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1.
Expert Rev Clin Pharmacol ; 13(2): 135-146, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31990596

RESUMO

Introduction: The use of ketamine infusions for chronic pain has surged, with utilization exceeding the proliferation of knowledge. A proposed mechanism for the long-term benefit in chronic pain is that ketamine may alter the affective-motivational component of pain.Areas covered: In this review, we discuss the classification and various dimensions of pain, and explore the effects of ketamine on different pain categories and components. The relationship between ketamine's action at the NMDA receptor, the development of chronic pain, and the its possible role in preventing the persistence of pain are examined. We also summarize animal models evaluating the antinociceptive effects of ketamine and risk mitigation strategies of ketamine-associated side effects.Expert opinion: Although ketamine exerts most of its analgesic effects via the NMDA receptor, recent evidence suggests that other receptors such as AMPA, and active metabolites such as nor-ketamine, may also play a role in pain relief and alleviation of depression. Data from clinical studies performed in patients with chronic pain and depression, and the observation that ketamine's analgesic benefits outlast its effects on quantitative sensory testing, suggest that the enduring effects on chronic pain may be predominantly due ketamine's ability to modulate the affective-motivational dimension of pain.


Assuntos
Analgésicos/administração & dosagem , Dor Crônica/tratamento farmacológico , Ketamina/administração & dosagem , Analgésicos/efeitos adversos , Analgésicos/farmacologia , Animais , Dor Crônica/fisiopatologia , Depressão/tratamento farmacológico , Depressão/fisiopatologia , Modelos Animais de Doenças , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Humanos , Infusões Intravenosas , Ketamina/efeitos adversos , Ketamina/farmacologia , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/metabolismo
3.
Expert Opin Drug Metab Toxicol ; 15(12): 1033-1041, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31693437

RESUMO

Introduction: Chronic neuropathic pain (NP) is an incapacitating illness caused by a lesion of the somatosensory nervous system and is associated with several diseases or syndromes. Since current treatment options lack adequate efficacy in the majority of patients, ketamine is often administered to treat refractory NP.Areas covered: This review gives an overview of new ketamine pharmacokinetic data including data on intranasal and inhaled ketamine. The outcome of seven systematic reviews and meta-analyses, published since 2012, on ketamine efficacy in NP is discussed. The reader will additionally get an understanding of ketamine's complex metabolism with emphasis on the metabolite hydroxynorketamine.Expert opinion: Proof of sustained, large effects of ketamine in the treatment of NP from randomized controlled clinical trials is lacking, although we cannot exclude selective ketamine efficacy in patients with central sensitization, opioid-induced hyperalgesia or opioid tolerance. Interestingly, data from observational trials and case series do suggest the efficacy of ketamine in producing effective pain relief in NP with positive patient-related outcome measures. Additional randomized trials in often ill-defined groups of chronic pain patients are not useful and we suggest to conduct future studies in NP patients with central sensitization and/or with opioid refractory severe NP.


Assuntos
Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Ketamina/administração & dosagem , Neuralgia/tratamento farmacológico , Analgésicos/administração & dosagem , Analgésicos/farmacocinética , Analgésicos/farmacologia , Animais , Dor Crônica/tratamento farmacológico , Dor Crônica/fisiopatologia , Antagonistas de Aminoácidos Excitatórios/farmacocinética , Antagonistas de Aminoácidos Excitatórios/farmacologia , Humanos , Ketamina/farmacocinética , Ketamina/farmacologia , Neuralgia/fisiopatologia
4.
Int J Mol Sci ; 20(18)2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31500132

RESUMO

Parkinson's disease is a progressive neurodegenerative disorder resulting from the degeneration of pigmented dopaminergic neurons in the substantia nigra pars compacta. It induces a series of functional modifications in the circuitry of the basal ganglia nuclei and leads to severe motor disturbances. The amino acid glutamate, as an excitatory neurotransmitter, plays a key role in the disruption of normal basal ganglia function regulated through the interaction with its receptor proteins. It has been proven that glutamate receptors participate in the modulation of neuronal excitability, transmitter release, and long-term synaptic plasticity, in addition to being related to the altered neurotransmission in Parkinson's disease. Therefore, they are considered new targets for improving the therapeutic strategies used to treat Parkinson's disease. In this review, we discuss the biological characteristics of these receptors and demonstrate the receptor-mediated neuroprotection in Parkinson's disease. Pharmacological manipulation of these receptors during anti-Parkinsonian processes in both experimental studies and clinical trials are also summarized.


