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1.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34360983

RESUMO

Febrile seizures (FSs) in early life are significant risk factors of neurological disorders and cognitive impairment in later life. However, existing data about the impact of FSs on the developing brain are conflicting. We aimed to investigate morphological and functional changes in the hippocampus of young rats exposed to hyperthermia-induced seizures at postnatal day 10. We found that FSs led to a slight morphological disturbance. The cell numbers decreased by 10% in the CA1 and hilus but did not reduce in the CA3 or dentate gyrus areas. In contrast, functional impairments were robust. Long-term potentiation (LTP) in CA3-CA1 synapses was strongly reduced, which we attribute to the insufficient activity of N-methyl-D-aspartate receptors (NMDARs). Using whole-cell recordings, we found higher desensitization of NMDAR currents in the FS group. Since the desensitization of NMDARs depends on subunit composition, we analyzed NMDAR current decays and gene expression of subunits, which revealed no differences between control and FS rats. We suggest that an increased desensitization is due to insufficient activation of the glycine site of NMDARs, as the application of D-serine, the glycine site agonist, allows the restoration of LTP to a control value. Our results reveal a new molecular mechanism of FS impact on the developing brain.


Assuntos
Hipocampo/fisiopatologia , Potenciação de Longa Duração , Animais , Hipocampo/crescimento & desenvolvimento , Hipocampo/metabolismo , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Convulsões Febris/metabolismo , Convulsões Febris/fisiopatologia , Potenciais Sinápticos
2.
Int J Mol Sci ; 22(15)2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34360755

RESUMO

Increasing attention is being focused on the use of polypeptide-based N-methyl-d-aspartate (NMDA) receptor antagonists for the treatment of nervous system disorders. In our study on Achyranthes bidentata Blume, we identified an NMDA receptor subtype 2B (NR2B) antagonist that exerts distinct neuroprotective actions. This antagonist is a 33 amino acid peptide, named bidentatide, which contains three disulfide bridges that form a cysteine knot motif. We determined the neuroactive potential of bidentatide by evaluating its in vitro effects against NMDA-mediated excitotoxicity. The results showed that pretreating primary cultured hippocampal neurons with bidentatide prevented NMDA-induced cell death and apoptosis via multiple mechanisms that involved intracellular Ca2+ inhibition, NMDA current inhibition, and apoptosis-related protein expression regulation. These mechanisms were all dependent on bidentatide-induced inhibitory regulation of NR2B-containing NMDA receptors; thus, bidentatide may contribute to the development of neuroprotective agents that would likely possess the high selectivity and safety profiles inherent in peptide drugs.


Assuntos
Achyranthes/química , Hipocampo/metabolismo , Neurônios/metabolismo , Fármacos Neuroprotetores , Peptídeos , Proteínas de Plantas , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Cálcio/metabolismo , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/isolamento & purificação , Fármacos Neuroprotetores/farmacologia , Peptídeos/química , Peptídeos/isolamento & purificação , Peptídeos/farmacologia , Proteínas de Plantas/química , Proteínas de Plantas/isolamento & purificação , Proteínas de Plantas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo
3.
Biomed Res Int ; 2021: 1156031, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34423030

RESUMO

Here, we report the participation of N-methyl-D-aspartate (NMDA) glutamate receptor in the mediation of cardiovascular and circulating vasopressin responses evoked by a hemorrhagic stimulus. In addition, once NMDA receptor activation is a prominent mechanism involved in nitric oxide (NO) synthesis in the brain, we investigated whether control of hemorrhagic shock by NMDA glutamate receptor was followed by changes in NO synthesis in brain supramedullary structures involved in cardiovascular and neuroendocrine control. Thus, we observed that intraperitoneal administration of the selective NMDA glutamate receptor antagonist dizocilpine maleate (MK801, 0.3 mg/kg) delayed and reduced the magnitude of hemorrhage-induced hypotension. Besides, hemorrhage induced a tachycardia response in the posthemorrhage period (i.e., recovery period) in control animals, and systemic treatment with MK801 caused a bradycardia response during hemorrhagic shock. Hemorrhagic stimulus increased plasma vasopressin levels during the recovery period and NMDA receptor antagonism increased concentration of this hormone during both the hemorrhage and postbleeding periods in relation to control animals. Moreover, hemorrhagic shock caused a decrease in NOx levels in the paraventricular nucleus of the hypothalamus (PVN), amygdala, bed nucleus of the stria terminalis (BNST), and ventral periaqueductal gray matter (vPAG). Nevertheless, treatment with MK801 did not affect these effects. Taken together, these results indicate that the NMDA glutamate receptor is involved in the hemorrhagic shock by inhibiting circulating vasopressin release. Our data also suggest a role of the NMDA receptor in tachycardia, but not in the decreased NO synthesis in the brain evoked by hemorrhage.


