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1.
Transl Psychiatry ; 14(1): 286, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-39009600

RESUMO

There is much interest in targeting the activity in the oxytocin system to regulate social bonding. However, studies with exogenous administration of oxytocin face the caveats of its low stability, poor brain permeability and insufficient receptor specificity. The use of a small-molecule oxytocin receptor-specific agonist could overcome these caveats. Prior to testing the potential effects of a brain-penetrant oxytocin receptor agonist in clinical settings, it is important to assess how such an agonist would affect social bonds in animal models. The facultatively monogamous prairie voles (Microtus ochrogaster), capable of forming long-term social attachments between adult individuals, are an ideal rodent model for such testing. Therefore, in a series of experiments we investigated the effects of the recently developed oxytocin receptor-specific agonist LIT-001 on the acquisition and expression of partner preference, a well-established model of pair bonding, in prairie voles. LIT-001 (10 mg/kg, intraperitoneal), as expected, facilitated the acquisition of partner preference when administered prior to a 4hr cohabitation. In contrast, while animals injected with vehicle after the 4hr cohabitation exhibited significant partner preference, animals that were injected with LIT-001 did not show such partner preference. This result suggests that OXTR activation during expression of pair bonding can inhibit partner preference. The difference in effects of LIT-001 on acquisition versus expression was not due to basal differences in partner preference between the experiments, as LIT-001 had no significant effects on expression of partner preference if administered following a shorter (2hr-long) cohabitation. Instead, this difference agrees with the hypothesis that the activation of oxytocin receptors acts as a signal of presence of a social partner. Our results indicate that the effects of pharmacological activation of oxytocin receptors crucially depend on the phase of social attachments.


Assuntos
Arvicolinae , Ligação do Par , Receptores de Ocitocina , Animais , Receptores de Ocitocina/agonistas , Masculino , Comportamento Social , Ocitocina/farmacologia , Feminino
2.
Res Sq ; 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38798348

RESUMO

There is much interest in targeting the activity in the oxytocin system to regulate social bonding. However, studies with exogenous administration of oxytocin face the caveats of its low stability, poor brain permeability and insufficient receptor specificity. The use of a small-molecule oxytocin receptor-specific agonist could overcome these caveats. Prior to testing the potential effects of a brain-penetrant oxytocin receptor agonist in clinical settings, it is important to assess how such an agonist would affect social bonds in animal models. The facultatively monogamous prairie voles (Microtus ochrogaster), capable of forming long-term social attachments between adult individuals, are an ideal rodent model for such testing. Therefore, in a series of experiments we investigated the effects of the recently developed oxytocin receptor-specific agonist LIT-001 on the acquisition and expression of partner preference, a well-established model of pair bonding, in prairie voles. LIT-001 (10 mg/kg, intraperitoneal), as expected, facilitated the acquisition of partner preference when administered prior to a 4-hour cohabitation. In contrast, while animals injected with vehicle after the 4-hour cohabitation exhibited significant partner preference, animals that were injected with LIT-001 did not show such partner preference. This result suggests that OXTR activation during expression of pair bonding can inhibit partner preference. The difference in effects of LIT-001 on acquisition versus expression was not due to basal differences in partner preference between the experiments, as LIT-001 had no significant effects on expression of partner preference if administered following a shorter (2 hour-long) cohabitation. Instead, this difference agrees with the hypothesis that the activation of oxytocin receptors acts as a signal of presence of a social partner. Our results indicate that the effects of pharmacological activation of oxytocin receptors crucially depend on the phase of social attachments.

3.
Front Behav Neurosci ; 18: 1380031, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38817806

RESUMO

Background: Excessive alcohol consumption leads to serious health problems. Mechanisms regulating the consumption of alcohol are insufficiently understood. Previous preclinical studies suggested that non-social environmental and social environmental complexities can regulate alcohol consumption in opposite directions. However, previous studies did not include all conditions and/or did not include female rodents. Therefore, in this study, we examined the effects of social versus single housing in standard versus non-standard housing conditions in male and female mice. Methods: Adult C57BL/6 J mice were housed in either standard shoebox cages or in automated Herdsman 2 (HM2) cages and exposed to a two-bottle choice procedure with 3% or 6% ethanol versus water for 5 days. The HM2 cages use radiotracking devices to measure the fluid consumption of individual mice in an undisturbed and automated manner. In both housing conditions, mice were housed either at one or at four per cage. Results: In standard cages, group housing of animals decreased alcohol consumption and water consumption. In HM2 cages, group housing significantly increased ethanol preference and decreased water intake. There were no significant differences in these effects between male and female animals. These observations were similar for 3 and 6% ethanol solutions but were more pronounced for the latter. The effects of social environment on ethanol preference in HM2 cages were accompanied by an increase in the number of approaches to the ethanol solution and a decrease in the number of approaches to water. The differences in ethanol intake could not be explained by differences in locomotor or exploratory activity as socially housed mice showed fewer non-consummatory visits to the ethanol solutions than single-housed animals. In addition, we observed that significant changes in behaviors measuring the approach to the fluid were not always accompanied by significant changes in fluid consumption, and vice versa, suggesting that it is important to assess both measures of motivation to consume alcohol. Conclusion: Our results indicate that the direction of the effects of social environment on alcohol intake in mice depends on the non-social housing environment. Understanding mechanisms by which social and non-social housing conditions modulate alcohol intake could suggest approaches to counteract environmental factors enhancing hazardous alcohol consumption.

