Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 4.992
Filtrar
1.
Nihon Yakurigaku Zasshi ; 155(6): 381-385, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-33132254

RESUMO

Conventional monoaminergic antidepressants have significant limitations, including delayed onset of therapeutic response and relatively low efficacy. Recent studies reveal that the NMDA receptor antagonist ketamine produces rapid and sustained antidepressant effects in treatment-resistant depressed patients. Despite the unique antidepressant efficacy, clinical use of ketamine as an antidepressant is limited due to its serious drawbacks, such as abuse potential and psychotomimetic/dissociative effects. The molecular and neuronal mechanisms underlying the antidepressant actions of ketamine have been intensively studied to pave the way for the development of novel, rapid and more efficacious antidepressants with fewer side effects than ketamine. Preclinical studies demonstrate that ketamine produces antidepressant effects through rapid release and/or expression of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF), and stimulation of mechanistic target of rapamycin complex 1 (mTORC1) signaling in the medial prefrontal cortex and hippocampus. We have recently found that resolvins (RvD1, RvD2, RvE1, RvE2 and RvE3), bioactive metabolites derived from docosahexaenoic acid and eicosapentaenoic acid, produce antidepressant effects, and that the antidepressant effects of RvD1, RvD2 and RvE1 require mTORC1 activation. These findings suggest that resolvins could be promising targets for the development of novel rapid antidepressants with fewer side effects than ketamine because they are endogenous lipid mediators that play an important role in homeostasis.


Assuntos
Ketamina , Fator A de Crescimento do Endotélio Vascular , Antidepressivos/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Humanos , Ketamina/farmacologia , Neurônios/metabolismo , Receptores de N-Metil-D-Aspartato
2.
Medicine (Baltimore) ; 99(36): e21859, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32899015

RESUMO

BACKGROUND: The purpose of this study was to evaluate the effects of adding ketamine to propofol on cognitive functions in patients undergoing sedation for colonoscopy. METHODS: In this randomized, double-blinded, and controlled study, 200 patients were randomly allocated to ketamine/propofol admixture group (Group KP, n = 100), and propofol group (Group P, n = 100). Patients in Group KP received 0.25 mg/kg of ketamine and 0.5 mg/kg of propofol. Patients in Group P received 0.5 mg/kg propofol. Cognitive functions were measured using CogState battery before and after the colonoscopy procedure. Ninety five patients in Group KP and 92 patients in Group P had completed the CogStates tests and were included in the data analysis. RESULTS: Compared with before procedure baseline, the performance on detection and identification tasks were significantly impaired after the procedure in both Group KP (P = .004, P = .001) and Group P patients (P = .005, P < .001). However, one-card learning accuracy and One-back memory was only impaired in Group KP patients (P = .006, P = .040) after the endoscopy but left intact in Group P patients. Group KP patients showed more severe impairment in one-card learning accuracy compared with Group P patients (P = .044). Group KP patients have better 5 minutes MAP (P = .005) and were also less likely to suffer from complications such as respiratory depression (P = .023) and hypotension (P = .015). OAA/S scores, BIS, MAP, complications, recovery times, and endoscopist and patient satisfaction were similar between the 2 groups. CONCLUSION: Although adding ketamine to propofol for sedation in colonoscopy provided fewer complications such as respiratory depression and hypotension, it also causes more impairment in cognitive functions.


Assuntos
Colonoscopia/métodos , Sedação Profunda/métodos , Hipnóticos e Sedativos/farmacologia , Ketamina/farmacologia , Complicações Cognitivas Pós-Operatórias/induzido quimicamente , Propofol/farmacologia , Adulto , Sedação Profunda/efeitos adversos , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Hipnóticos e Sedativos/administração & dosagem , Ketamina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Propofol/administração & dosagem , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto
3.
Clinics (Sao Paulo) ; 75: e1865, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32935825