Assuntos
Doença de Parkinson/etiologia , Doença de Parkinson/metabolismo , Receptores de Glutamato/metabolismo , Animais , Ensaios Clínicos como Assunto , Descoberta de Drogas , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Humanos , Terapia de Alvo Molecular , Neurotransmissores/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/patologia , Receptores de Glutamato/genética , Transdução de Sinais/efeitos dos fármacos , Substância Negra/metabolismo , Transmissão Sináptica , Resultado do Tratamento
5.
Psychopharmacology (Berl) ; 236(12): 3451-3463, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31267156

RESUMO

RATIONALE: The N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine is known to have not only a rapid antidepressant effect but also dissociative side effects. Traxoprodil and lanicemine, also NMDA antagonists, are candidate antidepressant drugs with fewer side effects. OBJECTIVES: In order to understand their mechanism of action, we investigated the acute effects of traxoprodil and lanicemine on brain connectivity using resting-state functional magnetic resonance imaging (rs-fMRI). METHODS: Functional connectivity (FC) alterations were examined using interregional correlation networks. Graph theoretical methods were used for whole brain network analysis. As interest in NMDAR antagonists as potential antidepressants was triggered by the antidepressant effect of ketamine, results were compared to previous findings from our ketamine studies. RESULTS: Similar to ketamine but to a smaller extent, traxoprodil increased hippocampal-prefrontal (Hc-PFC) coupling. Unlike ketamine, traxoprodil decreased connectivity within the PFC. Lanicemine had no effect on these properties. The improvement of Hc-PFC coupling corresponds well to clinical result, showing ketamine to have a greater antidepressant effect than traxoprodil, while lanicemine has a weak and transient effect. Connectivity changes overlapping between the drugs as well as alterations of local network properties occurred mostly in reward-related regions. CONCLUSION: The antidepressant effect of NMDA antagonists appears to be associated with enhanced Hc-PFC coupling. The effects on local network properties and regional connectivity suggest that improvement of reward processing might also be important for understanding the mechanisms underlying the antidepressant effects of these drugs.


Assuntos
Hipocampo/efeitos dos fármacos , Fenetilaminas/farmacologia , Piperidinas/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Piridinas/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Recompensa , Animais , Antidepressivos/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Hipocampo/diagnóstico por imagem , Hipocampo/fisiologia , Imagem por Ressonância Magnética/métodos , Masculino , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/fisiologia
6.
Nat Commun ; 10(1): 2655, 2019 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-31201320

RESUMO

CDKL5 deficiency disorder (CDD) is characterized by epilepsy, intellectual disability, and autistic features, and CDKL5-deficient mice exhibit a constellation of behavioral phenotypes reminiscent of the human disorder. We previously found that CDKL5 dysfunction in forebrain glutamatergic neurons results in deficits in learning and memory. However, the pathogenic origin of the autistic features of CDD remains unknown. Here, we find that selective loss of CDKL5 in GABAergic neurons leads to autistic-like phenotypes in mice accompanied by excessive glutamatergic transmission, hyperexcitability, and increased levels of postsynaptic NMDA receptors. Acute, low-dose inhibition of NMDAR signaling ameliorates autistic-like behaviors in GABAergic knockout mice, as well as a novel mouse model bearing a CDD-associated nonsense mutation, CDKL5 R59X, implicating the translational potential of this mechanism. Together, our findings suggest that enhanced NMDAR signaling and circuit hyperexcitability underlie autistic-like features in mouse models of CDD and provide a new therapeutic avenue to treat CDD-related symptoms.


Assuntos
Síndromes Epilépticas/patologia , Neurônios GABAérgicos/patologia , Proteínas Serina-Treonina Quinases/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Transdução de Sinais/genética , Espasmos Infantis/patologia , Animais , Comportamento Animal/efeitos dos fármacos , Códon sem Sentido , Modelos Animais de Doenças , Síndromes Epilépticas/tratamento farmacológico , Síndromes Epilépticas/genética , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Feminino , Humanos , Masculino , Memantina/farmacologia , Memantina/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Prosencéfalo/citologia , Prosencéfalo/efeitos dos fármacos , Prosencéfalo/patologia , Proteínas Serina-Treonina Quinases/deficiência , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Espasmos Infantis/tratamento farmacológico , Espasmos Infantis/genética , Resultado do Tratamento
7.
Exp Eye Res ; 185: 107694, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31199905

