relacionados ao Uso de Opioides/complicações , Transtornos Relacionados ao Uso de Opioides/patologia , Pesquisa Qualitativa , Distribuição Aleatória , Ratos , Transtornos Relacionados ao Uso de Substâncias/complicações , Transtornos Relacionados ao Uso de Substâncias/enzimologia , Transtornos Relacionados ao Uso de Substâncias/patologia , Redução de Peso/efeitos dos fármacos
11.
HIV Med ; 13(2): 98-106, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22103263

RESUMO

OBJECTIVES: HIV and antiretroviral (ART) exposure in utero may have deleterious effects on the infant, but uncertainty still exists. The objective of this study was to evaluate aspects of mitochondrial DNA (mtDNA) content, mitochondrial function and oxidative stress simultaneously in placenta, umbilical cord blood and infant blood in HIV/ART-exposed infants compared with uninfected controls. METHODS: HIV-1-infected pregnant women and HIV-1-uninfected healthy pregnant controls were enrolled in the study prospectively. Placenta and umbilical cord blood were obtained at delivery and infant blood was obtained within 48 h of delivery. mtDNA content was determined for each specimen. Nuclear [subunit IV of cytochrome c-oxidase (COX IV)]- and mitochondrial (COX II)-encoded polypeptides of the oxidative phosphorylation enzyme cytochrome c-oxidase were quantified in cord and infant blood. Placental mitochondria malondialdehyde (MDA) concentrations were measured as a marker of oxidative stress. RESULTS: Twenty HIV-positive/HIV-exposed and 26 control mother-infant pairs were enrolled in the study. All HIV-infected women and their infants received ART. Placental MDA concentration and mtDNA content in placenta and cord blood were similar between groups. The cord blood COX II:IV ratio was lower in the HIV-positive group than in the controls, whereas the infant peripheral blood mtDNA content was higher in the HIV-exposed infants, but the infant peripheral blood COX II:IV ratio was similar. No infant had clinical evidence of mitochondrial disease or acquired HIV infection. In multivariable regression analyses, the significant findings in cord and infant blood were both most associated with HIV/ART exposure. CONCLUSIONS: HIV-exposed infants showed reduced umbilical cord blood mitochondrial enzyme expression with increased infant peripheral blood mitochondrial DNA levels, the latter possibly reflecting a compensatory mechanism to overcome HIV/ART-associated mitochondrial toxicity.


Assuntos
Fármacos Anti-HIV/efeitos adversos , DNA Mitocondrial/efeitos dos fármacos , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Sangue Fetal/enzimologia , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Placenta/enzimologia , Efeitos Tardios da Exposição Pré-Natal , Adulto , Fármacos Anti-HIV/administração & dosagem , Estudos de Casos e Controles , DNA Mitocondrial/genética , Complexo IV da Cadeia de Transporte de Elétrons/efeitos dos fármacos , Complexo IV da Cadeia de Transporte de Elétrons/genética , Feminino , Sangue Fetal/efeitos dos fármacos , Infecções por HIV/enzimologia , Infecções por HIV/genética , Humanos , Recém-Nascido , Troca Materno-Fetal , Estresse Oxidativo/genética , Placenta/efeitos dos fármacos , Gravidez , Estudos Prospectivos , Adulto Jovem
12.
Toxicol Appl Pharmacol ; 264(2): 167-81, 2012 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-22889881

RESUMO

Mitochondrial DNA (mtDNA) variations including single nucleotide polymorphisms (SNPs) have been proposed to be involved in idiosyncratic drug reactions. However, current in vitro and in vivo models lack the genetic diversity seen in the human population. Our hypothesis is that different cell strains with distinct mtDNA SNPs may have different mitochondrial bioenergetic profiles and may therefore vary in their response to drug-induced toxicity. Therefore, we used an in vitro system composed of four strains of mouse embryonic fibroblasts (MEFs) with mtDNA polymorphisms. We sequenced mtDNA from embryonic fibroblasts isolated from four mouse strains, C57BL/6J, MOLF/EiJ, CZECHII/EiJ and PERA/EiJ, with the latter two being sequenced for the first time. The bioenergetic profile of the four strains of MEFs was investigated at both passages 3 and 10. Our results showed that there were clear differences among the four strains of MEFs at both passages, with CZECHII/EiJ having a lower mitochondrial robustness when compared to C57BL/6J, followed by MOLF/EiJ and PERA/EiJ. Seven drugs known to impair mitochondrial function were tested for their effect on the ATP content of the four strains of MEFs in both glucose- and galactose-containing media. Our results showed that there were strain-dependent differences in the response to some of the drugs. We propose that this model is a useful starting point to study compounds that may cause mitochondrial off-target toxicity in early stages of drug development, thus decreasing the number of experimental animals used.