4.
Eur J Pain ; 28(4): 578-598, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37985943

RESUMO

BACKGROUND: Social interactions with subjects experiencing pain can increase nociceptive sensitivity in observers, even without direct physical contact. In previous experiments, extended indirect exposure to soiled bedding from mice with alcohol withdrawal-related hyperalgesia enhanced nociception in their conspecifics. This finding suggested that olfactory cues could be sufficient for nociceptive hypersensitivity in otherwise untreated animals (also known as "bystanders"). AIM: The current study addressed this possibility using an inflammation-based hyperalgesia model and long- and short-term exposure paradigms in C57BL/6J mice. MATERIALS & METHOD: Adult male and female mice received intraplantar injection of complete Freund's adjuvant (CFA) and were used as stimulus animals to otherwise naïve same-sex bystander mice (BS). Another group of untreated mice (OLF) was simultaneously exposed to the bedding of the stimulus mice. RESULTS: In the long-term, 15-day exposure paradigm, the presence of CFA mice or their bedding resulted in reduced von Frey threshold but not Hargreaves paw withdrawal latency in BS or OLF mice. In the short-term paradigm, 1-hr interaction with CFA conspecifics or 1-hr exposure to their bedding induced mechanical hypersensitivity in BS and OLF mice lasting for 3 hrs. Chemical ablation of the main olfactory epithelium prevented bedding-induced and stimulus mice-induced mechanical hypersensitivity. Gas chromatography-mass spectrometry (GC-MS) analysis of the volatile compounds in the bedding of experimental mice revealed that CFA-treated mice released an increased number of compounds indicative of disease states. DISCUSSION AND CONCLUSION: These results demonstrate that CFA-induced inflammatory pain can modulate nociception in bystander mice via an olfactory mechanism involving dynamic changes in volatile compounds detectable in the rodent bedding. SIGNIFICANCE: Social context can influence nociceptive sensitivity. Recent studies suggested involvement of olfaction in this influence. In agreement with this idea, the present study shows that the presence of mice with inflammatory pain produces nociceptive hypersensitivity in nearby conspecifics. This enhanced nociception occurs via olfactory cues present in the mouse bedding. Analysis of the bedding from mice with inflammatory pain identifies a number of compounds indicative of disease states. These findings demonstrate the importance of olfactory system in influencing pain states.


Assuntos
Alcoolismo , Síndrome de Abstinência a Substâncias , Humanos , Camundongos , Masculino , Feminino , Animais , Hiperalgesia/induzido quimicamente , Adjuvante de Freund/efeitos adversos , Olfato , Camundongos Endogâmicos C57BL , Dor , Inflamação/induzido quimicamente
5.
Horm Behav ; 157: 105452, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37977023

RESUMO

Social hierarchies are a prevalent feature of all animal groups, and an individual's rank within the group can significantly affect their overall health, typically at the greatest expense of the lowest-ranked individuals, or omegas. These subjects have been shown to exhibit various stress-related phenotypes, such as increased hypothalamic-pituitary axis activity and increased amygdalar corticotropin-releasing factor levels compared to higher-ranked subjects. However, these findings have been primarily characterized in males and in models requiring exhibition of severe aggression. The goals of the current study, therefore, were to characterize the formation and maintenance of social hierarchies using the tube test and palatable liquid competition in same-sex groups of male and female C57BL/6 J mice. We also aimed to examine the effects of tube test-determined social rank on plasma and hypothalamic oxytocin and vasopressin levels, peptides with established roles in social behaviors and the stress response. Lastly, we assessed the effects of environmental enrichment and length of testing on the measures outlined above. Overall, we demonstrated that males and females develop social hierarchies and that these hierarchies can be determined using the tube test. While we were unable to establish a consistent connection between peptide levels and social rank, we observed transient changes in these peptides reflecting complex interactions between social rank, sex, environment, and length of testing. We also found that many male and female omegas began to exhibit passive coping behavior after repeated tube test losses, demonstrating the potential of this assay to serve as a model of chronic, mild psychosocial stress.