Assuntos
Bradicardia/induzido quimicamente , Sistema Cardiovascular/metabolismo , Maleato de Dizocilpina/administração & dosagem , Choque Hemorrágico/metabolismo , Vasopressinas/sangue , Animais , Bradicardia/sangue , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Sistema Cardiovascular/efeitos dos fármacos , Modelos Animais de Doenças , Maleato de Dizocilpina/efeitos adversos , Injeções Intraperitoneais , Masculino , Sistemas Neurossecretores/efeitos dos fármacos , Sistemas Neurossecretores/metabolismo , Óxido Nítrico/metabolismo , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo
4.
Biomolecules ; 11(7)2021 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-34356650

RESUMO

Evidence from clinical and preclinical studies implicates dysfunction of N-methyl-D-aspartate receptors (NMDARs) in schizophrenia progression and symptoms. We investigated the antipsychotic effect of two neuroactive steroids in an animal model of schizophrenia induced by systemic application of MK-801. The neuroactive steroids differ in their mechanism of action at NMDARs. MS-249 is positive, while PA-Glu is a negative allosteric NMDAR modulator. We hypothesized that the positive NMDA receptor modulator would attenuate deficits caused by MK-801 co-application more effectively than PA-Glu. The rats were tested in a battery of tests assessing spontaneous locomotion, anxiety and cognition. Contrary to our expectations, PA-Glu exhibited a superior antipsychotic effect to MS-249. The performance of MS-249-treated rats in cognitive tests differed depending on the level of stress the rats were exposed to during test sessions. In particular, with the increasing severity of stress exposure, the performance of animals worsened. Our results demonstrate that enhancement of NMDAR function may result in unspecific behavioral responses. Positive NMDAR modulation can influence other neurobiological processes besides memory formation, such as anxiety and response to stress.


Assuntos
Maleato de Dizocilpina/farmacologia , Receptores de N-Metil-D-Aspartato/metabolismo , Esquizofrenia/tratamento farmacológico , Esteroides/farmacologia , Animais , Antipsicóticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Modelos Animais de Doenças , Teste de Labirinto em Cruz Elevado , Células HEK293 , Humanos , Masculino , Pregnenolona/metabolismo , Pregnenolona/farmacologia , Ratos Long-Evans , Ratos Wistar , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Reflexo de Sobressalto/efeitos dos fármacos , Esquizofrenia/metabolismo
5.
Int J Mol Sci ; 22(16)2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34445376

RESUMO

Synaptic plasticity is the key to synaptic health, and aberrant synaptic plasticity, which in turn impairs the functioning of large-scale brain networks, has been associated with neurodegenerative and psychiatric disorders. The best known and most studied form of activity-dependent synaptic plasticity remains long-term potentiation (LTP), which is controlled by glutamatergic N-methyl-d-aspartate) receptors (NMDAR) and considered to be a mechanism crucial for cellular learning and memory. Over the past two decades, discrepancies have arisen in the literature regarding the contribution of NMDAR subunit assemblies in the direction of NMDAR-dependent synaptic plasticity. Here, the nonspecific NMDAR antagonist ketamine (5 and 10 mg/kg), and the selective NR2B antagonists CP-101606 and Ro 25-6981 (6 and 10 mg/kg), were administered intraperitoneally in Sprague Dawley rats to disentangle the contribution of NR2B subunit in the LTP induced at the Schaffer Collateral-CA1 synapse using the theta burst stimulation protocol (TBS). Ketamine reduced, while CP-101606 and Ro 25-6981 did not alter the LTP response. The administration of CP-101606 before TBS did not influence the effects of ketamine when administered half an hour after tetanization, suggesting a limited contribution of the NR2B subunit in the action of ketamine. This work confirms the role of NMDAR in the LTP form of synaptic plasticity, whereas specific blockade of the NR2B subunit was not sufficient to modify hippocampal LTP. Pharmacokinetics at the doses used may have contributed to the lack of effects with specific antagonists. The findings refute the role of the NR2B subunit in the plasticity mechanism of ketamine in the model.


Assuntos
Ketamina/administração & dosagem , Fenóis/administração & dosagem , Piperidinas/administração & dosagem , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapses/metabolismo , Animais , Injeções Intraperitoneais , Ketamina/farmacologia , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Plasticidade Neuronal/efeitos dos fármacos , Fenóis/farmacologia , Piperidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores
6.
Biol Psychiatry ; 90(7): 458-472, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34274107

RESUMO

BACKGROUND: Major depressive disorder is a common, recurrent illness. Recent studies have implicated the NMDA receptor in the pathophysiology of major depressive disorder. (R,S)-ketamine, an NMDA receptor antagonist, is an effective antidepressant but has numerous side effects. Here, we characterized a novel NMDA receptor antagonist, fluoroethylnormemantine (FENM), to determine its effectiveness as a prophylactic and/or antidepressant against stress-induced maladaptive behavior. METHODS: Saline, memantine (10 mg/kg), (R,S)-ketamine (30 mg/kg), or FENM (10, 20, or 30 mg/kg) was administered before or after contextual fear conditioning in 129S6/SvEv mice. Drug efficacy was assayed using various behavioral tests. Protein expression in the hippocampus was quantified with immunohistochemistry or Western blotting. In vitro radioligand binding was used to assay drug binding affinity. Patch clamp electrophysiology was used to determine the effect of drug administration on glutamatergic activity in ventral hippocampal cornu ammonis 3 (vCA3) 1 week after injection. RESULTS: Given after stress, FENM decreased behavioral despair and reduced perseverative behavior. When administered after re-exposure, FENM facilitated extinction learning. As a prophylactic, FENM attenuated learned fear and decreased stress-induced behavioral despair. FENM was behaviorally effective in both male and female mice. (R,S)-ketamine, but not FENM, increased expression of c-fos in vCA3. Both (R,S)-ketamine and FENM attenuated large-amplitude AMPA receptor-mediated bursts in vCA3, indicating a common neurobiological mechanism for further study. CONCLUSIONS: Our results indicate that FENM is a novel drug that is efficacious when administered at various times before or after stress. Future work will further characterize FENM's mechanism of action with the goal of clinical development.