RESUMO

OBJECTIVES: Hypoxia leads to endothelial cell inflammation, apoptosis, and damage, which plays an important role in the complications associated with ischemic cardiovascular disease. As an oxidoreductase, p66Shc plays an important role in the regulation of reactive oxygen species (ROS) production and apoptosis. Ketamine is widely used in clinics. This study was designed to assess the potential protective effect of ketamine against hypoxia-induced injury in human umbilical vein endothelial cells (HUVECs). Moreover, we explored the potential mechanism by which ketamine protected against hypoxia-induced endothelial injury. METHODS: The protective effects of ketamine against hypoxia-induced injury was assessed using cell viability and adhesion assays, quantitative polymerase chain reaction, and western blotting. RESULTS: Our data showed that hypoxia reduced HUVEC viability, increased the adhesion between HUVECs and monocytes, and upregulated the expression of endothelial adhesion molecules at the protein and mRNA levels. Moreover, hypoxia increased ROS accumulation and upregulated p66Shc expression. Furthermore, hypoxia downregulated sirt1 expression in HUVECs. Alternatively, ketamine was shown to reverse the hypoxia-mediated reduction of cell viability and increase in the adhesion between HUVECs and monocytes, ameliorate hypoxia-induced ROS accumulation, and suppress p66Shc expression. Moreover, EX527, a sirt1 inhibitor, reversed the protective effects of ketamine against the hypoxia-mediated reduction of cell viability and increase in adhesion between HUVECs and monocytes. CONCLUSION: Ketamine reduces hypoxia-induced p66Shc expression and attenuates ROS accumulation via upregulating sirt1 in HUVECs, thus attenuating hypoxia-induced endothelial cell inflammation and apoptosis.


Assuntos
Apoptose/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Hipóxia , Ketamina/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Sobrevivência Celular , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Estresse Oxidativo , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src , Veias Umbilicais
4.
Curr Opin Anaesthesiol ; 33(5): 633-638, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32826629

RESUMO

PURPOSE OF REVIEW: Ketamine has been used for decades for a variety of indications. Beyond the historical benefits and effects of ketamine, newer developments have occurred worthy of an update. This review will discuss common uses and indications for ketamine in the perioperative setting, as well as highlight newer indications in recent years. RECENT FINDINGS: Multiple studies have examined the use of ketamine in a variety of environments, as ketamine has become more popular in emergency rooms and ICUs. Ketamine may be particularly beneficial in management of burn patients, who often require multiple procedures over the course of their treatment. Ketamine's role in the ongoing opioid crisis has been of particular interest, with multiple studies evaluating its potential role in managing both acute and chronic pain conditions. Ongoing studies examining the role of ketamine in treatment of depressions show promise as well. SUMMARY: Ketamine is regaining popularity in the field of anesthesia and beyond. New studies provide insight on the many indications and use that anesthesia providers may encounter during their perioperative care of patients. Ongoing research is needed to further elucidate ketamine's effects on the management of psychiatric conditions and potential indications for ketamine metabolites.


Assuntos
Analgesia , Analgésicos/farmacologia , Anestesia , Anestésicos Dissociativos/farmacologia , Queimaduras/tratamento farmacológico , Depressão/tratamento farmacológico , Ketamina/farmacologia , Dor/tratamento farmacológico , Humanos , Manejo da Dor , Período Perioperatório
5.
PLoS One ; 15(8): e0236594, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32760073

RESUMO

Microglia, the resident immune cells of the brain, are highly ramified and motile and their morphology is strongly linked to their function. Microglia constantly monitor the brain parenchyma and are crucial for maintaining brain homeostasis and fine-tuning neuronal networks. Besides affecting neurons, anesthetics may have wide-ranging effects mediated by non-neuronal cells and in particular microglia. We thus examined the effect of two commonly used anesthetic agents, ketamine/xylazine and barbiturates, on microglial motility and morphology. A combination of two-photon in vivo imaging and electroencephalography (EEG) recordings in unanesthetized and anesthetized mice as well as automated analysis of ex vivo sections were used to assess morphology and dynamics of microglia. We found that administration of ketamine/xylazine and pentobarbital anesthesia resulted in quite distinct EEG profiles. Both anesthetics reduced microglial motility, but only ketamine/xylazine administration led to reduction of microglial complexity in vivo. The change of cellular dynamics in vivo was associated with a region-dependent reduction of several features of microglial cells ex vivo, such as the complexity index and the ramification length, whereas thiopental altered the size of the cytoplasm. Our results show that anesthetics have considerable effects on neuronal activity and microglial morphodynamics and that barbiturates may be a preferred anesthetic agent for the study of microglial morphology. These findings will undoubtedly raise compelling questions about the functional relevance of anesthetics on microglial cells in neuronal physiology and anesthesia-induced neurotoxicity.