RESUMO

Endogenous and synthetic cannabinoids have been shown to provide neuroprotection to retinal neurons in acute animal models of retinopathy. Chronic exposure to cannabinoid receptor (CB1R) agonists has been reported to induce downregulation of the CB1R in brain and behavioral tolerance. The aim of this study was to investigate the effect of subchronic/chronic cannabinoid administration on CB1R downregulation in normal rat retina, its downstream prosurvival signaling and subsequent effect on retinal neuroprotection against AMPA excitotoxicity. Sprague-Dawley rats were administered intraperitoneally with vehicle (Control), the endogenous N-arachidonoyl ethanolamine (AEA), and the synthetic cannabinoids R-(+)-Methanandamide (MethAEA) and HU-210 daily (25, 50, 100 µg/kg) for four or fourteen days (4d/14d, subchronic/chronic administration, respectively). HU-210 was also administered acutely as follows, vehicle injection for 13 days and a single dose of HU-210 on the 14th day. Immunohistochemistry studies and Western blot analysis were employed to assess CB1R expression in control and AMPA treated retinas and cannabinoid induced changes in Akt and ERK1/2 phosphorylation (ph). Real time PCR was employed to examine the effect of MethAEA (50 mg/kg,4d) on CB1R mRNA expression. AEA, MethAEA and HU-210 attenuated CB1R expression in a dose-dependent manner (25, 50, 100 µg/kg), after subchronic and chronic administration. No effect was observed at the lower dose of 25 µg/kg. MethAEA (50 mg/kg,4d) attenuated CB1R mRNA expression. AM251 (CB1 antagonist/inverse agonist, 0.5 mg/kg,4d), administered prior to HU-210 (50 µg/kg,4d) inhibited CB1R downregulation. Chronic/subchronic treatments (50 µg/kg) of HU-210 and MethAEA reduced levels of ph-Akt and ph-Akt/ph-ERK1/2, respectively. AEA had no effect on ph-Akt nor ph-ERK1/2. All three cannabinoids (50 µg/kg,4d) failed to protect brain nitric oxide synthetase (bNOS) expressing amacrine cells against AMPA excitotoxicity, in agreement with the downregulation of CB1 receptor. At the lower doses of 12.5 and 25 µg/kg, HU-210 protected bNOS-expressing amacrine cells. This study provides novel information regarding agonist-induced CB1R downregulation in rat retina after subchronic/chronic cannabinoid treatment, and its effect on downstream prosurvival signaling and neuroprotection.


Assuntos
Ácidos Araquidônicos/farmacologia , Dronabinol/análogos & derivados , Endocanabinoides/farmacologia , Receptor CB1 de Canabinoide/metabolismo , Retina/efeitos dos fármacos , Animais , Western Blotting , Regulação para Baixo , Dronabinol/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Feminino , Injeções Intraperitoneais , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Receptor CB1 de Canabinoide/genética , Retina/metabolismo , Transdução de Sinais/fisiologia
8.
Neuron ; 103(2): 309-322.e7, 2019 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-31151773

RESUMO

Body temperature control is essential for survival. In mammals, thermoregulation is mediated by the preoptic area of anterior hypothalamus (POA), with ∼30% of its neurons sensitive to brain temperature change. It is still unknown whether and how these temperature-sensitive neurons are involved in thermoregulation, because for eight decades they have only been identified via electrophysiological recording. By combining single-cell RNA-seq with whole-cell patch-clamp recordings, we identified Ptgds as a genetic marker for temperature-sensitive POA neurons. Then, we demonstrated these neurons' role in thermoregulation via chemogenetics. Given that Ptgds encodes the enzyme that synthesizes prostaglandin D2 (PGD2), we further explored its role in thermoregulation. Our study revealed that rising temperature of POA alters the activity of Ptgds-expressing neurons so as to increase PGD2 production. PGD2 activates its receptor DP1 and excites downstream neurons in the ventral medial preoptic area (vMPO) that mediates body temperature decrease, a negative feedback loop for thermoregulation.


Assuntos
Regulação da Temperatura Corporal/fisiologia , Neurônios/fisiologia , Área Pré-Óptica/citologia , Área Pré-Óptica/fisiologia , Prostaglandina D2/metabolismo , Temperatura Ambiente , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Temperatura Corporal/efeitos dos fármacos , Temperatura Corporal/fisiologia , Regulação da Temperatura Corporal/genética , Proteína 9 Associada à CRISPR/genética , Proteína 9 Associada à CRISPR/metabolismo , Clozapina/farmacologia , Dinoprostona/genética , Dinoprostona/metabolismo , Antagonistas de Aminoácidos Excitatórios/farmacologia , Regulação da Expressão Gênica/genética , Células HEK293 , Humanos , Locomoção/efeitos dos fármacos , Locomoção/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Área Pré-Óptica/efeitos dos fármacos , Prostaglandina D2/genética
9.
Cell Mol Neurobiol ; 39(7): 1039-1049, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31197744