Assuntos
Transtorno Depressivo Maior , Ketamina , Memantina/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Feminino , Ketamina/farmacologia , Masculino , Memantina/análogos & derivados , Camundongos , Estresse Psicológico
7.
Nature ; 596(7871): 301-305, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34321660

RESUMO

Ketamine is a non-competitive channel blocker of N-methyl-D-aspartate (NMDA) receptors1. A single sub-anaesthetic dose of ketamine produces rapid (within hours) and long-lasting antidepressant effects in patients who are resistant to other antidepressants2,3. Ketamine is a racemic mixture of S- and R-ketamine enantiomers, with S-ketamine isomer being the more active antidepressant4. Here we describe the cryo-electron microscope structures of human GluN1-GluN2A and GluN1-GluN2B NMDA receptors in complex with S-ketamine, glycine and glutamate. Both electron density maps uncovered the binding pocket for S-ketamine in the central vestibule between the channel gate and selectivity filter. Molecular dynamics simulation showed that S-ketamine moves between two distinct locations within the binding pocket. Two amino acids-leucine 642 on GluN2A (homologous to leucine 643 on GluN2B) and asparagine 616 on GluN1-were identified as key residues that form hydrophobic and hydrogen-bond interactions with ketamine, and mutations at these residues reduced the potency of ketamine in blocking NMDA receptor channel activity. These findings show structurally how ketamine binds to and acts on human NMDA receptors, and pave the way for the future development of ketamine-based antidepressants.


Assuntos
Microscopia Crioeletrônica , Ketamina/química , Ketamina/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/ultraestrutura , Antidepressivos/química , Antidepressivos/metabolismo , Antidepressivos/farmacologia , Asparagina/química , Asparagina/metabolismo , Sítios de Ligação , Ácido Glutâmico/química , Ácido Glutâmico/metabolismo , Ácido Glutâmico/farmacologia , Glicina/química , Glicina/metabolismo , Glicina/farmacologia , Humanos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Ketamina/metabolismo , Leucina/química , Leucina/metabolismo , Simulação de Dinâmica Molecular , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/ultraestrutura , Receptores de N-Metil-D-Aspartato/química , Receptores de N-Metil-D-Aspartato/metabolismo
8.
PLoS Comput Biol ; 17(5): e1009002, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33974632

RESUMO

NMDA receptors promote repolarization in pancreatic beta cells and thereby reduce glucose-stimulated insulin secretion. Therefore, NMDA receptors are a potential therapeutic target for diabetes. While the mechanism of NMDA receptor inhibition in beta cells is rather well understood at the molecular level, its possible effects on the collective cellular activity have not been addressed to date, even though proper insulin secretion patterns result from well-synchronized beta cell behavior. The latter is enabled by strong intercellular connectivity, which governs propagating calcium waves across the islets and makes the heterogeneous beta cell population work in synchrony. Since a disrupted collective activity is an important and possibly early contributor to impaired insulin secretion and glucose intolerance, it is of utmost importance to understand possible effects of NMDA receptor inhibition on beta cell functional connectivity. To address this issue, we combined confocal functional multicellular calcium imaging in mouse tissue slices with network science approaches. Our results revealed that NMDA receptor inhibition increases, synchronizes, and stabilizes beta cell activity without affecting the velocity or size of calcium waves. To explore intercellular interactions more precisely, we made use of the multilayer network formalism by regarding each calcium wave as an individual network layer, with weighted directed connections portraying the intercellular propagation. NMDA receptor inhibition stabilized both the role of wave initiators and the course of waves. The findings obtained with the experimental antagonist of NMDA receptors, MK-801, were additionally validated with dextrorphan, the active metabolite of the approved drug dextromethorphan, as well as with experiments on NMDA receptor KO mice. In sum, our results provide additional and new evidence for a possible role of NMDA receptor inhibition in treatment of type 2 diabetes and introduce the multilayer network paradigm as a general strategy to examine effects of drugs on connectivity in multicellular systems.