Assuntos
DNA Mitocondrial/metabolismo , Embrião de Mamíferos/metabolismo , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/genética , Fibroblastos/metabolismo , Mitocôndrias/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Polimorfismo de Nucleotídeo Único/fisiologia , Trifosfato de Adenosina/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citrato (si)-Sintase/metabolismo , DNA Mitocondrial/efeitos dos fármacos , Complexo I de Transporte de Elétrons/efeitos dos fármacos , Complexo I de Transporte de Elétrons/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/efeitos dos fármacos , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Embrião de Mamíferos/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Ratos Endogâmicos , Rotenona/farmacologia , Especificidade da Espécie , Desacopladores/farmacologia
13.
J Appl Toxicol ; 32(9): 714-21, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21538410

RESUMO

Apocynin is a naturally occurring methoxy-substituted catechol, experimentally used as an inhibitor of NADPH-oxidase. In the present study, we investigated the protective effects of apocynin on antimycin A (AMA)-induced toxicicy in osteoblastic MC3T3-E1 cells. Exposure of MC3T3-E1 cells to AMA caused significant cell viability loss, as well as mitochondrial membrane potential (MMP) dissipation, complex IV inactivation, ATP loss, intracellular calcium ([Ca2+]i) elevation and oxidative stress. Pretreatment with apocynin prior to AMA exposure significantly reduced AMA-induced cell damage by preventing MMP dissipation, complex IV inactivation, ATP loss, [Ca2+]i elevation and oxidative stress. These results suggest that apocynin has a protective effect against AMA-induced cell damage by its antioxidant effects and the attenuation of mitochondrial dysfunction. Apocynin also induced the activation of PI3K (phosphoinositide 3-kinase), Akt (protein kinase B) and CREB (cAMP-response element-binding protein) inhibited by AMA. All these data indicate that apocynin may reduce or prevent osteoblasts degeneration in osteoporosis or other degenerative disorders.


Assuntos
Acetofenonas/farmacologia , Antibacterianos/toxicidade , Antimicina A/toxicidade , Antioxidantes/farmacologia , Citoproteção/efeitos dos fármacos , Osteoblastos/efeitos dos fármacos , Células 3T3 , Trifosfato de Adenosina/metabolismo , Animais , Cálcio/metabolismo , Cardiolipinas/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/biossíntese , Antagonismo de Drogas , Complexo IV da Cadeia de Transporte de Elétrons/efeitos dos fármacos , Ativação Enzimática , Peroxidação de Lipídeos/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Osteoblastos/patologia , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/biossíntese , Proteínas Proto-Oncogênicas c-akt/biossíntese
14.
Toxicol Appl Pharmacol ; 256(3): 241-8, 2011 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-21513725

RESUMO

Arsenicosis, due to contaminated drinking water, is a serious health hazard in terms of morbidity and mortality. Arsenic induced free radicals generated are known to cause cellular apoptosis through mitochondrial driven pathway. In the present study, we investigated the effect of arsenic interactions with various complexes of the electron transport chain and attempted to evaluate if there was any complex preference of arsenic that could trigger apoptosis. We also evaluated if chelation with monoisoamyl dimercaptosuccinic acid (MiADMSA) could reverse these detrimental effects. Our results indicate that arsenic exposure induced free radical generation in rat neuronal cells, which diminished mitochondrial potential and enzyme activities of all the complexes of the electron transport chain. Moreover, these complexes showed differential responses towards arsenic. These early events along with diminished ATP levels could be co-related with the later events of cytosolic migration of cytochrome c, altered bax/bcl(2) ratio, and increased caspase 3 activity. Although MiADMSA could reverse most of these arsenic-induced altered variables to various extents, DNA damage remained unaffected. Our study for the first time demonstrates the differential effect of arsenic on the complexes leading to deficits in bioenergetics leading to apoptosis in rat brain. However, more in depth studies are warranted for better understanding of arsenic interactions with the mitochondria.