Assuntos
Anestésicos/farmacologia , Moduladores GABAérgicos/farmacologia , Ketamina/farmacologia , Microglia/efeitos dos fármacos , Pentobarbital/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Tiopental/farmacologia , Xilazina/farmacologia , Animais , Movimento Celular/efeitos dos fármacos , Masculino , Camundongos , Camundongos Transgênicos
6.
Adv Pharmacol ; 89: 195-235, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32616207

RESUMO

As a field, psychiatry is undergoing an exciting paradigm shift toward early identification and intervention that will likely minimize both the burden associated with severe mental illnesses as well as their duration. In this context, the rapid-acting antidepressant ketamine has revolutionized our understanding of antidepressant response and greatly expanded the pharmacologic armamentarium for treatment-resistant depression. Efforts to characterize biomarkers of ketamine response support a growing emphasis on early identification, which would allow clinicians to identify biologically enriched subgroups with treatment-resistant depression who are more likely to benefit from ketamine therapy. This chapter presents a broad overview of a range of translational biomarkers, including those drawn from imaging and electrophysiological studies, sleep and circadian rhythms, and HPA axis/endocrine function as well as metabolic, immune, (epi)genetic, and neurotrophic biomarkers related to ketamine response. Ketamine's unique, rapid-acting properties may serve as a model to explore a whole new class of novel rapid-acting treatments with the potential to revolutionize drug development and discovery. However, it should be noted that although several of the biomarkers reviewed here provide promising insights into ketamine's mechanism of action, most studies have focused on acute rather than longer-term antidepressant effects and, at present, none of the biomarkers are ready for clinical use.


Assuntos
Biomarcadores/metabolismo , Encéfalo/metabolismo , Ketamina/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Ritmo Circadiano/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Humanos , Ketamina/farmacologia
7.
Adv Pharmacol ; 89: 163-194, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32616206

RESUMO

A paradigm shift in the conceptualization of the neurobiology of depression and the serendipitous discovery of ketamine's rapid-acting antidepressant (RAAD) effects has ushered in a new era of innovative research and novel drug development. Since the initial discovery of ketamine's RAAD effects, multiple studies have supported its short-term efficacy for fast-tracked improvements in treatment-resistant depression. Evidence from MRI studies have repeatedly demonstrated functional connectivity alterations in stress- and trauma-related disorders suggesting this may be a viable biomarker of chronic stress pathology (CSP). Human mechanistic studies further support this by coupling functional connectivity to ketamine's RAAD effects including connectivity to glutamate neurotransmission, ketamine to normalized connectivity, and these advantageous normalizations to symptom improvement/ketamine response. This review provides an abridged discussion of the suspected neurobiological underpinnings of ketamine's RAAD effects, highlighting ketamine-induced alterations in prefrontal, striatal, and anterior cingulate cortex functional connectivity in major depressive disorder. We present a model of CSP underscoring the role of synaptic loss and dysconnectivity and discuss how ketamine may be used both as (1) a treatment to restore and normalize these stress-induced neural alterations and (2) a tool to study potential biomarkers of CSP and treatment response. We conclude by noting challenges and future directions including heterogeneity, sex differences, the role of early life stress, and the need for proliferation of new methods, paradigms, and tools that will optimize signal and allow analyses at different levels of complexity, according to the needs of the question at hand, perhaps by thinking hierarchically about both clinical and biological phenotypes.


Assuntos
Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/fisiopatologia , Ketamina/uso terapêutico , Rede Nervosa/fisiopatologia , Estresse Psicológico/fisiopatologia , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Doença Crônica , Humanos , Ketamina/farmacologia
8.
Adv Pharmacol ; 89: 261-286, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32616209

RESUMO

A serious lack of effective pharmacotherapeutic interventions for posttraumatic stress disorder (PTSD) raises the urgent need for the development of novel treatments. Ketamine-a noncompetitive glutamate N-methyl-d-aspartate (NMDA) receptor antagonist in use for decades as an anesthetic and analgesic agent-has more recently been demonstrated to have rapid-onset antidepressant effects in patients with treatment-resistant depression (TRD). In the present review of ketamine as an emerging novel pharmacotherapeutic intervention for chronic PTSD, we discuss findings from the first proof-of-concept, randomized clinical trial (RCT) of single-dose intravenous ketamine in patients with chronic PTSD, as well as open-label studies and current practice. We introduce ongoing RCTs investigating the efficacy of repeated ketamine infusions in rapidly reducing symptoms and maintaining improvement in samples of individuals with PTSD stemming from civilian and military traumas. Additionally, we discuss mixed findings from published reports on ketamine administration in the acute aftermath of trauma. Studies in animal models of chronic stress have investigated molecular mechanisms underlying ketamine's effects, generating a shift in the conceptualization of PTSD as a disorder of impaired neural connectivity. We review animal studies examining the potential of ketamine to modify the expression of fear by altering memory reconsolidation or enhancing fear extinction, as well as others investigating ketamine administration prophylactically prior to stress exposure. We introduce the need for additional study in humans to evaluate whether ketamine might enhance the efficacy of psychotherapeutic interventions in individuals with chronic PTSD, harnessing a window of ketamine-induced neuroplasticity. While research on ketamine for PTSD is still in its early stages, it brings about the promise of novel and more effective treatments for this disabling condition.