Assuntos
Células Secretoras de Insulina/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Diabetes Mellitus Tipo 2/metabolismo , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Glucose/metabolismo , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Camundongos , Camundongos Knockout
9.
Psychopharmacology (Berl) ; 238(8): 2325-2334, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33944972

RESUMO

RATIONALE: Schizophrenia patients consistently show deficits in sensory-evoked broadband gamma oscillations and click-evoked entrainment at 40 Hz, called the 40-Hz auditory steady-state response (ASSR). Since such evoked oscillations depend on cortical N-methyl D-aspartic acid (NMDA)-mediated network activity, they can serve as pharmacodynamic biomarkers in the preclinical and clinical development of drug candidates engaging these circuits. However, there are few test-retest reliability data in preclinical species, a prerequisite for within-subject testing paradigms. OBJECTIVE: We investigated the long-term psychometric stability of these measures in a rodent model. METHODS: Female rats with chronic epidural implants were used to record tone- and 40 Hz click-evoked responses at multiple time points and across six sessions, spread over 3 weeks. We assessed reliability using intraclass correlation coefficients (ICC). Separately, we used mixed-effects ANOVA to examine time and session effects. Individual subject variability was determined using the coefficient of variation (CV). Lastly, to illustrate the importance of long-term measure stability for within-subject testing design, we used low to moderate doses of an NMDA antagonist MK801 (0.025-0.15 mg/kg) to disrupt the evoked response. RESULTS: We found that 40-Hz ASSR showed good reliability (ICC=0.60-0.75), while the reliability of tone-evoked gamma ranged from poor to good (0.33-0.67). We noted time but no session effects. Subjects showed a lower variance for ASSR over tone-evoked gamma. Both measures were dose-dependently attenuated by NMDA antagonism. CONCLUSION: Overall, while both evoked gamma measures use NMDA transmission, 40-Hz ASSR showed superior psychometric properties of higher ICC and lower CV, relative to tone-evoked gamma.


Assuntos
Antagonistas de Aminoácidos Excitatórios/farmacologia , Ritmo Gama/efeitos dos fármacos , Ritmo Gama/fisiologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/fisiologia , Estimulação Acústica/métodos , Estimulação Acústica/normas , Animais , Maleato de Dizocilpina/farmacologia , Relação Dose-Resposta a Droga , Potenciais Evocados Auditivos/efeitos dos fármacos , Potenciais Evocados Auditivos/fisiologia , Agonistas de Aminoácidos Excitatórios/farmacologia , Feminino , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/agonistas , Reprodutibilidade dos Testes
10.
Int J Mol Sci ; 22(9)2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33946908

RESUMO

Alterations of zinc homeostasis have long been implicated in Parkinson's disease (PD). Zinc plays a complex role as both deficiency and excess of intracellular zinc levels have been incriminated in the pathophysiology of the disease. Besides its role in multiple cellular functions, Zn2+ also acts as a synaptic transmitter in the brain. In the forebrain, subset of glutamatergic neurons, namely cortical neurons projecting to the striatum, use Zn2+ as a messenger alongside glutamate. Overactivation of the cortico-striatal glutamatergic system is a key feature contributing to the development of PD symptoms and dopaminergic neurotoxicity. Here, we will cover recent evidence implicating synaptic Zn2+ in the pathophysiology of PD and discuss its potential mechanisms of actions. Emphasis will be placed on the functional interaction between Zn2+ and glutamatergic NMDA receptors, the most extensively studied synaptic target of Zn2+.


Assuntos
Doença de Parkinson/fisiopatologia , Sinapses/fisiologia , Zinco/fisiologia , Animais , Gânglios da Base/fisiopatologia , Proteínas de Transporte de Cátions/deficiência , Córtex Cerebral/fisiopatologia , Quelantes/farmacologia , Quelantes/uso terapêutico , Corpo Estriado/fisiopatologia , Feminino , Homeostase , Humanos , Líquido Intracelular/metabolismo , Masculino , Camundongos , Camundongos Knockout , Degeneração Neural/fisiopatologia , Oxidopamina/toxicidade , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/fisiopatologia , Ratos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/fisiologia , Transmissão Sináptica/fisiologia
11.
Eur J Med Chem ; 219: 113434, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-33892271

RESUMO

Tacrine is a classic drug whose efficacy against neurodegenerative diseases is still shrouded in mystery. It seems that besides its inhibitory effect on cholinesterases, the clinical benefit is co-determined by NMDAR-antagonizing activity. Our previous data showed that the direct inhibitory effect of tacrine, as well as its 7-methoxy derivative (7-MEOTA), is ensured via a "foot-in-the-door" open-channel blockage, and that interestingly both tacrine and 7-MEOTA are slightly more potent at the GluN1/GluN2A receptors when compared with the GluN1/GluN2B receptors. Here, we report that in a series of 30 novel tacrine derivatives, designed for assessment of structure-activity relationship, blocking efficacy differs among different compounds and receptors using electrophysiology with HEK293 cells expressing the defined types of NMDARs. Selected compounds (4 and 5) potently inhibited both GluN1/GluN2A and GluN1/GluN2B receptors; other compounds (7 and 23) more effectively inhibited the GluN1/GluN2B receptors; or the GluN1/GluN2A receptors (21 and 28). QSAR study revealed statistically significant model for the data obtained for inhibition of GluN1/Glu2B at -60 mV expressed as IC50 values, and for relative inhibition of GluN1/Glu2A at +40 mV caused by a concentration of 100 µM. The models can be utilized for a ligand-based virtual screening to detect potential candidates for inhibition of GluN1/Glu2A and/or GluN1/Glu2B subtypes. Using in vivo experiments in rats we observed that unlike MK-801, the tested novel compounds did not induce hyperlocomotion in open field, and also did not impair prepulse inhibition of startle response, suggesting minimal induction of psychotomimetic side effects. We conclude that tacrine derivatives are promising compounds since they are centrally available subtype-specific inhibitors of the NMDARs without detrimental behavioral side-effects.