Assuntos
Apoptose/efeitos dos fármacos , Intoxicação por Arsênico/tratamento farmacológico , Quelantes/farmacologia , Metabolismo Energético/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Succímero/análogos & derivados , Animais , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Células Cultivadas , Transporte de Elétrons/efeitos dos fármacos , Complexo IV da Cadeia de Transporte de Elétrons/efeitos dos fármacos , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , NADH Desidrogenase/efeitos dos fármacos , NADH Desidrogenase/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/análise , Succímero/farmacologia , Succinato Desidrogenase/efeitos dos fármacos , Succinato Desidrogenase/metabolismo
15.
J Nat Prod ; 74(5): 949-55, 2011 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-21510636

RESUMO

Eucomic acid [(2R)-2-(p-hydroxybenzyl)malic acid)] (1) and three new glucopyranosyloxybenzyl eucomate derivatives, vandaterosides I (2), II (3), and III (4), were isolated and identified from the stems of Vanda teres. Their cellular antiaging properties were evaluated in a human immortalized keratinocyte cell line (HaCaT) by monitoring their effect on cytochrome c oxidase activity, implicated in mitochondrial respiratory function and cellular energy production. Eucomic acid (1) and vandateroside II (3) increased cytochrome c oxidase activity and/or expression, without enhancing cellular mitochondrial content. These two V. teres biomarkers apparently contributed to stimulate respiratory functions in keratinocytes. Since aging and its pathologies may be ascribed to a decline in mitochondrial functions, these biomarkers have the potential to become new natural ingredients for antiaging preparations to remedy age-related disorders such as skin aging.


Assuntos
Complexo IV da Cadeia de Transporte de Elétrons/efeitos dos fármacos , Glucosídeos/isolamento & purificação , Glucosídeos/farmacologia , Glucosídeos Iridoides/isolamento & purificação , Glucosídeos Iridoides/farmacologia , Malatos/isolamento & purificação , Malatos/farmacologia , Orchidaceae/química , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Glucosídeos/química , Humanos , Glucosídeos Iridoides/química , Queratinócitos/efeitos dos fármacos , Malatos/química , Mitocôndrias/metabolismo , Estrutura Molecular , Caules de Planta/química , Tailândia
16.
Behav Brain Res ; 403: 113164, 2021 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-33549685

RESUMO

Mitochondrial dysfunction plays a central role in hepatic encephalopathy (HE), due to changes in enzyme cytochrome c-oxidase (CCO), causing a decline in brain metabolism. We used an HE animal model and applied intracranial administration of methylene blue (MB) and transcranial photobiomodulation (PBM), both targeting CCO, to determine their differential effects on recovering cognition. Five groups of rats were used: sham-operated group + saline (SHAM + SAL, n = 6), hepatic encephalopathy + SAL (HE + SAL, n = 7), SHAM + methylene blue (SHAM + MB, n = 7), HE + MB (n = 7), HE + PBM (n = 7). PBM animals were exposed transcranially to 670 +/- 10 nm LED light at a dose of 9 J/cm2 once a day for 7 days, and the MB and SAL groups were injected with 2.2 µg/0.5 µL in the accumbens. Cognitive dysfunction was evaluated on a striatal stimulus-response task using the Morris water maze. Our results showed cognitive improvement in the HE group when treated with MB. This improvement was accompanied by a decrease in CCO activity in the prefrontal cortex, dorsal striatum, and dorsal hippocampus. When comparing MB and PBM, we found that, although both treatments effectively improved the HE-memory deficit, there was a differential effect on CCO. A general decrease in CCO activity was found in the prefrontal and entorhinal cortices, dorsal striatum, and hippocampus when PBM, compared to MB, was applied. Our results suggest that mitochondrial dysfunction and brain metabolic decline in HE might involve CCO alteration and can be improved by administering MB and PBM.