RESUMO

Serotonin (5-HT) has been recognized as a neurotransmitter in the vertebrate retina, restricted mainly to amacrine and bipolar cells. It is involved with synaptic processing and possibly as a mitogenic factor. We confirm that chick retina amacrine and bipolar cells are, respectively, heavily and faintly immunolabeled for 5-HT. Amacrine serotonergic cells also co-express tyrosine hydroxylase (TH), a marker of dopaminergic cells in the retina. Previous reports demonstrated that serotonin transport can be modulated by neurotransmitter receptor activation. As 5-HT is diffusely released as a neuromodulator and co-localized with other transmitters, we evaluated if 5-HT uptake or release is modulated by several mediators in the avian retina. The role of different glutamate receptors on serotonin transport and release in vitro and in vivo was also studied. We show that L-glutamate induces an inhibitory effect on [3H]5-HT uptake and this effect was specific to kainate receptor activation. Kainate-induced decrease in [3H]5-HT uptake was blocked by CNQX, an AMPA/kainate receptor antagonist, but not by MK-801, a NMDA receptor antagonist. [3H]5-HT uptake was not observed in the presence of AMPA, thus suggesting that the decrease in serotonin uptake is mediated by kainate. 5-HT (10-50 µM) had no intrinsic activity in raising intracellular Ca2+, but addition of 10 µM 5-HT decreased Ca2+ shifts induced by KCl in retinal neurons. Moreover, kainate decreased the number of bipolar and amacrine cells labeled to serotonin in chick retina. In conclusion, our data suggest a highly selective effect of kainate receptors in the regulation of serotonin functions in the retinal cells.


Assuntos
Ácido Caínico/farmacologia , Retina/metabolismo , Serotonina/metabolismo , Animais , Cálcio/metabolismo , Células Cultivadas , Embrião de Galinha , Agonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Neurotransmissores/metabolismo , Receptores de Glutamato/metabolismo , Receptores de Ácido Caínico/metabolismo , Retina/citologia , Retina/efeitos dos fármacos , Retina/embriologia , Neurônios Retinianos/efeitos dos fármacos , Neurônios Retinianos/metabolismo , Trítio/metabolismo
10.
Life Sci ; 231: 116567, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31202839

RESUMO

AIMS: Metabotropic glutamate receptor 5 (mGluR5), a member of group I mGluR, exerts its effect via elevation of intracellular Ca2+ level. We here characterized Ca2+ signals in the tsA201 cells transfected with mGluR5 and investigated the role of passages for mGluR5-induced Ca2+ signals in synaptic plasticity. MAIN METHODS: Using a genetically encoded Ca2+ indicator, GCamp2, Ca2+ signals were reliably induced by bath application of (S)-3,5-dihydroxyphenylglycine, the group I mGluR agonist, in the tsA201 cells transfected with mGluR5. Using whole-cell recordings in the substantia gelatinosa (SG) neurons of the spinal trigeminal subnucleus caudalis (Vc), excitatory postsynaptic currents were recorded by stimulating the trigeminal tract. KEY FINDINGS: Ca2+ signals were mediated by "classical" or "canonical" transient receptor potential (TRPC) channels, particularly TRPC1/3/4/6, but not TRPC5, naturally existing in the tsA201 cells. Interestingly, the induction of Ca2+ signals was independent of the phospholipase C signaling pathway; instead, it critically involves the cyclic adenosine diphosphate ribose/ryanodine receptor-dependent signaling pathway and only partially protein kinase C. On the other hand, both TRPC3 and TRPC4 mediated mGluR1/5-induced long-lasting potentiation of excitatory synaptic transmission from the trigeminal primary afferents to the SG neurons of the Vc. SIGNIFICANCE: This study demonstrates that endogenous TRPC channels contribute to mGluR5-induced Ca2+ signals in tsA201 cells and synaptic plasticity at excitatory synapses.