Assuntos
Inibidores da Colinesterase/química , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Tacrina/química , Acetilcolinesterase/química , Acetilcolinesterase/genética , Acetilcolinesterase/metabolismo , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Cães , Desenho de Fármacos , Meia-Vida , Humanos , Locomoção/efeitos dos fármacos , Masculino , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Relação Quantitativa Estrutura-Atividade , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Tacrina/metabolismo , Tacrina/farmacologia
12.
Molecules ; 26(8)2021 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-33920326

RESUMO

Neurodegenerative diseases (ND), including Alzheimer's (AD) and Parkinson's Disease (PD), are becoming increasingly more common and are recognized as a social problem in modern societies. These disorders are characterized by a progressive neurodegeneration and are considered one of the main causes of disability and mortality worldwide. Currently, there is no existing cure for AD nor PD and the clinically used drugs aim only at symptomatic relief, and are not capable of stopping neurodegeneration. Over the last years, several drug candidates reached clinical trials phases, but they were suspended, mainly because of the unsatisfactory pharmacological benefits. Recently, the number of compounds developed using in silico approaches has been increasing at a promising rate, mainly evaluating the affinity for several macromolecular targets and applying filters to exclude compounds with potentially unfavorable pharmacokinetics. Thus, in this review, an overview of the current therapeutics in use for these two ND, the main targets in drug development, and the primary studies published in the last five years that used in silico approaches to design novel drug candidates for AD and PD treatment will be presented. In addition, future perspectives for the treatment of these ND will also be briefly discussed.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Antiparkinsonianos/uso terapêutico , Inibidores da Colinesterase/uso terapêutico , Dopaminérgicos/uso terapêutico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Acetilcolinesterase/genética , Acetilcolinesterase/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Antiparkinsonianos/síntese química , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/genética , Ácido Aspártico Endopeptidases/metabolismo , Catecol O-Metiltransferase/genética , Catecol O-Metiltransferase/metabolismo , Inibidores da Colinesterase/síntese química , Ensaios Clínicos como Assunto , Simulação por Computador , Dopaminérgicos/síntese química , Desenho de Fármacos , Antagonistas de Aminoácidos Excitatórios/síntese química , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Regulação da Expressão Gênica , Humanos , Fármacos Neuroprotetores/síntese química , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Sirtuínas/antagonistas & inibidores , Sirtuínas/genética , Sirtuínas/metabolismo
13.
Sci Rep ; 11(1): 6151, 2021 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-33731780

RESUMO

The pathophysiology of Alzheimer's disease (AD) is related to neuroinflammatory responses mediated by microglia. Memantine, an antagonist of N-methyl-D-aspartate (NMDA) receptors used as an anti-Alzheimer's drug, protects from neuronal death accompanied by suppression of proliferation and activation of microglial cells in animal models of AD. However, it remains to be tested whether memantine can directly affect microglial cell function. In this study, we examined whether pretreatment with memantine affects intracellular NO and Ca2+ mobilization using DAF-2 and Fura-2 imaging, respectively, and tested the effects of memantine on phagocytic activity by human ß-Amyloid (1-42) phagocytosis assay in rodent microglial cells. Pretreatment with memantine did not affect production of NO or intracellular Ca2+ elevation induced by TNF in rodent microglial cells. Pretreatment with memantine also did not affect the mRNA expression of pro-inflammatory (TNF, IL-1ß, IL-6 and CD45) or anti-inflammatory (IL-10, TGF-ß and arginase) phenotypes in rodent microglial cells. In addition, pretreatment with memantine did not affect the amount of human ß-Amyloid (1-42) phagocytosed by rodent microglial cells. Moreover, we observed that pretreatment with memantine did not affect 11 major proteins, which mainly function in the phagocytosis and degradation of ß-Amyloid (1-42), including TREM2, DAP12 and neprilysin in rodent microglial cells. To the best of our knowledge, this is the first report to suggest that memantine does not directly modulate intracellular NO and Ca2+ mobilization or phagocytic activity in rodent microglial cells. Considering the neuroinflammation hypothesis of AD, the results might be important to understand the effect of memantine in the brain.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/farmacologia , Memantina/farmacologia , Microglia/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Camundongos Endogâmicos C57BL , Cultura Primária de Células
14.
Biochem Pharmacol ; 186: 114496, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33667472