Assuntos
Hierarquia Social , Comportamento Social , Humanos , Animais , Camundongos , Masculino , Feminino , Camundongos Endogâmicos C57BL , Agressão/fisiologia , Hipotálamo
6.
Neuropsychopharmacology ; 48(6): 920-928, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36369481

RESUMO

Targeting the oxytocin (OXT) peptide system has emerged as a promising new approach for the treatment of alcohol use disorder (AUD). However, further advancements in this development depend on properly modeling various complex social aspects of AUD and its treatment. Here we examined behavioral and molecular underpinnings of OXT receptor (OXTR) agonism in prairie voles, a rodent species with demonstrated translational validity for neurobiological mechanisms regulating social affiliations. To further improve translational validity of these studies, we examined effects of intranasal (IN) OXT administration in male and female prairie voles socially housed in the presence of untreated cagemates. IN OXT selectively inhibited alcohol drinking in male, but not female, animals. Further, we confirmed that exogenously administered OXT penetrates the prairie vole brain and showed that Receptor for Advanced Glycation End-products assists this penetration after IN, but not intraperitoneal (IP), OXT administration. Finally, we demonstrated that IP administration of LIT-001, a small-molecule OXTR agonist, inhibits alcohol intake in male, but not female, prairie voles socially housed in the presence of untreated cagemates. Taken together, results of this study support the promise of selectively targeting OXTR for individualized treatment of AUD.


Assuntos
Alcoolismo , Ocitocina , Animais , Masculino , Ocitocina/farmacologia , Pradaria , Receptor para Produtos Finais de Glicação Avançada , Consumo de Bebidas Alcoólicas/tratamento farmacológico , Receptores de Ocitocina , Arvicolinae , Comportamento Social
7.
Front Psychiatry ; 13: 842609, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35295777

RESUMO

Development of better treatments for alcohol use disorder (AUD) is urgently needed. One promising opportunity for this development is the potential of targeting the oxytocin peptide system. Preclinical studies showed that administration of exogenous oxytocin or, more recently, stimulation of neurons expressing endogenous oxytocin lead to a decreased alcohol consumption across several rodent models. Initial clinical studies also showed that administration of oxytocin decreased craving for alcohol and heavy alcohol drinking. However, several more recent clinical studies were not able to replicate these effects. Thus, although targeting the oxytocin system holds promise for the treatment of AUD, more nuanced approaches toward development and application of these treatments are needed. In this mini-review we discuss potential caveats resulting in differential success of attempts to use oxytocin for modulating alcohol use disorder-related behaviors in clinical studies and evaluate three directions in which targeting the oxytocin system could be improved: (1) increasing potency of exogenously administered oxytocin, (2) developing oxytocin receptor agonists, and (3) stimulating components of the endogenous oxytocin system. Both advances and potential pitfalls of these directions are discussed.

8.
Brain Res ; 1711: 41-47, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30629945

RESUMO

Research has demonstrated that hyperbaric oxygen (HBO2) treatment produced relief of both acute and chronic pain in patients and animal models. However, the mechanism of HBO2 antinociceptive effect is still elusive. Based on our earlier findings that implicate NO in the acute antinociceptive effect of HBO2, the purpose of this study was to ascertain whether HBO2-induced antinociception in a chronic neuropathic pain model is likewise dependent on NO. Neuropathic pain was induced in male Sprague Dawley rats by four injections of paclitaxel (1.0 mg/kg, i.p.). Twenty-four hours after the last paclitaxel injection, rats were treated for one day or four consecutive days with 60-min HBO2 at 3.5 atmospheres absolute (ATA). Two days before HBO2 treatment, some groups of rats were implanted with Alzet® osmotic minipumps that continuously infused a selective inhibitor of neuronal NO synthase (nNOS) into the lateral cerebral ventricle for 7 days. Mechanical and cold allodynia were assessed every other day, using electronic von Frey and acetone assays, respectively. Rats in the paclitaxel control group exhibited a mechanical or cold allodynia that was significantly reversed by one HBO2 treatment for mechanical allodynia and four HBO2 treatments for cold allodynic. In rats treated with the nNOS inhibitor, the effects of HBO2 were nullified in the mechanical allodynia test but unaffected in the cold allodynia test. In summary, these results demonstrate that the antiallodynic effect of HBO2 in two different pain tests is dependent on NO in the CNS.