Assuntos
Sinalização do Cálcio/fisiologia , Plasticidade Neuronal/efeitos dos fármacos , Receptor de Glutamato Metabotrópico 5/metabolismo , Canais de Cátion TRPC/metabolismo , Animais , Cálcio/metabolismo , Canais de Cálcio/metabolismo , Antagonistas de Aminoácidos Excitatórios/farmacologia , Potenciais Pós-Sinápticos Excitadores , Feminino , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Plasticidade Neuronal/fisiologia , Neurônios/metabolismo , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley , Receptores de Glutamato Metabotrópico/metabolismo , Sinapses/metabolismo , Transmissão Sináptica , Nervo Trigêmeo/metabolismo , Núcleo Espinal do Trigêmeo/metabolismo
11.
Biomolecules ; 9(5)2019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-31108896

RESUMO

A glutamate/NMDA receptor (NMDA-R) antagonist, amantadine (AMA) exhibits a broad spectrum of clinically important properties, including antiviral, antiparkinsonian, neuroprotective, neuro-reparative and cognitive-enhancing effects. However, both clinical and pre-clinical studies have demonstrated that noncompetitive NMDA-R antagonists induce severe schizophrenia-like cognitive deficits. Therefore, this study aims to clarify the clinical discrepancy between AMA and noncompetitive NMDA-R antagonists by comparing the effects of AMA with those of a noncompetitive NMDA-R antagonist, MK801, on rat tripartite glutamatergic synaptic transmission using microdialysis and primary cultured astrocytes. Microdialysis study demonstrated that the stimulatory effects of AMA on L-glutamate release differed from those of MK801 in the globus pallidus, entorhinal cortex and entopeduncular nucleus. The stimulatory effect of AMA on L-glutamate release was modulated by activation of cystine/glutamate antiporter (Sxc). Primary cultured astrocytes study demonstrated that AMA also enhanced glutathione synthesis via Sxc activation. Furthermore, carbon-monoxide induced damage of the astroglial glutathione synthesis system was repaired by AMA but not MK801. Additionally, glutamate/AMPA receptor (AMPA-R) antagonist, perampanel enhanced the protective effects of AMA. The findings of microdialysis and cultured astrocyte studies suggest that a combination of Sxc activation with inhibitions of ionotropic glutamate receptors contributes to neuroprotective, neuro-reparative and cognitive-enhancing activities that can mitigate several neuropsychiatric disorders.


Assuntos
Amantadina/farmacologia , Sistemas de Transporte de Aminoácidos Acídicos/agonistas , Astrócitos/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Sistemas de Transporte de Aminoácidos Acídicos/metabolismo , Animais , Astrócitos/metabolismo , Células Cultivadas , Maleato de Dizocilpina/farmacologia , Glutationa/metabolismo , Masculino , Piridonas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de AMPA/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Transmissão Sináptica
12.
Neurosci Lett ; 706: 36-42, 2019 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-31078678

RESUMO

Ketamine, an anesthetic, is a non-competitive antagonist of the calcium-permeable N-methyl-d-aspartate (NMDA) receptor. High concentrations of ketamine have been implicated in cardiotoxicity and neurotoxicity. Often, these toxicities are thought to be mediated by reactive oxygen species (ROS). However, findings to the contrary showing ketamine reducing ROS in mammalian cells and neurons in vitro, are emerging. Here, we determined the effects of ketamine on ROS levels in zebrafish larvae in vivo. Based on our earlier studies demonstrating reduction in ATP levels by ketamine, we hypothesized that as a calcium antagonist, ketamine would also prevent ROS generation, which is a by-product of ATP synthesis. To confirm that the detected ROS in a whole organism, such as the zebrafish larva, is specific, we used diphenyleneiodonium (DPI) that blocks ROS production by inhibiting the NADPH Oxidases (NOX). Upon 20 h exposure, DPI (5 and 10 µM) and ketamine at (1 and 2 mM) reduced ROS in the zebrafish larvae in vivo. Using acetyl l-carnitine (ALCAR), a dietary supplement, that induces mitochondrial ATP synthesis, we show elevated ROS generation with increasing ALCAR concentrations. Combined, ketamine and ALCAR counter-balanced ROS generation in the larvae suggesting that ketamine and ALCAR have opposing effects on mitochondrial metabolism, which may be key to maintaining ROS homeostasis in the larvae and affords ALCAR the ability to prevent ketamine toxicity. These results for the first time show ketamine's antioxidative and ALCAR's prooxidative effects in a live vertebrate.