RESUMO

High mobility box 1 (HMGB1), a damage-associated molecular pattern, has crucial roles in induction of neuropathic pain. Upregulation of HMGB1 around the injured sciatic nerve contributes to mechanical hypersensitivity following partial sciatic nerve ligation (PSNL) of mice. However, central mechanisms mediating perineural HMGB1-induced nociceptive hypersensitivity, especially within the spinal dorsal horn, have not been determined. The current study shows that perineural treatment of naïve mice with recombinant HMGB1, which mimics increased HMGB1 around the injured sciatic nerve of PSNL mice, significantly induced activation of microglia, but not astrocytes, in the spinal dorsal horn. Intraperitoneal injection of minocycline, a microglial inhibitor, ameliorated perineural rHMGB1-induced mechanical hypersensitivity. In addition, blockade of spinal N-methyl-D-aspartate (NMDA) receptors significantly prevented perineural rHMGB1-induced mechanical hypersensitivity and microglial activation. In contrast, non-NMDA receptors, neurokinin 1 receptor, colony-stimulating factor 1 receptor and P2Y12 receptor were not involved in perineural rHMGB1-induced mechanical hypersensitivity. Furthermore, repeated perineural treatment with an anti-HMGB1 antibody blocked activation of spinal microglia in PSNL mice. Collectively, the current findings demonstrate that increased HMGB1 around injured sciatic nerve might induce nociceptive hypersensitivity through activation of spinal microglia. Thus, HMGB1-dependent mechanisms between the injured sciatic nerve and spinal dorsal horn could be crucial in induction of neuropathic pain.


Assuntos
Glutamatos/metabolismo , Proteína HMGB1/metabolismo , Hiperalgesia/metabolismo , Microglia/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Corno Dorsal da Medula Espinal/metabolismo , Animais , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Proteína HMGB1/toxicidade , Humanos , Hiperalgesia/induzido quimicamente , Injeções Espinhais , Masculino , Camundongos , Microglia/efeitos dos fármacos , N-Metilaspartato/administração & dosagem , Nervos Periféricos/efeitos dos fármacos , Nervos Periféricos/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Corno Dorsal da Medula Espinal/efeitos dos fármacos
15.
Cell Physiol Biochem ; 55(S3): 1-13, 2021 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-33656308

RESUMO

BACKGROUND/AIMS: The NMDA receptor plays a key role in the pathogenesis of neurodegenerative disorders including Alzheimer's and Huntington's disease, as well as depression and drug or alcohol dependence. Due to its participation in these pathologies, the development of selective modulators for this ion channel is a promising strategy for rational drug therapy. The prototypical negative allosteric modulator ifenprodil inhibits selectively GluN2B subunit containing NMDA receptors. It was conformationally restricted as 2-methyl-3-(4-phenylbutyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-1,7-diol, which showed high GluN2B affinity and inhibitory activity. For a better understanding of the relevance of the functional groups and structural elements, the substituents of this 3-benzazepine were removed successively (deconstruction). Then, additional structural elements were introduced (reconstruction) with the aim to analyze, which additional modifications were tolerated by the GluN2B receptor. METHODS: The GluN2B affinity was recorded in radioligand receptor binding studies with the radioligand [3H]ifenprodil. The activity of the ligands was determined in two-electrode voltage clamp experiments using Xenopus laevis oocytes transfected with cRNA encoding the GluN1-1a and GluN2B subunits of the NMDA receptor. Docking studies showed the crucial interactions with the NMDA receptor protein. RESULTS: The deconstruction approach showed that removal of the methyl moiety and the phenolic OH moiety in 7-positon resulted in almost the same GluN2B affinity as the parent 3-benzazepine. A considerably reduced GluN2B affinity was found for the 3-benzazepine without further substituents. However, removal of one or both OH moieties led to considerably reduced NMDA receptor inhibition. Introduction of a NO2 moiety or bioisosteric replacement of the phenol by a benzoxazolone resulted in comparable GluN2B affinity, but almost complete loss of inhibitory activity. An O-atom, a carbonyl moiety or a F-atom in the tetramethylene spacer led to 6-7-fold reduced ion channel inhibition. CONCLUSION: The results reveal an uncoupling of affinity and activity for the tested 3-benzazepines. Strong inhibition of [3H]ifenprodil binding by a test compound does not necessarily translate into strong inhibition of the ion flux through the NMDA receptor associated ion channel. 3-(4-Phenylbutyl)-2,3,4,5-tetrahydro-1H-3-benzazepine- 1,7-diol (WMS-1410) shows high GluN2B affinity and strong inhibition of the ion channel. Deconstruction by removal of one or both OH moieties reduced the inhibitory activity proving the importance of the OH groups for ion channel blockade. Reconstruction by introduction of various structural elements into the left benzene ring or into the tetramethylene spacer reduced the NMDA receptor inhibition. It can be concluded that these modifications are not able to translate binding into inhibition.


Assuntos
Antagonistas Adrenérgicos alfa/farmacologia , Benzazepinas/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Piperidinas/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Antagonistas Adrenérgicos alfa/síntese química , Regulação Alostérica , Animais , Benzazepinas/síntese química , Benzoxazóis/química , Sítios de Ligação , Antagonistas de Aminoácidos Excitatórios/síntese química , Humanos , Cinética , Simulação de Acoplamento Molecular , Oócitos/efeitos dos fármacos , Oócitos/metabolismo , Técnicas de Patch-Clamp , Piperidinas/síntese química , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Ensaio Radioligante , Receptores de N-Metil-D-Aspartato/química , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade , Trítio , Xenopus laevis
16.
Eur J Med Chem ; 216: 113320, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33652356