Assuntos
Hiperalgesia/prevenção & controle , Oxigenoterapia Hiperbárica/métodos , Óxido Nítrico Sintase/metabolismo , Animais , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Hiperalgesia/induzido quimicamente , Masculino , Neuralgia/terapia , Oxigênio/farmacologia , Paclitaxel/farmacologia , Medição da Dor , Limiar da Dor/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
9.
Brain Res ; 1698: 170-178, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30081038

RESUMO

The present study examined the co-expression of neuronal nitric oxide synthase (nNOS) in the rostral ventromedial medulla (RVM) and A5 regions of the mouse brainstem within several neurochemical populations involved in nociceptive modulation. Double immunohistochemical methods showed that nNOS+ neurons do not co-localize with serotonergic neurons within any of these regions. Within the RVM, the nuclei raphe magnus and gigantocellularis contain a population of nNOS+/GAD67+ neurons, and within the paragigantocellularis lateralis, there is a smaller population of nNOS+/CHAT+ neurons. Further, nNOS+ neurons overlap the region of expression of ß-endorphinergic and met-enkephalinergic fibers within the RVM. No co-labeling was found within the A5 for any of these populations. These findings suggest that pain-modulatory serotonergic neurons within the brainstem do not directly produce nitric oxide (NO). Rather, NO-producing neurons within the RVM belong to GABAergic and cholinergic cell populations, and are in a position to modulate or be modulated by local opioidergic neurons.


Assuntos
Tronco Encefálico/metabolismo , Neurônios Colinérgicos/metabolismo , Neurônios GABAérgicos/metabolismo , Núcleos da Rafe do Mesencéfalo/metabolismo , Óxido Nítrico Sintase Tipo I/metabolismo , beta-Endorfina/metabolismo , Animais , Tronco Encefálico/citologia , Neurônios Colinérgicos/citologia , Encefalinas/metabolismo , Neurônios GABAérgicos/citologia , Masculino , Bulbo/metabolismo , Camundongos , Núcleos da Rafe do Mesencéfalo/citologia , Dor/metabolismo , Córtex Pré-Frontal/metabolismo , Receptores Opioides/metabolismo , Neurônios Serotoninérgicos/metabolismo , Serotonina/metabolismo
10.
eNeuro ; 4(3)2017.
Artigo em Inglês | MEDLINE | ID: mdl-28660248

RESUMO

The parabrachial complex (PB) is a functionally and anatomically complex structure involved in a range of homeostatic and sensory functions, including nociceptive transmission. There is also evidence that PB can engage descending pain-modulating systems, the best characterized of which is the rostral ventromedial medulla (RVM). Two distinct classes of RVM neurons, "ON-cells" and "OFF-cells," exert net pronociceptive and anti-nociceptive effects, respectively. PB was recently shown to be a relay of nociceptive information to RVM ON- and OFF-cells. The present experiments used optogenetic methods in a lightly anesthetized rat and an adult RVM slice to determine whether there are direct, functionally relevant inputs to RVM pain-modulating neurons from PB. Whole-cell patch-clamp recordings demonstrated that PB conveys direct glutamatergic and GABAergic inputs to RVM neurons. Consistent with this, in vivo recording showed that nociceptive-evoked responses of ON- and OFF-cells were suppressed by optogenetic inactivation of archaerhodopsin (ArchT)-expressing PB terminals in RVM, demonstrating that a net inhibitory input to OFF-cells and net excitatory input to ON-cells are engaged by acute noxious stimulation. Further, the majority of ON- and OFF-cells responded to optogenetic activation of channelrhodopsin (ChR2)-expressing terminals in the RVM, confirming a direct PB influence on RVM pain-modulating neurons. These data show that a direct connection from the PB to the RVM conveys nociceptive information to the pain-modulating neurons of RVM under basal conditions. They also reveal additional inputs from PB with the capacity to activate both classes of RVM pain-modulating neurons and the potential to be recruited under different physiological and pathophysiological conditions.


Assuntos
Bulbo/fisiopatologia , Neurônios/fisiologia , Dor Nociceptiva/fisiopatologia , Percepção da Dor/fisiologia , Núcleos Parabraquiais/fisiopatologia , Potenciais de Ação , Animais , Ácido Glutâmico/metabolismo , Masculino , Bulbo/patologia , Vias Neurais/patologia , Vias Neurais/fisiopatologia , Neurônios/patologia , Dor Nociceptiva/patologia , Optogenética , Núcleos Parabraquiais/patologia , Técnicas de Patch-Clamp , Ratos Sprague-Dawley , Técnicas de Cultura de Tecidos , Ácido gama-Aminobutírico/metabolismo
11.
Brain Res ; 1648(Pt A): 434-437, 2016 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-27534375