Assuntos
Acetilcarnitina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ketamina/farmacologia , Neurônios/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Animais , Embrião não Mamífero/efeitos dos fármacos , Microscopia de Fluorescência , Neurônios/metabolismo , Oniocompostos/farmacologia , Peixe-Zebra
13.
Exp Brain Res ; 237(7): 1593-1614, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31079238

RESUMO

Antidepressant drugs are a standard biological treatment for various neuropsychiatric disorders, yet relatively little is known about their electrophysiologic and synaptic effects on mood systems that set moment-to-moment emotional tone. In vivo electrical recording of local field potentials (LFPs) and single neuron spiking has been crucial for elucidating important details of neural processing and control in many other systems, and yet electrical approaches have not been broadly applied to the actions of antidepressants on mood-related circuits. Here we review the literature encompassing electrophysiologic effects of antidepressants in animals, including studies that examine older drugs, and extending to more recently synthesized novel compounds, as well as rapidly acting antidepressants. The existing studies on neuromodulator-based drugs have focused on recording in the brainstem nuclei, with much less known about their effects on prefrontal or sensory cortex. Studies on neuromodulatory drugs have moreover focused on single unit firing patterns with less emphasis on LFPs, whereas the rapidly acting antidepressant literature shows the opposite trend. In a synthesis of this information, we hypothesize that all classes of antidepressants could have common final effects on limbic circuitry. Whereas NMDA receptor blockade may induce a high powered gamma oscillatory state via direct and fast alteration of glutamatergic systems in mood-related circuits, neuromodulatory antidepressants may induce similar effects over slower timescales, corresponding with the timecourse of response in patients, while resetting synaptic excitatory versus inhibitory signaling to a normal level. Thus, gamma signaling may provide a biomarker (or "neural readout") of the therapeutic effects of all classes of antidepressants.


Assuntos
Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Ritmo Gama/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Antidepressivos/farmacologia , Depressão/fisiopatologia , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Fenômenos Eletrofisiológicos/fisiologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Ritmo Gama/fisiologia , Humanos , Córtex Pré-Frontal/fisiopatologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/fisiologia
14.
Neurobiol Learn Mem ; 162: 59-66, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31085330

RESUMO

Memory is related to the function of N-methyl-D-aspartate (NMDA) receptors. Depending on the dose, NMDA receptor antagonists (such as memantine or MK-801) can impair memory and/or cognitive as well as procedural functions, while they also can prevent the long-term toxic effects of over-excitation of these receptors in pathophysiological processes. There is an unresolved question of whether memantine at low doses could exert an acute pro-cognitive activity. A therapeutic dose of memantine was found to improve short-term spatial memory tested in the alternation version of active place avoidance in a Carousel Maze, whereas no data are available on long-term memory in various versions of place avoidance. In an effort to reconcile this issue, rats were administered memantine (5 mg/kg) 30 min before a training session and trained in two different versions of place avoidance. A control group received saline injections. In an active place avoidance task (hereby referred to as Room+Arena-), this place was fixed to distal room cues, whereas cues from the arena were misleading. Performance thus demanded the on-going segregation of information that engages cognitive coordination. Following the Room+Arena- training, rats were trained in another place avoidance task (hereby referred to as Arena+), which requires focusing on substratal and idiothetic cues from the arena. In this version, a to-be-avoided sector rotated along with the arena in darkness that hid the extramaze cues. The rats given memantine avoided better than the control rats in the Room+Arena- task. In the Arena+ task, both groups had problems with acquiring the task. Subsequently, memantine was withdrawn and both groups relearned Room+Arena- avoidance with a new sector position. In this task, no effect of groups was seen. In conclusion, memantine at a therapeutic dose improved performance in a task that required the segregation of spatial stimuli into coherent subsets.


Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Memantina/farmacologia , Memória Espacial/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Sinais (Psicologia) , Masculino , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores
15.
ACS Chem Biol ; 14(5): 1002-1010, 2019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-31026143

RESUMO

Plasma-membrane glutamate transporters of the excitatory amino acid transporter (EAAT) family are important for maintaining a low glutamate concentration in the extracellular space of the mammalian brain. Glutamate is believed to be transported in its negatively charged form and energetically driven by the cotransport of three sodium ions, at least two of which are bound within the dielectric of the membrane. It was hypothesized that binding of substrates and competitive inhibitors is also electrogenic because the binding site is located near the center of the membrane. To test this hypothesis, we rapidly applied a low-affinity competitive inhibitor, kainate, to the glutamate transporter subtype EAAT2, resulting in outward transient current caused by movement of net negative charge of the inhibitor into the low dielectric of the protein/membrane. Consistent with these data, rate constants for inhibitor dissociation and binding were also voltage dependent. Our results are supported by electrostatic calculations and molecular dynamics simulations of spontaneous substrate dissociation, showing that the substrate and inhibitor binding site is located within the membrane environment of low dielectric constant. Charge movement caused by binding of negatively charged amino acid substrate is compensated by the charge of cotransported Na+ ion(s), thus preventing inhibition of substrate binding at negative membrane potentials. This charge compensation mechanism may be relevant for other Na+-driven transporters which recognize negatively charged substrates.