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disorder that impairs mental ability development and interrupts neurocognitive function. This neuropathological condition is depicted by neurodegeneration, neural loss, and development of neurofibrillary tangles and Aß plaques. There is also a greater risk of developing AD at a later age for people with cardiovascular diseases, hypertension and diabetes. In the biomedical sciences, effective treatment for Alzheimer's disease is a severe obstacle. There is no such treatment to cure Alzheimer's disease. The drug present in the market show only symptomatic relief. The cause of Alzheimer's disease is not fully understood and the blood-brain barrier restricts drug efficacy are two main factors that hamper research. Stem cell-based therapy has been seen as an effective, secure, and creative therapeutic solution to overcoming AD because of AD's multifactorial nature and inadequate care. Current developments in nanotechnology often offer possibilities for the delivery of active drug candidates to address certain limitations. The key nanoformulations being tested against AD include polymeric nanoparticles (NP), inorganic NPs and lipid-based NPs. Nano drug delivery systems are promising vehicles for targeting several therapeutic moieties by easing drug molecules' penetration across the CNS and improving their bioavailability. In this review, we focus on the causes of the AD and their treatment by different approaches.


Assuntos
Doença de Alzheimer/terapia , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/patologia , Animais , Biomarcadores/metabolismo , Barreira Hematoencefálica/metabolismo , Inibidores da Colinesterase/uso terapêutico , Ensaios Clínicos como Assunto , Humanos , Nanopartículas/uso terapêutico , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Transplante de Células-Tronco
17.
Am J Physiol Renal Physiol ; 320(5): F799-F813, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33749324

RESUMO

Glutamate N-methyl-d-aspartate receptor (NMDAR) hyperfunction is known to contribute to acute renal failure due to ischemia-reperfusion and endotoxemia. d-Serine is a coagonist for NMDAR activation, but whether NMDARs play a role in d-serine-mediated nephrotoxicity remains unclear. Here, we demonstrate that NMDAR blockade ameliorated d-serine-induced renal injury. In NMDAR-expressing LLC-PK1 cells, which were used as a proximal tubule model, d-serine but not l-serine induced cytotoxicity in a dose-dependent manner, which was abrogated by the selective NMDAR blockers MK-801 and AP-5. Time-dependent oxidative stress, evidenced by gradually increased superoxide and H2O2 production, was associated with d-serine-mediated cytotoxicity; these reactive oxygen species could be alleviated not only after NMDAR inhibition but also by NADPH oxidase (NOX) inhibition. Activation of protein kinase C (PKC)-δ and PKC-ζ is a downstream signal for NMDAR-mediated NOX activation because PKC inhibition diminishes the NOX activity that is induced by d-serine. Renal injury was further confirmed in male Wistar rats that intraperitoneally received d-serine but not l-serine. Peak changes in glucosuria, proteinuria, and urinary excretion of lactate dehydrogenase and malondialdehyde were found after 24 h of treatment. Persistent tubular damage was observed after 7 days of treatment. Cotreatment with the NMDAR blocker MK-801 for 24 h abolished d-serine-induced functional insufficiency and tubular damage. MK-801 attenuated renal superoxide formation by lowering NOX activity and protein upregulation of NOX4 but not NOX2. These results reveal that NMDAR hyperfunction underlies d-serine-induced renal injury via the effects of NOX4 on triggering oxidative stress.NEW & NOTEWORTHY Ionotropic N-methyl-d-aspartate receptors (NMDARs) are not only present in the nervous system but also expressed in the kidney. Overstimulation of renal NMDARs leads to oxidative stress via the signal pathway of calcium/protein kinase C/NADPH oxidase in d-serine-mediated tubular cell damage. Intervention of NMDAR blockade may prevent acute renal injury caused by d-serine.


Assuntos
Túbulos Renais Proximais/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Insuficiência Renal/metabolismo , Serina , Animais , Cálcio/metabolismo , Modelos Animais de Doenças , Antagonistas de Aminoácidos Excitatórios/farmacologia , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/patologia , Células LLC-PK1 , Masculino , NADPH Oxidase 4/metabolismo , Estresse Oxidativo , Proteína Quinase C/metabolismo , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Insuficiência Renal/induzido quimicamente , Insuficiência Renal/patologia , Insuficiência Renal/prevenção & controle , Transdução de Sinais , Suínos
18.
Pharmacol Biochem Behav ; 203: 173152, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33577868

RESUMO

R-(-)-ketamine has emerged as a potentially improved medication over that of the (S)-isomer (marketed as Spravato for depression). Recent data have suggested (R)-ketamine could have value in the treatment of substance use disorder. The present set of experiments was undertaken to examine whether (R)-ketamine might prevent tolerance development. Rapid ethanol (ETOH) tolerance was studied since racemic ketamine had previously been shown to block this tolerance development in rats. In the present study, male Sprague-Dawley rats were given two large doses of ETOH on Day 1 (2.3 + 1.7 g/kg) and 2.3 g/kg ETOH on Day 2. Animals were tested for effects of 2.3 g/kg ETOH on grip strength, inclined screen performance and rotarod performance on Day 1 with or without (R)-ketamine as a pretreatment. (R)-ketamine alone was tested at the highest dose studied (10 mg/kg) and did not significantly influence any dependent measure. (R)-ketamine (1-10 mg/kg) did not alter the acute effects of ETOH except for enhancing the effects of ETOH on the inclined screen test at 3 mg/kg. Between-subjects analysis documented that tolerance developed to the effects of ETOH only on the measure of grip strength. (R)-ketamine (3 mg/kg) given prior to ETOH on Day 1 exhibited a strong trend toward preventing tolerance development (p = 0.062). The present results extend prior findings on the potential value of (R)-ketamine in substance abuse disorder therapeutics and add to the literature on NMDA receptor blockade as a tolerance-regulating mechanism.