Assuntos
Disfunção Cognitiva/terapia , Complexo IV da Cadeia de Transporte de Elétrons , Inibidores Enzimáticos/farmacologia , Encefalopatia Hepática , Hipocampo , Terapia com Luz de Baixa Intensidade , Azul de Metileno/farmacologia , Neostriado , Córtex Pré-Frontal , Animais , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Modelos Animais de Doenças , Complexo IV da Cadeia de Transporte de Elétrons/efeitos dos fármacos , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Inibidores Enzimáticos/administração & dosagem , Encefalopatia Hepática/complicações , Encefalopatia Hepática/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Azul de Metileno/administração & dosagem , Neostriado/efeitos dos fármacos , Neostriado/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Ratos Wistar
17.
Glia ; 58(15): 1827-37, 2010 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-20665559

RESUMO

Oligodendrocyte lineage cells are susceptible to a variety of insults including hypoxia, excitotoxicity, and reactive oxygen species. Demyelination is a well-recognized feature of several CNS disorders including multiple sclerosis, white matter strokes, progressive multifocal leukoencephalopathy, and disorders due to mitochondrial DNA mutations. Although mitochondria have been implicated in the demise of oligodendrocyte lineage cells, the consequences of mitochondrial respiratory chain defects have not been examined. We determine the in vitro impact of established inhibitors of mitochondrial respiratory chain complex IV or cytochrome c oxidase on oligodendrocyte progenitor cells (OPCs) and mature oligodendrocytes as well as on differentiation capacity of OPCs from P0 rat. Injury to mature oligodendrocytes following complex IV inhibition was significantly greater than to OPCs, judged by cell detachment and mitochondrial membrane potential (MMP) changes, although viability of cells that remained attached was not compromised. Active mitochondria were abundant in processes of differentiated oligodendrocytes and MMP was significantly greater in differentiated oligodendrocytes than OPCs. MMP dissipated following complex IV inhibition in oligodendrocytes. Furthermore, complex IV inhibition impaired process formation within oligodendrocyte lineage cells. Injury to and impaired process formation of oligodendrocytes following complex IV inhibition has potentially important implications for the pathogenesis and repair of CNS myelin disorders.


Assuntos
Diferenciação Celular/fisiologia , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Mitocôndrias/metabolismo , Oligodendroglia/fisiologia , Oligodendroglia/ultraestrutura , Animais , Animais Recém-Nascidos , Fator de Indução de Apoptose/metabolismo , Encéfalo/citologia , Caspase 9/metabolismo , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Complexo IV da Cadeia de Transporte de Elétrons/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Marcação In Situ das Extremidades Cortadas/métodos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Potencial da Membrana Mitocondrial/fisiologia , Mitocôndrias/efeitos dos fármacos , Neuroglia/efeitos dos fármacos , Neuroglia/fisiologia , Oligodendroglia/efeitos dos fármacos , Ratos , Espécies Reativas de Oxigênio/metabolismo , Azida Sódica/farmacologia , Espectrofotometria/métodos , Células-Tronco/efeitos dos fármacos , Células-Tronco/fisiologia , Fatores de Tempo
18.
Metab Brain Dis ; 25(2): 169-76, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20505986

RESUMO

Since chronic stress has been used widely for studying clinical depression and that brain energy metabolism and oxidative stress might be involved in the pathophysiology of this illness, the objective of this study was investigate the activities of pyruvate kinase, complex II and IV (cytocrome c oxidase) in hippocampus and prefrontal cortex of rats submitted to chronic variable stress. We also evaluated if vitamins E and C administration could prevent such effects. During 40 days adult rats from the stressed group were subjected to one stressor per day, at a different time each day, in order to minimize predictability. The stressed group had gained less weight while its immobilization time in the forced swimming test was greater than that of the control group. Results showed that stressed group presented an inhibition in the activities of complex II and cytochrome c oxidase in prefrontal cortex, while in hippocampus just complex IV was inhibited. Pyruvate kinase activity was not altered in stressed group when compared to control. Vitamins E and C administration prevented the alterations on respiratory chain caused by stress. These data suggest that the impairment of energy metabolism and oxidative stress could be related with the pathogenic pathways in stress related disorders.