Assuntos
Sistema X-AG de Transporte de Aminoácidos/metabolismo , Antagonistas de Aminoácidos Excitatórios/farmacologia , Sistema X-AG de Transporte de Aminoácidos/antagonistas & inibidores , Animais , Fenômenos Biofísicos , Encéfalo/metabolismo , Ácido Caínico/metabolismo , Cinética , Mamíferos , Potenciais da Membrana , Simulação de Dinâmica Molecular , Especificidade por Substrato
17.
Neurobiol Dis ; 127: 390-397, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30928642

RESUMO

Tuberous sclerosis (TSC) is an autosomal dominant disorder caused by heterozygous mutations in the TSC1 or TSC2 gene. TSC is often associated with neurological, cognitive, and behavioral deficits. TSC patients also express co-morbidity with anxiety and mood disorders. The mechanism of pathogenesis in TSC is not entirely clear, but TSC-related neurological symptoms are accompanied by excessive glutamatergic activity and altered synaptic spine structures. To address whether extrasynaptic (e)NMDA-type glutamate receptor (NMDAR) antagonists, as opposed to antagonists that block physiological phasic synaptic activity, can ameliorate the synaptic and behavioral features of this disease, we utilized the Tsc2+/- mouse model of TSC to measure biochemical, electrophysiological, histological, and behavioral parameters in the mice. We found that antagonists that preferentially block tonic activity as found at eNMDARs, particularly the newer drug NitroSynapsin, provide biological and statistically significant improvement in Tsc2+/- phenotypes. Accompanying this improvement was correction of activity in the p38 MAPK-TSC-Rheb-mTORC1-S6K1 pathway. Deficits in hippocampal long-term potentiation (LTP), histological loss of synapses, and behavioral fear conditioning in Tsc2+/- mice were all improved after treatment with NitroSynapsin. Taken together, these results suggest that amelioration of excessive excitation, by limiting aberrant eNMDAR activity, may represent a novel treatment approach for TSC.


Assuntos
Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Hipocampo/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Esclerose Tuberosa/tratamento farmacológico , Animais , Modelos Animais de Doenças , Antagonistas de Aminoácidos Excitatórios/farmacologia , Hipocampo/metabolismo , Camundongos , Camundongos Knockout , Esclerose Tuberosa/genética , Esclerose Tuberosa/metabolismo , Proteína 2 do Complexo Esclerose Tuberosa/genética , Proteína 2 do Complexo Esclerose Tuberosa/metabolismo
18.
Neuropharmacology ; 151: 74-83, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30959020

RESUMO

Consistent experimental evidence supports an important role of the glutamatergic system in the etiopathogenesis of schizophrenia. Numerous studies propose that blockade of the NMDA receptor by its antagonist ketamine impairs cognition and can mimic certain aspects of positive and negative symptoms of schizophrenia in rodents. Neuroactive steroids, including dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulphate (DHEAS) were shown to affect brain glutamatergic system and to be implicated in schizophrenia. BNN27 is a novel DHEA derivative, which is devoid of steroidogenic activity. The neuroprotective effects of BNN27 have been recently evidenced. The aim of the present study was to investigate the ability of BNN27 to counteract schizophrenia-like behavioural deficits produced by ketamine in rats. BNN27's ability to attenuate hypermotility, stereotypies and ataxia induced by ketamine were evaluated using a motor activity cage. To assess the efficacy of BNN27 to reverse non-spatial and spatial recognition memory deficits caused by ketamine, the object recognition task and the object location task were used. Finally, the social interaction test was utilized in order to examine the effects of BNN27 on ketamine-induced social withdrawal. BNN27 (3 and 6 mg/kg, i.p.) attenuated ketamine (10 mg/kg, i.p.)-induced ataxia and to some extent also hypermotility. BNN27 (3-6 mg/kg, i.p.) counteracted ketamine (3 mg/kg, i.p.)-induced non-spatial and spatial recognition memory deficits. Further, BNN27 (6 mg/kg, i.p.) reduced the ketamine (8 mg/kg, i.p.)-induced social isolation. Our findings show that BNN27 is sensitive to glutamate hypofunction produced by ketamine since it reduced schizophrenia-like behavioural deficits induced by this NMDA receptor antagonist in rats.