Assuntos
Ketamina/uso terapêutico , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Modelos Animais de Doenças , Humanos , Ketamina/administração & dosagem , Ketamina/efeitos adversos , Ketamina/farmacologia , Padrões de Prática Médica , Ensaios Clínicos Controlados Aleatórios como Assunto , Transtornos de Estresse Pós-Traumáticos/terapia
9.
Adv Pharmacol ; 89: 289-309, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32616210

RESUMO

Given that ketamine, a noncompetitive N-methyl-d-aspartate receptor antagonist that exerts rapid antidepressant effects in patients with treatment-resistant depression, also has undesirable adverse effects, agents that can be used as alternatives to ketamine have been actively pursued. Group II metabotropic glutamate (mGlu) receptors, consisting of mGlu2 and mGlu3 receptors, have emerged as one of the most promising targets in the development of ketamine-like antidepressants. Indeed, mGlu2/3 receptor antagonists have been demonstrated to exert rapid antidepressant effects in animal models and to be efficacious in animal models refractory to conventional antidepressants. Moreover, there are striking similarities between mGlu2/3 receptor antagonists and ketamine in terms of not only their antidepressant profiles, but also the underlying mechanisms of their antidepressant effects. Nonetheless, studies in rodents have shown that mGlu2/3 receptor antagonists do not cause ketamine-like adverse events, such as psychotomimetic-like behavior, abuse potential or neurotoxicity, supporting the usefulness of mGlu2/3 receptor antagonists as alternatives to ketamine. In this chapter, the past and recent research on the antidepressant effects of mGlu2/3 receptor antagonists will be reviewed. In particular, the potential of mGlu2/3 receptor antagonists as novel ketamine-like antidepressants will be emphasized.


Assuntos
Antidepressivos/farmacologia , Terapia de Alvo Molecular , Receptores de Glutamato Metabotrópico/metabolismo , Animais , Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Humanos , Ketamina/farmacologia , Ketamina/uso terapêutico , Receptores de Glutamato Metabotrópico/antagonistas & inibidores
10.
Adv Pharmacol ; 89: 3-41, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32616211

RESUMO

A single sub-anesthetic intravascular dose of the use-dependent NMDAR antagonist, ketamine, improves mood in patients with treatment resistant depression within hours that can last for days, creating an entirely new treatment strategy for the most seriously ill patients. However, the psychomimetic effects and abuse potential of ketamine require that new therapies be developed that maintain the rapid antidepressant effects of ketamine without the unwanted side effects. This necessitates a detailed understanding of what cellular and synaptic mechanisms are immediately activated once ketamine reaches the brain that triggers the needed changes to elicit the improved behavior. Intense research has centered on the effects of ketamine, and the other rapidly acting antidepressants, on excitatory and inhibitory circuits in hippocampus and medial prefrontal cortex to determine common mechanisms, including key modifications in synaptic transmission and the precise location of the NMDARs that mediate the rapid and sustained antidepressant response. We review data comparing the effects of ketamine with other NMDAR receptor modulators and the muscarinic M1 acetylcholine receptor antagonist, scopolamine, together with evidence supporting the disinhibition hypothesis and the direct inhibition hypothesis of ketamine's mechanism of action on synaptic circuits using preclinical models.


Assuntos
Antidepressivos/farmacologia , Hipocampo/fisiologia , Ketamina/farmacologia , Inibição Neural/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Animais , Hipocampo/efeitos dos fármacos , Humanos , Ketamina/administração & dosagem , Ketamina/uso terapêutico , Caracteres Sexuais
11.
Adv Pharmacol ; 89: 43-78, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32616214