Assuntos
Antioxidantes/uso terapêutico , Encefalopatias Metabólicas/tratamento farmacológico , Metabolismo Energético/efeitos dos fármacos , Hipocampo/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Estresse Psicológico/metabolismo , Estresse Psicológico/prevenção & controle , Animais , Antioxidantes/farmacologia , Ácido Ascórbico/farmacologia , Ácido Ascórbico/uso terapêutico , Encefalopatias Metabólicas/etiologia , Doença Crônica , Modelos Animais de Doenças , Transporte de Elétrons/efeitos dos fármacos , Transporte de Elétrons/fisiologia , Complexo IV da Cadeia de Transporte de Elétrons/efeitos dos fármacos , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Metabolismo Energético/fisiologia , Hipocampo/efeitos dos fármacos , Hipocampo/enzimologia , Estresse Oxidativo/fisiologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/enzimologia , Piruvato Quinase/metabolismo , Ratos , Ratos Wistar , Estresse Psicológico/complicações , Vitamina E/farmacologia , Vitamina E/uso terapêutico
19.
Mitochondrion ; 50: 58-62, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31678601

RESUMO

BACKGROUND: Cuprizone administration in mice leads to oligodendrocyte death and demyelination. The effect is thought to reflect copper-chelation that leads to inhibition of complex IV of the mitochondrial respiratory chain. The effects this drug has on neurons are less well known. OBJECTIVE: To investigate the toxic effects of cuprizone on mitochondria in neurons. METHODS: Male c57Bl/6 mice were fed 0.2% cuprizone for up to 5 weeks. Cuprizone-fed and control mice were examined at week 1, 3, 5 and 4 weeks after cessation of cuprizone exposure. The brain was examined for myelin, complex I, complex IV and for COX/SDH activities. Mitochondrial-DNA was investigated for deletions and copy number variation. RESULTS: We found decreased levels of complex IV in the cerebellar Purkinje neurons of mice exposed to cuprizone. This decrease was not related to a general decrease in mitochondrial volume or mass, as there were no differences in the levels of complex I or TOMM20. CONCLUSION: Neurons are affected by cuprizone-treatment. Whether this mitochondrial dysfunction acts as a subclinical trigger for demyelination and the long-term axonal degeneration that proceeds after cuprizone treatment stops remains unclear.


Assuntos
Cuprizona/toxicidade , Complexo IV da Cadeia de Transporte de Elétrons/efeitos dos fármacos , Células de Purkinje/efeitos dos fármacos , Animais , Quelantes/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células de Purkinje/patologia
20.
Neurotox Res ; 38(2): 478-486, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32415526

RESUMO

In the last years, clinical and preclinical researchers have increased their interest in non-psychotomimetic cannabinoids, like cannabidiol (CBD), as a strategy for treating psychostimulant use disorders. However, there are discrepancies in the pharmacological effects and brain targets of CBD. We evaluated if CBD was able to prevent the locomotor sensitization elicited by cocaine and caffeine co-administration. The effect of CBD on putative alterations in the metabolic activity of the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc), and its respective subregions (cingulated, prelimbic, and infralimbic cortices, and NAc core and shell) associated to the behavioral response, was also investigated. Rats were intraperitoneally and repeatedly treated with CBD (20 mg/kg) or its vehicle, followed by the combination of cocaine and caffeine (Coc+Caf; 5 mg/kg and 2.5 mg/kg, respectively) or saline for 3 days. After 5 days of withdrawal, all animals were challenged with Coc+Caf (day 9). Locomotor activity was automatically recorded and analyzed by a video-tracking software. The metabolic activity was determined by measuring cytochrome oxidase-I (CO-I) staining. Locomotion was significantly and similarly increased both in Veh-Coc+Caf- and CBD-Coc+Caf-treated animals during the pretreatment period (3 days); however, on day 9, the expression of the sensitization was blunted in CBD-treated animals. A hypoactive metabolic response and a hyperactive metabolic response in mPFC and NAc subregions respectively were observed after the behavioral sensitization. CBD prevented almost all these changes. Our findings substantially contribute to the understanding of the functional changes associated with cocaine- and caffeine-induced sensitization and the effect of CBD on this process.


Assuntos
Comportamento Animal/efeitos dos fármacos , Cafeína/toxicidade , Canabidiol/farmacologia , Estimulantes do Sistema Nervoso Central/toxicidade , Cocaína/toxicidade , Locomoção/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Animais , Complexo IV da Cadeia de Transporte de Elétrons/efeitos dos fármacos , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Núcleo Accumbens/metabolismo , Córtex Pré-Frontal/metabolismo , Ratos
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