RESUMO
NSG-SGM3 and NOG-EXL mice combine severe immunodeficiency with transgenic expression of human myeloid stimulatory cytokines, resulting in marked expansion of myeloid populations upon humanization with CD34+ hematopoietic stem cells (HSCs). Humanized NSG-SGM3 mice typically develop a lethal macrophage activation syndrome and mast cell hyperplasia that limit their use in long-term studies (e.g., humanization followed by tumor xenotransplantation). It is currently unclear to what extent humanized NOG-EXL mice suffer from the same condition observed in humanized NSG-SGM3 mice. We compared the effects of human CD34+ HSC engraftment in these two strains in an orthotopic patient-derived glioblastoma model. NSG-SGM3 mice humanized in-house were compared to NOG-EXL mice humanized in-house and commercially available humanized NOG-EXL mice. Mice were euthanized at humane or study endpoints, and complete pathological assessments were performed. A semiquantitative multiparametric clinicopathological scoring system was developed to characterize chimeric myeloid cell hyperactivation (MCH) syndrome. NSG-SGM3 mice were euthanized at 16 weeks after humanization because of severe deterioration of clinical conditions. Humanized NOG-EXL mice survived to the study endpoint at 22 weeks after humanization and showed less-severe MCH phenotypes than NSG-SGM3 mice. Major differences included the lack of mast cell expansion and limited tissue/organ involvement in NOG-EXL mice compared to NSG-SGM3 mice. Engraftment of human lymphocytes, assessed by immunohistochemistry, was similar in the two strains. The longer survival and decreased MCH phenotype severity in NOG-EXL mice enabled their use in a tumor xenotransplantation study. The NOG-EXL model is better suited than the NSG-SGM3 model for immuno-oncology studies requiring long-term survival after humanization.
Assuntos
Antígenos CD34 , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas , Camundongos Transgênicos , Células Mieloides , Animais , Camundongos , Humanos , Células-Tronco Hematopoéticas/patologia , Antígenos CD34/metabolismo , Células Mieloides/patologia , Fenótipo , Modelos Animais de DoençasRESUMO
Exposure to stressful stimuli activates kappa opioid receptor (KOR) signaling, a process known to produce aversion and dysphoria in humans and other species. This endogenous opioid system is dysregulated in stress-related disorders, specifically in major depressive disorder (MDD). These findings serve as the foundation for a growing interest in the therapeutic potential of KOR antagonists as novel antidepressants. In this review, data supporting the hypothesis of dysregulated KOR function in MDD are considered. The clinical data demonstrating the therapeutic efficacy and safety of selective and mixed opioid antagonists are then presented. Finally, the preclinical evidence illustrating the induction of behaviors relevant to the endophenotypes of MDD and KOR antagonist activity in stress-naïve and stress-exposed animals is evaluated. Overall, this review highlights the emergent literature supporting the pursuit of KOR antagonists as novel therapeutics for MDD and other stress-related disorders.
Assuntos
Transtorno Depressivo Maior/tratamento farmacológico , Receptores Opioides kappa/antagonistas & inibidores , Estresse Psicológico/tratamento farmacológico , Animais , Transtorno Depressivo Maior/fisiopatologia , Humanos , Antagonistas de Entorpecentes/efeitos adversos , Antagonistas de Entorpecentes/farmacologia , Transdução de Sinais/efeitos dos fármacos , Estresse Psicológico/fisiopatologiaRESUMO
Neurobehavioral deficits emerge in nearly 50% of patients following a mild traumatic brain injury (TBI) and may persist for months. Ketamine is used frequently as an anesthetic/analgesic and for management of persistent psychiatric complications. Although ketamine may produce beneficial effects in patients with a history of TBI, differential sensitivity to its impairing effects could make the therapeutic use of ketamine in TBI patients unsafe. This series of studies examined male C57BL/6â¯J mice exposed to a mild single blast overpressure (mbTBI) for indications of altered sensitivity to ketamine at varying times after injury. Dystaxia (altered gait), diminished sensorimotor gating (reduced prepulse inhibition) and impaired working memory (step-down inhibitory avoidance) were examined in mbTBI and sham animals 15â¯min following intraperitoneal injections of saline or R,S-ketamine hydrochloride, from day 7-16 post injury and again from day 35-43 post injury. Behavioral performance in the forced swim test and sucrose preference test were evaluated on day 28 and day 74 post injury respectively, 24â¯h following drug administration. Dynamic gait stability was compromised in mbTBI mice on day 7 and 35 post injury and further exacerbated following ketamine administration. On day 14 and 42 post injury, prepulse inhibition was robustly decreased by mbTBI, which ketamine further reduced. Ketamine-associated memory impairment was apparent selectively in mbTBI animals 1â¯h, 24â¯h and day 28 post shock (tested on day 15/16/43 post injury). Ketamine selectively reduced immobility scores in the FST in mbTBI animals (day 28) and reversed mbTBI induced decreases in sucrose consumption (Day 74). These results demonstrate increased sensitivity to ketamine in mice when tested for extended periods after TBI. The results suggest that ketamine may be effective for treating neuropsychiatric complications that emerge after TBI but urge caution when used in clinical practice for enhanced sensitivity to its side effects in this patient population.