RESUMO

There has been much recent progress in understanding of the mechanism of ketamine's rapid and enduring antidepressant effects. Here we review recent insights from clinical and preclinical studies, with special emphasis of ketamine-induced changes in GABAergic synaptic transmission that are considered essential for its antidepressant therapeutic effects. Subanesthetic ketamine is now understood to exert its initial action by selectively blocking a subset of NMDA receptors on GABAergic interneurons, which results in disinhibition of glutamatergic target neurons, a surge in extracellular glutamate and correspondingly elevated glutamatergic synaptic transmission. This surge in glutamate appears to be corroborated by the rapid metabolism of ketamine into hydroxynorketamine, which acts at presynaptic sites to disinhibit the release of glutamate. Preclinical studies indicate that glutamate-induced activity triggers the release of BDNF, followed by transient activation of the mTOR pathway and increased expression of synaptic proteins, along with functional strengthening of glutamatergic synapses. This drug-on phase lasts for approximately 2h and is followed by a period of days characterized by structural maturation of newly formed glutamatergic synapses and prominently enhanced GABAergic synaptic inhibition. Evidence from mouse models with constitutive antidepressant-like phenotypes suggests that this phase involves strengthened inhibition of dendrites by somatostatin-positive GABAergic interneurons and correspondingly reduced NMDA receptor-mediated Ca2+ entry into dendrites, which activates an intracellular signaling cascade that converges with the mTOR pathway onto increased activity of the eukaryotic elongation factor eEF2 and enhanced translation of dendritic mRNAs. Newly synthesized proteins such as BDNF may be important for the prolonged therapeutic effects of ketamine.


Assuntos
Antidepressivos/farmacologia , Neurônios GABAérgicos/fisiologia , Ketamina/farmacologia , Inibição Neural/efeitos dos fármacos , Animais , Depressão/fisiopatologia , Neurônios GABAérgicos/efeitos dos fármacos , Humanos , Metaboloma/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos
12.
Adv Pharmacol ; 89: 79-99, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32616215

RESUMO

Major depressive disorder is a prevalent and serious form of mental illness. While traditional antidepressants ameliorate some of the symptoms associated with depression, the onset of action typically takes several weeks leaving severely depressed individuals vulnerable to self-injurious behavior and possibly suicide. There has been a major unmet need for the development of pharmacological therapies that can quickly alleviate symptoms associated with depression. Clinical data shows that a single sub-psychomimetic dose of ketamine, a noncompetitive glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist, has rapid antidepressant responses in patients with treatment-resistant major depressive disorder. We have studied key signaling pathways and synaptic mechanisms underlying the rapid antidepressant action of ketamine. Our studies show ketamine blocks synaptic NMDA receptors involved in spontaneous synaptic transmission, which deactivates calcium/calmodulin-dependent kinase eukaryotic elongation factor 2 kinase (eEF2K), resulting in dephosphorylation of eukaryotic elongation factor 2 (eEF2), and the subsequent desuppression of brain-derived neurotrophic factor (BDNF) protein synthesis in the hippocampus. This signaling pathway then potentiates synaptic α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor responses that results in a novel form of synaptic potentiation which corresponds with antidepressant efficacy. In this chapter, we focus on our studies examining ketamine's action and the instructive role of eEF2K in rapid antidepressant action. Our recent studies highlight eEF2K as a major molecular substrate mediating synaptic plasticity and the rapid antidepressant effects of ketamine.


Assuntos
Antidepressivos/farmacologia , Quinase do Fator 2 de Elongação/metabolismo , Ketamina/farmacologia , Animais , Depressão/tratamento farmacológico , Depressão/fisiopatologia , Humanos , Ketamina/uso terapêutico , Plasticidade Neuronal/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/metabolismo
13.
Adv Clin Exp Med ; 29(7): 813-817, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32725973

RESUMO

BACKGROUND: Acute lung injury (ALI) is a common critical respiratory disease that seriously threatens human health. Ketamine has good anti-inflammatory and immune-regulating properties that can delay the lung injury process. OBJECTIVES: High mobility group box protein 1 (HMGB1) plays an important role in the occurrence, development and treatment of ALI. Toll-like receptor 4 (TLR4) is the receptor for HMGB1. The aim of this study was to determine the role of the HMGB1 TLR4 signaling pathway in the treatment of ALI using ketamine. MATERIAL AND METHODS: A total of 30 healthy, male, 8-week-old Sprague-Dawley rats were randomly, equally divided into a control group, an lipopolysaccharide (LPS) group and a ketamine group. In order to establish a rat ALI model, 15 mg/kg of LPS was injected into the femoral veins. Ketamine was intravenously injected (10 mg/kg) into the experimental group rats. The rats were euthanized 24 h after modeling and lung tissue samples were collected. Western blot was used to test TLR4, MyD88, TRAF-6, LOX-1, and HMGB1 protein expression in the lung tissue. Real-time polymerase chain reaction (RT-PCR) was performed to detect TLR4, MyD88, TRAF-6, LOX-1, and HMGB1 mRNA levels. RESULTS: Compared with the controls, the LPS group had significantly higher TLR4, MyD88, TRAF-6, LOX-1, and HMGB1 mRNA and protein levels (p < 0.05). These levels were significantly lower after ketamine intervention in comparison with the LPS group (p < 0.05). A positive correlation was found between TLR4 and HMGB1 expression in the LPS and ketamine groups (r = 0.952, p < 0.001; r = 0.941, p < 0.001). CONCLUSIONS: Ketamine attenuates HMGB1-induced ALI, possibly by regulating the TLR4 signaling pathway.