RESUMO

Hyperbaric oxygen (HBO2) therapy reportedly reduces opiate withdrawal in human subjects. The purpose of this research was to determine whether HBO2 treatment could suppress physical signs of withdrawal in opiate-dependent mice. Male NIH Swiss mice were injected s.c. with morphine sulfate twice a day for 4 days, the daily dose gradually increasing from 50mg/kg on day 1 to 125mg/kg on day 4. On day 5, withdrawal was precipitated by i.p. injection of 5.0mg/kg naloxone. Mice were observed for physical withdrawal signs, including jumping, forepaw tremor, wet-dog shakes, rearing and defecation for 30min. Sixty min prior to the naloxone injection, different groups of mice received either a 30-min or 60-min HBO2 treatment at 3.5atm absolute. HBO2 treatment significantly reduced naloxone-precipitated jumping, forepaw tremor, wet-dog shakes, rearing and defecation. Based on these experimental findings, we concluded that treatment with HBO2 can suppress physical signs of withdrawal syndrome in morphine-dependent mice.


Assuntos
Comportamento Animal/efeitos dos fármacos , Oxigenoterapia Hiperbárica , Morfina/administração & dosagem , Entorpecentes/administração & dosagem , Síndrome de Abstinência a Substâncias/prevenção & controle , Animais , Masculino , Camundongos , Naloxona/administração & dosagem
12.
Brain Res ; 1540: 42-7, 2013 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-24113418

RESUMO

Earlier research has demonstrated that treatment with hyperbaric oxygen (HBO2) can elicit an antinociceptive response in models of acute pain. We have demonstrated that this antinociceptive effect is centrally-mediated and is dependent on opioid receptors. The purpose of the present study was to examine the role of endogenous opioid peptides and opioid receptors specifically in the spinal cord in the acute antinociceptive effect of HBO2 in mice. Male NIH Swiss mice were exposed to HBO2 (100% oxygen at 3.5atm absolute) for 11min and their antinociceptive responsiveness was determined using the glacial acetic acid-induced abdominal constriction test. HBO2-induced antinociception was sensitive to antagonism by intrathecal (i.t.) pretreatment with the κ- and µ-selective opioid antagonists norbinaltorphimine and ß-funaltrexamine, respectively, but not the δ-selective antagonist naltrindole. The antinociceptive effect of HBO2 was also significantly attenuated by i.t. pretreatment with a rabbit antiserum against rat dynorphin1-13 but not antisera against ß-endorphin or methionine-enkephalin. Based on these experimental findings, the acute antinociceptive effect of HBO2 appears to involve neuronal release of dynorphin and activation of κ- and µ-opioid receptors in the spinal cord.


Assuntos
Analgesia , Oxigenoterapia Hiperbárica , Medula Espinal/metabolismo , Ácido Acético/toxicidade , Animais , Dinorfinas/metabolismo , Encefalina Metionina/metabolismo , Injeções Espinhais , Masculino , Camundongos , Naltrexona/análogos & derivados , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Medula Espinal/efeitos dos fármacos , beta-Endorfina/metabolismo
13.
Brain Res ; 1537: 111-6, 2013 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-23998986

RESUMO

Earlier research has demonstrated that hyperbaric oxygen (HBO2) can produce an antinociceptive effect in models of acute pain. Recent studies have revealed that HBO2 can produce pain relief in animal models of chronic pain as well. The purpose of the present investigation was to ascertain whether HBO2 treatment might suppress allodynia in rats with neuropathic pain and whether this effect might be blocked by the opioid antagonist naltrexone (NTX). Male Sprague Dawley rats were subjected to a sciatic nerve crush under anesthesia and mechanical thresholds were assessed using an electronic von Frey anesthesiometer. The time course of the HBO2-induced anti-allodynic effect in different treatment groups was plotted, and the area-under-the-curve (AUC) was determined for each group. Seven days after the nerve crush procedure, rats were treated with HBO2 at 3.5 atm absolute (ATA) for 60 min and exhibited an anti-allodynic effect, compared to nerve crush-only control rats. Twenty-four hours before HBO2 treatment, another group of rats was implanted with Alzet(®) osmotic minipumps that continuously released NTX into the lateral cerebral ventricle for 7 days. These NTX-infused, HBO2-treated rats exhibited an allodynic response comparable to that exhibited by rats receiving nerve crush only. Analysis of the AUC data showed that HBO2 significantly reduced the nerve crush-induced allodynia; this anti-allodynic effect of HBO2 was reversed by NTX. These results implicate opioid receptors in the pain relief induced by HBO2.