Assuntos
Comportamento Animal/efeitos dos fármacos , Desidroepiandrosterona/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ketamina/farmacologia , Atividade Motora/efeitos dos fármacos , Comportamento Social , Memória Espacial/efeitos dos fármacos , Animais , Masculino , Ratos , Ratos Wistar , Isolamento Social
19.
Neuropharmacology ; 151: 64-73, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30943384

RESUMO

Behavioral studies using pharmacological tools have implicated histamine H1 receptors in cognitive function via their interactions with N-methyl-D-aspartate receptors (NMDARs) in the hippocampus. However, little is known about the neurophysiological mechanism that underlies the interaction between H1 receptors and NMDARs. To explore how H1 receptor activation affects hippocampal excitatory neurotransmission and synaptic plasticity, this study aimed to examine the effect of H1 receptor ligands on both NMDAR-mediated synaptic currents and long-term potentiation (LTP) at synapses between Schaffer collaterals and CA1 pyramidal neurons using acute mouse hippocampal slices. We found that the H1 receptor antagonist/inverse agonists, pyrilamine (0.1 µM) and cetirizine (10 µM), decreased the NMDAR-mediated component of stimulation-induced excitatory postsynaptic currents (EPSCs) recorded from CA1 pyramidal neurons without affecting the AMPA receptor-mediated component of EPSCs and its paired pulse ratio. Pretreatment of slices with either the glial metabolism inhibitor, fluoroacetate (5 mM), or D-serine (100 µM) diminished the pyrilamine- or cetirizine-induced attenuation of the NMDAR-mediated EPSCs. Furthermore, the LTP of field excitatory postsynaptic potentials induced following high frequency stimulation of Schaffer collaterals was attenuated with application of pyrilamine or cetirizine. Pretreatment with D-serine again attenuated the pyrilamine-induced suppression of LTP. Our data suggest that H1 receptors in the CA1 can undergo persistent activation induced by their constitutive receptor activity and/or tonic release of endogenous histamine, resulting in facilitation of the NMDAR activity in a manner dependent of astrocytes and the release of D-serine. This led to the enhancement of NMDA-component EPSC and LTP at the Schaffer collateral-CA1 pyramidal neuron synapses.


Assuntos
Astrócitos/efeitos dos fármacos , Região CA1 Hipocampal/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos H1/farmacologia , Potenciação de Longa Duração/efeitos dos fármacos , Receptores Histamínicos H1/metabolismo , Serina/farmacologia , Animais , Astrócitos/metabolismo , Região CA1 Hipocampal/fisiologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciação de Longa Duração/fisiologia , Camundongos , N-Metilaspartato/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Pirilamina/farmacologia , Receptores de N-Metil-D-Aspartato/agonistas , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Valina/análogos & derivados , Valina/farmacologia
20.
Exp Neurol ; 316: 27-38, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30974102

RESUMO

In amyotrophic lateral sclerosis (ALS), upregulation in expression and activity of the ABC transporter P-glycoprotein (P-gp) driven by disease advancement progressively reduces CNS penetration and efficacy of the ALS drug, riluzole. Post-mortem spinal cord tissues from ALS patients revealed elevated P-gp expression levels in endothelial cells of the blood-spinal cord barrier compared to levels measured in control, non-diseased individuals. We recently found that astrocytes expressing familial ALS-linked SOD1 mutations regulate expression levels of P-gp in endothelial cells, which also exhibit a concomitant, significant increase in reactive oxygen species production and NFκB nuclear translocation when exposed to mutant SOD1 astrocyte conditioned media. In this study, we found that glutamate, which is abnormally secreted by mutant SOD1 and sporadic ALS astrocytes, drives upregulation of P-gp expression and activity levels in endothelial cells via activation of N-Methyl-D-Aspartic acid (NMDA) receptors. Surprisingly, astrocyte-secreted glutamate regulation of endothelial P-gp levels is not a mechanism shared by all forms of ALS. C9orf72-ALS astrocytes had no effect on endothelial cell P-gp expression and did not display increased glutamate secretion. Utilizing an optimized in vitro human BBB model consisting of patient-derived induced pluripotent stem cells, we showed that co-culture of endothelial cells with patient-derived astrocytes increased P-gp expression levels and transport activity, which was significantly reduced when endothelial cells were incubated with the NMDAR antagonist, MK801. Overall, our findings unraveled a complex molecular interplay between astrocytes of different ALS genotypes and endothelial cells potentially occurring in disease that could differentially impact ALS prognosis and efficacy of pharmacotherapies.


Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/biossíntese , Esclerose Amiotrófica Lateral/metabolismo , Astrócitos/metabolismo , Células Endoteliais/metabolismo , Ácido Glutâmico/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Animais , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Capilares/metabolismo , Células Cultivadas , Meios de Cultivo Condicionados , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Humanos , Mutação/genética , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/biossíntese , Receptores de N-Metil-D-Aspartato/genética , Superóxido Dismutase-1/genética , Regulação para Cima
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