Assuntos
Lesão Pulmonar Aguda , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Animais , Proteína HMGB1 , Ketamina/farmacologia , Lipopolissacarídeos/toxicidade , Pulmão/metabolismo , Masculino , NF-kappa B/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Receptor 4 Toll-Like/genética
14.
Chem Biol Interact ; 327: 109164, 2020 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-32524992

RESUMO

General anaesthetics are some of the most widely used and essential therapeutic agents. However, despite over a century of research, the molecular mechanisms of general anaesthesia in the central nervous system remain elusive. Ketamine (ketamine hydrochloride) has been approved for use in general anaesthesia either alone or in combination with other medications. It is a superb drug for use in short-term medical procedures that do not require skeletal muscle relaxation, and it has approval for the induction of general anaesthesia as a pre-anaesthetic to other general anaesthetic agents. However, Several questions remain unsolved, including the exact identification of the neural substrate of consciousness and its components, the pharmacodynamic interactions between anaesthetic agents, the mechanisms of cognitive alterations that follow an anaesthetic procedure, the identification of an eventual unitary mechanism of anaesthesia-induced alteration of consciousness, the relationship between network effects and the biochemical targets of anaesthetic agents, leading to difficulties in between-studies comparisons. Thus, the glutamate and dopamine systems play distinct roles in terms of neuronal signalling, yet both have proposed to contribute significantly to the pathophysiology of neuropsychiatric diseases. Imaging of the glutamate system and other aspects of research on the dopamine system have produced less consistent findings, potentially due to methodological limitations and the heterogeneity of the disorder. In this review, we discuss the neural circuits through which the two systems interact and how their disruption may cause psychotic symptoms. We also summarize from a molecular perspective of mechanisms of action of ketamine as general anaesthetics on ligand-gated ion channels mediated modulation of dopamine in the brain region.


Assuntos
Anestésicos Dissociativos/farmacologia , Dopamina/metabolismo , Ácido Glutâmico/metabolismo , Ketamina/farmacologia , Anestesia/efeitos adversos , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Humanos , Transtornos Psicóticos/fisiopatologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Esquizofrenia/fisiopatologia
15.
Neuron ; 106(5): 715-726, 2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32497508

RESUMO

Ketamine exerts rapid antidepressant action in depressed and treatment-resistant depressed patients within hours. At the same time, ketamine elicits a unique form of functional synaptic plasticity that shares several attributes and molecular mechanisms with well-characterized forms of homeostatic synaptic scaling. Lithium is a widely used mood stabilizer also proposed to act via synaptic scaling for its antimanic effects. Several studies to date have identified specific forms of homeostatic synaptic plasticity that are elicited by these drugs used to treat neuropsychiatric disorders. In the last two decades, extensive work on homeostatic synaptic plasticity mechanisms have shown that they diverge from classical synaptic plasticity mechanisms that process and store information and thus present a novel avenue for synaptic regulation with limited direct interference with cognitive processes. In this review, we discuss the intersection of the findings from neuropsychiatric treatments and homeostatic plasticity studies to highlight a potentially wider paradigm for treatment advance.


Assuntos
Antimaníacos/farmacologia , Transtorno Bipolar/tratamento farmacológico , Transtorno Depressivo Maior/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/farmacologia , Homeostase/efeitos dos fármacos , Ketamina/farmacologia , Compostos de Lítio/farmacologia , Plasticidade Neuronal/efeitos dos fármacos , Animais , Antimaníacos/uso terapêutico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Humanos , Ketamina/uso terapêutico , Compostos de Lítio/uso terapêutico , Transtornos do Humor/tratamento farmacológico , Sinapses/efeitos dos fármacos
16.
PLoS One ; 15(5): e0233778, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32469999