Assuntos
Alcoolismo/tratamento farmacológico , Tolerância a Medicamentos , Etanol/administração & dosagem , Ketamina/administração & dosagem , Ketamina/química , Animais , Comportamento Animal/efeitos dos fármacos , Força da Mão , Isomerismo , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores
19.
Pharmacol Biochem Behav ; 203: 173154, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33609599

RESUMO

Interest in developing NMDA receptor antagonists with reduced side-effects for neurological and psychiatric disorders has been re-energized by the recent introduction of esketamine into clinical practice for treatment-resistant depression. Structural analogs of dextromethorphan bind with low affinity to the NMDA receptor ion channel, have functional effects in vivo, and generally display a lower propensity for side-effects than that of ketamine and other higher affinity antagonists. As such, the aim of the present study was to determine whether a series of N-substituted-3-alkoxy-substituted dextromethorphan analogs produce their anticonvulsant effects through NMDA receptor blockade. Compounds were studied against NMDA-induced seizures in rats. Compounds were administered intracerebroventricularly in order to mitigate confounds of drug metabolism that arise from systemic administration. Comparison of the anticonvulsant potencies to their affinities for NMDA, σ1, and σ2 binding sites were made in order to evaluate the contribution of these receptors to anticonvulsant efficacy. The potencies to block convulsions were positively associated with their affinities to bind to the NMDA receptor ion channel ([3H]-TCP binding) (r = 0.71, p < 0.05) but not to σ1 receptors ([3H]-SKF 10047 binding) (r = -0.31, p = 0.46) or to σ2 receptors ([3H]-DTG binding) (p = -0.38, p = 0.36). This is the first report demonstrating that these dextromethorphan analogs are functional NMDA receptor antagonists in vivo. Given their potential therapeutic utility and favorable side-effect profiles, such low affinity NMDA receptor antagonists could be considered for further development in neurological (e.g., anticonvulsant) and psychiatric (e.g., antidepressant) disorders.


Assuntos
Anticonvulsivantes/administração & dosagem , Dextrometorfano/análogos & derivados , Dextrometorfano/administração & dosagem , Dextrorfano/administração & dosagem , Agonistas de Aminoácidos Excitatórios/efeitos adversos , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , N-Metilaspartato/efeitos adversos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Álcoois/química , Animais , Anticonvulsivantes/metabolismo , Sítios de Ligação , Dextrometorfano/metabolismo , Dextrorfano/metabolismo , Modelos Animais de Doenças , Antagonistas de Aminoácidos Excitatórios/metabolismo , Infusões Intraventriculares , Ligantes , Masculino , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores sigma/metabolismo , Resultado do Tratamento
20.
Proc Natl Acad Sci U S A ; 118(9)2021 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-33619110

RESUMO

The organization of sensory maps in the cerebral cortex depends on experience, which drives homeostatic and long-term synaptic plasticity of cortico-cortical circuits. In the mouse primary somatosensory cortex (S1) afferents from the higher-order, posterior medial thalamic nucleus (POm) gate synaptic plasticity in layer (L) 2/3 pyramidal neurons via disinhibition and the production of dendritic plateau potentials. Here we address whether these thalamocortically mediated responses play a role in whisker map plasticity in S1. We find that trimming all but two whiskers causes a partial fusion of the representations of the two spared whiskers, concomitantly with an increase in the occurrence of POm-driven N-methyl-D-aspartate receptor-dependent plateau potentials. Blocking the plateau potentials restores the archetypical organization of the sensory map. Our results reveal a mechanism for experience-dependent cortical map plasticity in which higher-order thalamocortically mediated plateau potentials facilitate the fusion of normally segregated cortical representations.


Assuntos
Potenciais de Ação/fisiologia , Potenciais Somatossensoriais Evocados/fisiologia , Rede Nervosa/fisiologia , Córtex Somatossensorial/fisiologia , Tálamo/fisiologia , Vibrissas/fisiologia , Potenciais de Ação/efeitos dos fármacos , Animais , Mapeamento Encefálico/métodos , Maleato de Dizocilpina/farmacologia , Potenciais Somatossensoriais Evocados/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas GABAérgicos/farmacologia , Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Rede Nervosa/anatomia & histologia , Plasticidade Neuronal/efeitos dos fármacos , Imagem Óptica , Técnicas de Patch-Clamp , Picrotoxina/farmacologia , Células Piramidais/citologia , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Receptores de GABA-A/genética , Receptores de GABA-A/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Córtex Somatossensorial/anatomia & histologia , Tálamo/anatomia & histologia , Vibrissas/lesões
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