Assuntos
Hiperalgesia/terapia , Oxigenoterapia Hiperbárica , Neuralgia/metabolismo , Receptores Opioides/metabolismo , Nervo Isquiático/fisiopatologia , Medula Espinal/fisiopatologia , Animais , Oxigenoterapia Hiperbárica/métodos , Masculino , Naltrexona/administração & dosagem , Naltrexona/uso terapêutico , Antagonistas de Entorpecentes/uso terapêutico , Neuralgia/tratamento farmacológico , Medição da Dor/métodos , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/lesões , Nervo Isquiático/ultraestrutura , Medula Espinal/efeitos dos fármacos
14.
Autophagy ; 9(7): 996-1008, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23580233

RESUMO

Failure to engage apoptosis appears to be a leading mechanism of resistance to traditional platinum drugs in patients with ovarian cancer. Therefore, an alternative strategy to induce cell death is needed for the chemotherapy of this apoptosis-resistant cancer. Here we report that autophagic cell death, distinct from cisplatin-induced apoptosis, is triggered by a novel monofunctional platinum (II) complex named Mono-Pt in human ovarian carcinoma cells. Mono-Pt-induced cell death has the following features: cytoplasmic vacuolation, caspase-independent, no nuclear fragmentation or chromatin condensation, and no apoptotic bodies. These characteristics integrally indicated that Mono-Pt, rather than cisplatin, initiated a nonapoptotic cell death in Caov-3 ovarian carcinoma cells. Furthermore, incubation of the cells with Mono-Pt but not with cisplatin produced an increasing punctate distribution of microtubule-associated protein 1 light chain 3 (LC3), and an increasing ratio of LC3-II to LC3-I. Mono-Pt also caused the formation of autophagic vacuoles as revealed by monodansylcadaverine staining and transmission electron microscopy. In addition, Mono-Pt-induced cell death was significantly inhibited by the knockdown of either BECN1 or ATG7 gene expression, or by autophagy inhibitors 3-methyladenine, chloroquine and bafilomycin A 1. Moreover, the effect of Mono-Pt involved the AKT1-MTOR-RPS6KB1 pathway and MAPK1 (ERK2)/MAPK3 (ERK1) signaling, since the MTOR inhibitor rapamycin increased, while the MAPK1/3 inhibitor U0126 decreased Mono-Pt-induced autophagic cell death. Taken together, our results suggest that Mono-Pt exerts anticancer effect via autophagic cell death in apoptosis-resistant ovarian cancer. These findings lead to increased options for anticancer platinum drugs to induce cell death in cancer.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Cisplatino/química , Neoplasias Ovarianas/patologia , Platina/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cisplatino/farmacologia , Dano ao DNA , Feminino , Humanos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neoplasias Ovarianas/ultraestrutura , Platina/química , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
15.
Biomed Chromatogr ; 27(5): 548-50, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23070926

RESUMO

The complete pharmacokinetic disposition of the chiral flavonoid (±) pinostrobin remains unknown without the development of an analytical method of detection and quantitation of its individual enantiomers. Resolution of the enantiomers of pinostrobin was achieved using as simple high-performance liquid chromatographic method. A Chiralpak(®) AD-RH column was employed to perform baseline separation with UV detection at 287 nm. The standard curves were linear ranging from 0.5 to 100 µg/mL for each enantiomer. The limit of quantification was 0.5 µg/mL. Precision and accuracy of the assay was < 15% (RSD) and was with a bias <15% for all points on the calibration curve. The assay was applied successfully to stereoselective serum disposition of pinostrobin enantiomers in rats. Both enantiomers had a serum half-life of ~7 h. They also shared similar values of volume of distribution (V(d) S-pinostrobin, 8.2 L/kg; V(d) R-pinostrobin, 8.9 L/kg), total clearance (S-pinostrobin CL(total), 0.959 L//h/kg; R-pinostrobin CL(total), 1.055 L//h/kg), and area under the curve (S-pinostrobin AUC(inf), 23.16 µg h/mL; R-pinostrobin AUC(inf), 21.296 µg h/mL). The large volume of distribution suggests extensive distribution of pinostrobin into tissues.


Assuntos
Flavanonas/sangue , Flavanonas/farmacocinética , Animais , Cromatografia Líquida de Alta Pressão , Flavanonas/química , Análise dos Mínimos Quadrados , Masculino , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Estereoisomerismo
16.
J Inorg Biochem ; 106(1): 46-51, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22112839

RESUMO

Palladium(II) complexes are potential antitumor metallodrugs for their chemical resemblance to platinum(II) complexes. Two palladium(II) complexes (1 and 2) in the formula of [PdL(n)Cl] [L(1) = N-(tert-butoxycarbonyl)-l-methionine-N'-8-quinolylamide, L(2) = L-alanine-N'-8-quinolylamide] have been synthesized accordingly. The structures of the complexes were fully characterized by X-ray crystallography. The palladium(II) center in 1 is coordinated by two N atoms and an S atom from L(1) with one chloride anion as the leaving group; while that in 2 is coordinated by three N atoms from L(2) with one chloride anion as the leaving group. The interaction between complex 1 and human serum albumin (HSA) has been investigated using fluorescence and circular dichroism spectroscopies. The complex seems to react with HSA chiefly through hydrophobic and electrostatic interactions, and it does not alter the α-helical nature of HSA. The cytotoxicity of these complexes has been tested against the human cervical cancer (HeLa), human mammary cancer (MCF-7), and human lung cancer (A-549) cell lines. Complex 1 displays a cytotoxic activity comparable to that of cisplatin, but complex 2 is less active than cisplatin.


Assuntos
Aminoquinolinas/química , Compostos Organoplatínicos/química , Paládio/química , Albumina Sérica/química , Algoritmos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dicroísmo Circular , Cristalografia por Raios X , Células HeLa , Humanos , Modelos Químicos , Estrutura Molecular , Compostos Organoplatínicos/farmacologia , Paládio/metabolismo , Paládio/farmacologia , Ligação Proteica , Albumina Sérica/metabolismo , Espectrometria de Fluorescência , Termodinâmica
17.
Apoptosis ; 16(3): 288-300, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21107699

RESUMO

Polynuclear platinum(II) complexes represent a class of potential anticancer agents that have shown promising pharmacological properties in preclinical studies. The nature of cellular responses induced by these complexes, however, is poorly understood. In this research, the cellular responses of human ovarian cancer COC1 cells to dinuclear platinum(II) complexes {[cis-Pt(NH3)2Cl]2L¹}(NO3)2 (1) and {[cis-Pt(NH3)2Cl]2L²}(NO3)2 (2) (L¹ = α,α'-diamino-p-xylene, L² = 4,4'-methylenedianiline) has been studied using cisplatin as a reference. The effect of platinum complexes on the proliferation, death mode, mitochondrial membrane potential, and cell cycle progression has been examined by MTT assay and flow cytometry. The activation of cell cycle checkpoint kinases (CHK1/2), extracellular signal-regulated kinases (ERK1/2), and p38 mitogen-activated protein kinase (p38 MAPK) of the cells by the complexes has also been analyzed using phospho-specific flow cytometry. Complex 1 is more cytotoxic than complex 2 and cisplatin at most concentrations; complex 2 and cisplatin are comparably cytotoxic. These complexes kill the cells through an apoptotic or apoptosis-like pathway characterized by exposure of phosphatidylserine and dissipation of mitochondrial membrane potential. Complex 1 shows the strongest inductive effect on the morphological changes of the cells, followed by cisplatin and complex 2. Complexes 1 and 2 arrest the cell cycle in G2 or M phase, while cisplatin arrests the cell cycle in S phase. The influence of these complexes on CHK1/2, ERK1/2, and p38 MAPK varies with the dose of the drugs or reaction time. Activation of phospho-ERK1/2 and phospho-p38 MAPK by these complexes is closely related to the cytostatic activity. The results demonstrate that dinuclear platinum(II) complexes can induce some cellular responses different from those caused by cisplatin.


Assuntos
Cisplatino/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Platina/uso terapêutico , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Forma Celular/efeitos dos fármacos , Tamanho Celular/efeitos dos fármacos , Quinase 1 do Ponto de Checagem , Quinase do Ponto de Checagem 2 , Cisplatino/química , Cisplatino/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Citometria de Fluxo , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Neoplasias Ovarianas/enzimologia , Fosforilação/efeitos dos fármacos , Platina/química , Platina/farmacologia , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
18.
Chemistry ; 16(47): 14181-9, 2010 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-20967899

RESUMO

DNA condensing agents play a critical role in gene therapy. A tetranuclear nickel(II) complex, [Ni(II)(4)(L-2H)(H(2)O)(6)(CH(3)CH(2)OH)(2)]·6NO(3) (L=3,3',5,5'-tetrakis{[(2-hydroxyethyl)(pyridin-2-ylmethyl)amino]methyl}biphenyl-4,4'-diol), has been synthesized as a nonviral vector to induce DNA condensation. X-ray crystallographic data indicate that the complex crystallizes in the monoclinic system with space group P2(1)/n, a=10.291(9), b=24.15(2), c=13.896(11) Å, and ß=98.175(13)°. The DNA condensation induced by the complex has been investigated by means of UV/Vis spectroscopy, fluorescence spectroscopy, circular dichroism spectroscopy, dynamic light scattering, atomic force microscopy, gel electrophoresis assay, and zeta potential analysis. The complex interacts strongly with DNA through electrostatic attraction and induces its condensation into globular nanoparticles at low concentration. The release of DNA from its compact state has been achieved using the chelator ethylenediaminetetraacetic acid (EDTA) for the first time. Other essential properties, such as DNA cleavage inactivity and biocompatibility, have also been examined in vitro. In general, the complex satisfies the requirements of a gene vector in all of these respects.


Assuntos
DNA/química , Vetores Genéticos/química , Níquel/química , Compostos Organometálicos/química , Animais , Cristalografia por Raios X , Clivagem do DNA , Eletroquímica , Ligantes , Estrutura Molecular , Espectrofotometria Ultravioleta
19.
J Biochem Mol Toxicol ; 23(4): 295-302, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19705364

RESUMO

Two copper(II) terpyridine complexes, [Cu(atpy)(NO(3))(H(2)O)](NO(3)) 3H(2)O (1) and [Cu(ttpy)(NO(3))(2)] (2) (atpy = 4'-p-N9-adeninylmethyl-phenyl-2,2':6,2''-terpyridine; ttpy = 4'-p-tolyl-2,2':6,2''-terpyridine) exhibited high cytotoxicity, with average ten times more potency than cisplatin against the human cervix carcinoma cell line (HeLa), the human liver carcinoma cell line (HepG2), the human galactophore carcinoma cell line (MCF7), and the human prostate carcinoma cell line (PC-3). The cytotoxicity of the complex 1 was lower than that of the complex 2. Both complexes showed more efficient oxidative DNA cleavage activity under irradiation with UV light at 260 nm than in the presence of ascorbic acid. Especially, complex 1 exhibited evident photoinduced double-stranded DNA cleavage activity. The preliminary mechanism experiments revealed that hydrogen peroxide was involved in the oxidative DNA damage induced by both complexes. From the absorption titration data, the DNA-binding affinity of the complexes with surpersoiled plasmid pUC19 DNA, polydAdT, and polydGdC was calculated and complex 2 showed higher binding affinity than complex 1 with all these substrates. The DNA cleavage ability and DNA-binding affinity of both complexes depended on the substituent group on the terpyrdine ligands.


Assuntos
Cobre/toxicidade , DNA/metabolismo , Desoxirribonucleases/metabolismo , Piridinas/toxicidade , Morte Celular/efeitos dos fármacos , Morte Celular/efeitos da radiação , Linhagem Celular Tumoral , Eletroforese em Gel de Ágar , Humanos , Concentração Inibidora 50 , Plasmídeos/genética , Espectrofotometria Ultravioleta , Raios Ultravioleta
20.
J Inorg Biochem ; 103(7): 1039-44, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19501911

RESUMO

Clinical application of platinum-based anticancer drugs is largely limited by severe general toxicity and drug resistance. Drug delivery systems with tumor-targeting potential are highly desired for improving the efficacy and applicability of these drugs. This study describes an alternative strategy for the delivery of platinum drugs (cisplatin, carboplatin and oxaliplatin) by encapsulating each of them in the cavity of apoferritin (AFt). The encapsulation was achieved through manipulating the pH-dependent unfolding-refolding process of AFt at pH 2.0 and 7.4, respectively, in saturated drug solution. UV-vis spectrometry, circular dichroism spectrometry, dynamic light scattering, and inductively coupled plasma mass spectrometry were used to characterize the AFt-drug complexes. The loading capacity of AFt varies with respective drugs and the structural integrity of the protein shell remains intact after encapsulation. In vitro assays on the rat pheochromocytoma cell line (PC12) show that AFt-cisplatin inhibits the cells in a slow but sustaining mode and the cellular uptake of platinum is enhanced by AFt. AFt-carboplatin and AFt-oxaliplatin complexes only exhibit a marginal cytotoxicity towards this cell line under similar concentrations.


Assuntos
Antineoplásicos/farmacocinética , Apoferritinas/administração & dosagem , Carboplatina/farmacocinética , Cisplatino/farmacocinética , Sistemas de Liberação de Medicamentos , Compostos Organoplatínicos/farmacocinética , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Apoferritinas/química , Carboplatina/administração & dosagem , Carboplatina/química , Linhagem Celular Tumoral , Cisplatino/administração & dosagem , Cisplatino/química , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/química , Oxaliplatina , Ratos
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