RESUMO

The selection of the anesthetic regime is a crucial component in many experimental animal studies. In rodent models of liver disease, the combination of ketamine and diazepam (KD), generally by the intramuscular (i.m.) route, has traditionally been the anesthesia of choice for the evaluation of systemic and hepatic hemodynamics but it presents several problems. Here, we compared the performance of inhalational sevoflurane (Sevo) against the KD combination as the anesthesia used for hemodynamic studies involving the measurement of portal pressure in normal rats (Ctrl) and rats with non-cirrhotic portal hypertension induced by partial portal vein ligation (PPVL). Compared with Ctrl rats, rats with PPVL presented characteristic alterations that were not influenced by the anesthetic regime, which included liver atrophy, splenomegaly, increased plasma fibrinogen, decreased alkaline phosphatase and glycemia, and frequent ascites. The use of the KD combination presented several disadvantages compared with the inhalational anesthesia with sevoflurane, including considerable mortality, a higher need of dose adjustments to maintain an optimal depth of anesthesia, increases of heart rate, and alteration of blood biochemical parameters such as the concentration of aspartate aminotransferase, lactate, and lactic dehydrogenase. Rats anesthetized with sevoflurane, on the other hand, presented lower respiratory rates. Importantly, the anesthetic regime did not influence the measurement of portal pressure either in Ctrl or PPVL rats, with the increase of portal pressure being similar in Sevo- and KD- anesthetized groups of PPVL rats compared with their respective control groups. Overall, our results suggest that anesthesia with sevoflurane is preferable to the combination of KD for performing systemic and hepatic hemodynamic studies in rats with non-cirrhotic portal hypertension.


Assuntos
Diazepam/farmacologia , Hipertensão Portal/tratamento farmacológico , Ketamina/farmacologia , Pressão na Veia Porta/efeitos dos fármacos , Sevoflurano/farmacologia , Anestesia por Inalação , Anestesiologia , Anestésicos Dissociativos/farmacologia , Anestésicos Inalatórios/farmacologia , Animais , Modelos Animais de Doenças , Fígado/irrigação sanguínea , Masculino , Veia Porta/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
17.
J Pharmacol Exp Ther ; 374(1): 200-210, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32265323

RESUMO

Both an agonist and its associated prodrug for metabotropic glutamate2/3 (mGlu2/3) receptors demonstrated anxiolytic efficacy in large, randomized, multicenter, double-blind, placebo-controlled trials studying patients with generalized anxiety disorder (GAD). These mGlu2/3 receptor agonists produced robust preclinical anxiolytic-like effects in rodent models. Several different metabotropic glutamate2 receptor positive allosteric modulators have been found to produce antidepressant-like effects on several preclinical screening paradigms, including differential-reinforcement-of-low-rate 72-second (DRL 72-s) behavior [increased reinforcers, decreased response rate, and cohesive rightward shifts in inter-response time distributions]. Although mGlu2/3 receptor agonists have not been tested formally for therapeutic effects in treating patients with major depressive disorder, these compounds generally fail to exert antidepressant-like effects in preclinical screening paradigms and did not improve depressive symptoms in GAD trials. Thus, the present studies were designed to test the potential antidepressant-like effects of the mGlu2/3 receptor agonist 1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6-bicarboxylate monohydrate (LY354740) on the DRL 72-s schedule. LY354740 did not test similarly to clinically validated antidepressant drugs when administered alone or when coadministered with the selective serotonin reuptake inhibitor fluoxetine in rats. Another glutamate-based antidepressant drug, the uncompetitive N-methyl-D-aspartate channel blocker racemic ketamine, exerted antidepressant-like effects when administered at subanesthetic doses in rats. The findings further support the specificity of rat DRL 72-s behavior when screening for anxiolytic versus antidepressant drugs and extend testing of compounds with glutamatergic mechanisms of action. SIGNIFICANCE STATEMENT: The metabotropic glutamate2/3 receptor agonist and clinically validated anxiolytic drug 1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6-bicarboxylate monohydrate did not test similar to antidepressant drugs (increased reinforcers, decreased response rate, and cohesive rightward shifts in the inter-response time distribution) when tested on differential-reinforcement-of-low-rate 72-second (DRL 72-s) behavior and also did not enhance the antidepressant-like effects of the serotonin reuptake inhibitor fluoxetine. The uncompetitive N-methyl-D-aspartate receptor antagonist ketamine increased the reinforcement rate, decreased the response rate, and induced a rightward shift in the inter-response time distribution similar to antidepressant drugs; these results confirm the utility of DRL 72-s schedule of reinforcement when testing clinically validated anxiolytic versus antidepressant glutamatergic drugs.