Assuntos
Anestésicos Dissociativos/farmacologia , Comportamento Animal/efeitos dos fármacos , Traumatismos por Explosões/psicologia , Lesões Encefálicas Traumáticas/psicologia , Ketamina/farmacologia , Anestésicos Dissociativos/efeitos adversos , Animais , Ataxia/etiologia , Ataxia/psicologia , Concussão Encefálica , Ketamina/efeitos adversos , Coxeadura Animal/induzido quimicamente , Coxeadura Animal/psicologia , Masculino , Transtornos da Memória/etiologia , Transtornos da Memória/psicologia , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Inibição Pré-Pulso , Desempenho Psicomotor/efeitos dos fármacos , Filtro Sensorial/efeitos dos fármacosRESUMO
LEARNING OBJECTIVES: After participating in this activity, learners should be better able to:⢠Identify the effects of dysregulated opioid signalling in depression⢠Evaluate the use of opioid compounds and ketamine in patients with depression ABSTRACT: Major depressive disorder (MDD) remains one of the leading causes of disability and functional impairment worldwide. Current antidepressant therapeutics require weeks to months of treatment prior to the onset of clinical efficacy on depressed mood but remain ineffective in treating suicidal ideation and cognitive impairment. Moreover, 30%-40% of individuals fail to respond to currently available antidepressant medications. MDD is a heterogeneous disorder with an unknown etiology; novel strategies must be developed to treat MDD more effectively. Emerging evidence suggests that targeting one or more of the four opioid receptors-mu (MOR), kappa (KOR), delta (DOR), and the nociceptin/orphanin FQ receptor (NOP)-may yield effective therapeutics for stress-related psychiatric disorders. Furthermore, the effects of the rapidly acting antidepressant ketamine may involve opioid receptors. This review highlights dysregulated opioid signaling in depression, evaluates clinical trials with opioid compounds, and considers the role of opioid mechanisms in rapidly acting antidepressants.
Assuntos
Antidepressivos/farmacologia , Transtorno Depressivo Maior/tratamento farmacológico , Receptores Opioides/efeitos dos fármacos , Analgésicos Opioides/farmacologia , Animais , Desenvolvimento de Medicamentos , Humanos , Antagonistas de Entorpecentes/farmacologia , Resultado do TratamentoRESUMO
Emerging evidence suggests that females are less sensitive than males to the effects of kappa opioid receptor (KOR) ligands across multiple behavioral measures. The effects of the KOR agonist U50,488 and the KOR antagonist aticaprant were assessed on nest building behavior, an ethologically relevant indicator of overall well-being and affect, in adult male and female C57BL/6J mice. Females required a higher dose of U50,488 to suppress nesting, and a higher dose of aticaprant to restore U50,488-induced impairment of nesting. Females also required a higher dose of aticaprant to decrease immobility scores in the forced swim test. Pretreatment with the estrogen receptor modulator tamoxifen, at a dose which blocked estrogen receptors, augmented the effect of U50,488 on nesting in female mice, suggesting that estrogen receptors play a key role in attenuating the effects of KOR ligands in female mice. Together, these results suggest that females are less sensitive to KOR mediation, requiring a higher dose to achieve comparable results to males. This behavioral sensitivity, as measured by nesting, may be mediated by estrogen receptors. Together these studies highlight the importance of comparing sex differences in response to KOR regulation on behaviors related to affective states.
Assuntos
Comportamento de Nidação/fisiologia , Receptores Opioides kappa/metabolismo , Caracteres Sexuais , Transdução de Sinais/fisiologia , Analgésicos não Narcóticos/farmacologia , Analgésicos Opioides/farmacologia , Animais , Feminino , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Antagonistas de Entorpecentes/farmacologia , Comportamento de Nidação/efeitos dos fármacos , Receptores Opioides kappa/agonistas , Receptores Opioides kappa/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacosRESUMO
RATIONALE: Major depressive disorder is a leading cause of disability worldwide and is likely precipitated by chronic stress. Although many antidepressants are currently available, these drugs require weeks to months of daily administration before reduction of symptoms occurs and many patients remain treatment-resistant despite several courses of treatment. There is a pressing need for new treatments for stress-related disorders. Kappa opioid receptors (KORs) are a promising new therapeutic target for major depressive disorder and anhedonia because acute KOR blockade prevents many effects of stress in rodents. OBJECTIVES: The following study assessed whether repeated treatment with the selective KOR antagonist aticaprant (also known as JNJ-67953964, and previously LY-2456302 and CERC-501) was effective in reversing behaviors in rodents following exposure to unpredictable chronic mild stress (UCMS). METHODS: Adult male C57BL/6J mice were exposed to 4 weeks of UCMS. After 3 weeks of stress, aticaprant (10 mg/kg) was administered daily for 11 treatments. Behavioral assessments included the sucrose preference test, nesting, forced swim test, hot plate test, light-dark test, and social interaction test. RESULTS: Aticaprant significantly reversed stress-induced deficits produced by UCMS on the SPT, nesting, FST, and hot plate test. The effects of aticaprant persisted through a stress and treatment recovery period. Aticaprant was not effective at reversing behavioral effects caused by stress in the light-dark and social interaction tests. CONCLUSIONS: The results support further study of the role of KORs in regulating circuits related to reward, self-care, and cognition when they are disrupted by chronic stress. They are also consistent with the clinical development of aticaprant as a therapeutic for stress-related disorders targeted at anhedonia, such as depression and post-traumatic stress disorder.
Assuntos
Benzamidas/uso terapêutico , Antagonistas de Entorpecentes/uso terapêutico , Pirrolidinas/uso terapêutico , Receptores Opioides kappa/antagonistas & inibidores , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/psicologia , Animais , Benzamidas/farmacologia , Doença Crônica , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Antagonistas de Entorpecentes/farmacologia , Pirrolidinas/farmacologia , Receptores Opioides kappa/fisiologia , Natação/psicologiaRESUMO
The failure of traditional antidepressant medications to adequately target cognitive impairment is associated with poor treatment response, increased risk of relapse, and greater lifetime disability. Opioid receptor antagonists are currently under development as novel therapeutics for major depressive disorder (MDD) and other stress-related illnesses. Although it is known that dysregulation of the endogenous opioid system is observed in patients diagnosed with MDD, the impact of opioidergic neurotransmission on cognitive impairment has not been systematically evaluated. Here we review the literature indicating that opioid manipulations can alter cognitive functions in humans. Furthermore, we detail the preclinical studies that demonstrate the ability of mu-opioid receptor and kappa-opioid receptor ligands to modulate several cognitive processes. Specifically, this review focuses on domains within higher order cognitive processing, including attention and executive functioning, which can differentiate cognitive processes influenced by motivational state.
Assuntos
Analgésicos Opioides/farmacologia , Cognição/efeitos dos fármacos , Disfunção Cognitiva/tratamento farmacológico , Transtorno Depressivo/complicações , Função Executiva/efeitos dos fármacos , Analgésicos Opioides/uso terapêutico , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Transtorno Depressivo/metabolismo , Humanos , Testes Neuropsicológicos , Receptores Opioides mu/metabolismoRESUMO
The effect of six different traumatic stress protocols on the transcriptome of the rat adrenal gland was examined using RNA sequencing. These protocols included chronic variable stress, chronic shock, social defeat and social isolation. The response of the transcriptome to stress suggested that there are genes that respond in a universal or stress modality-independent manner, as well as genes that respond in a stress modality-specific manner. Using a small number of the genes selected from the modality-independent set of stress-sensitive genes, a sensitive and robust measure of chronic stress exposure was developed. This stress-sensitive gene expression (SSGE) index could detect chronic traumatic stress exposure in a wide range of different stress models in a manner that was relatively independent of the modality of stress exposure and that paralleled the intensity of stress exposure in a dose-dependent manner. This measure could reliably distinguish control and stressed individuals in the case of animals exposed to the most intense stress protocols. The response of a subset of the modality-specific genes could also distinguish some types of stress exposure, based solely on changes in the pattern of gene expression. The results suggest that it is possible to develop diagnostic measures of traumatic stress exposure based solely on changes in the level of expression of a relatively small number of genes.