Assuntos
Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Reforço Psicológico , Animais , Compostos Bicíclicos com Pontes/farmacologia , Cognição/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Função Executiva/efeitos dos fármacos , Comportamento Impulsivo/efeitos dos fármacos , Ketamina/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes
18.
Cell Prolif ; 53(5): e12804, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32266752

RESUMO

Major depressive disorder takes at least 3 weeks for clinical anti-depressants, such as serotonin selective reuptake inhibitors, to take effect, and only one-third of patients remit. Ketamine, a kind of anaesthetic, can alleviate symptoms of major depressive disorder patients in a short time and is reported to be effective to treatment-resistant depression patients. The rapid and strong anti-depressant-like effects of ketamine cause wide concern. In addition to ketamine, caloric restriction and sleep deprivation also elicit similar rapid anti-depressant-like effects. However, mechanisms about the rapid anti-depressant-like effects remain unclear. Elucidating the mechanisms of rapid anti-depressant effects is the key to finding new therapeutic targets and developing therapeutic patterns. Therefore, in this review we summarize potential molecular and cellular mechanisms of rapid anti-depressant-like effects based on the pre-clinical and clinical evidence, trying to provide new insight into future therapy.


Assuntos
Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Ketamina/farmacologia , Ketamina/uso terapêutico , Animais , Humanos
19.
Cell ; 181(1): 7, 2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32243798

RESUMO

The discovery of the strikingly rapid and robust antidepressant effects of r/s-ketamine for the treatment of antidepressant-resistant symptoms of depression has led to new insights into the biology of antidepressants and the FDA approval of its s-isomer, Esketamine (Spravato), the first mechanistically new treatment for depression in over 60 years. To view this Bench to Bedside, open or download the PDF.


Assuntos
Antidepressivos , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Aprovação de Drogas , Ketamina , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Neurônios GABAérgicos/efeitos dos fármacos , Humanos , Ketamina/farmacologia , Ketamina/uso terapêutico , Receptores de AMPA/metabolismo
20.
J Cardiovasc Pharmacol Ther ; 25(4): 346-353, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32292050

RESUMO

BACKGROUND: We investigated whether the cardioprotective, volatile gas anesthetic agent, isoflurane, could improve survival and organ function from hemorrhagic shock in an experimental rat model, compared to standard nonvolatile anesthetic agent ketamine/xylazine. METHODS: Sprague Dawley rats (both genders) were randomized to receive either intraperitoneal ketamine/xylazine (K/X, 90 and 10 mg/kg; n = 12) or isoflurane (5% isoflurane induction and 2% maintenance in room air; n = 12) for anesthesia. Blood was withdrawn to maintain mean arterial blood pressure at 30 mm Hg for 1 hour, followed by 30 minutes of resuscitation with shed blood. Rats were allowed to recover and survive for 6 weeks. RESULTS: During the shock phase, the total withdrawn blood volume (expressed as % of estimated total blood volume) to maintain a level of hypotension of 30 mm Hg was significantly higher in the isoflurane group (51.0% ± 1.5%) than in the K/X group (45.3% ± 1.8%; P = .023). Recovery of blood pressure during the resuscitation phase was significantly improved in the isoflurane group compared to the K/X group. The survival rate at 6 weeks was 1 (8.3%) of 12 in rats receiving K/X and 10 (83.3%) of 12 in rats receiving isoflurane (P < .001). Histology performed at 6 weeks demonstrated brain infarction in the 1 surviving rat receiving K/X; no brain infarction occurred in the 10 surviving rats that received isoflurane. No infarction was detected in heart, lung, liver, or kidneys among the surviving rats. CONCLUSIONS: Isoflurane improved blood pressure response to resuscitation and resulted in significantly higher long-term survival rate.


Assuntos
Anestésicos Dissociativos/farmacologia , Anestésicos Inalatórios/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Infarto Encefálico/prevenção & controle , Encéfalo/efeitos dos fármacos , Isoflurano/farmacologia , Ketamina/farmacologia , Ressuscitação , Choque Hemorrágico/tratamento farmacológico , Animais , Encéfalo/patologia , Infarto Encefálico/etiologia , Infarto Encefálico/patologia , Modelos Animais de Doenças , Feminino , Masculino , Ratos Sprague-Dawley , Choque Hemorrágico/complicações , Choque Hemorrágico/fisiopatologia , Fatores de Tempo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA