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1.
J Theor Biol ; 556: 111326, 2023 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-36279957

RESUMO

The synaptic tagging and capture (STC) hypothesis not only explain the integration and association of synaptic activities, but also the formation of learning and memory. The synaptic pathways involved in the synaptic tagging and capture phenomenon are called STC pathways. The STC hypothesis provides a potential explanation of the neuronal and synaptic processes underlying the synaptic consolidation of memories. Several mechanisms and molecules have been proposed to explain the process of memory allocation and synaptic tags, respectively. However, a clear link between the STC hypothesis and memory allocation is still missing because the encoding of memories in neural circuits is mainly associated with strongly recurrently connected groups of neurons. To explore the mechanisms of potential synaptic tagging candidates and their involvement in the process of memory allocation, we develop a mathematical model for a single dendritic spine based on five essential criteria of a synaptic tag. By developing a mathematical model, we attempt to understand the roles of the potentially critical molecular networks underlying the STC and the essential attributes of a synaptic tag. We include essential memory molecules in the STC model that have been identified in earlier studies as crucial for STC pathways. CaMKII activation is critical for the setting of the initial tag; however, coordinated activities with other kinases and the biochemical pathways are necessary for the tag to be stable. PKA modulates NMDAR-mediated Ca2+ signalling. Similarly, PKA and ERK crosstalk is essential for Ca2+ - mediated protein synthesis during l-LTP. Our theoretical model explains the quantitative contribution of Tags and protein synthesis during l-LTP in synaptic strength.


Assuntos
Plasticidade Neuronal , Sinapses , Sinapses/fisiologia , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Modelos Teóricos , Potenciação de Longa Duração/fisiologia
2.
Synapse ; 77(1): e22252, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36099479

RESUMO

Previous studies demonstrated that in vitro preparations of the isolated vestibular system of diverse animal species still exhibit stable resting electrical activity and mechanically evoked synaptic transmission between hair cells and primary afferent endings. However, there are no reports related to their neurodevelopment. Therefore, this research aimed to examine whether NMDA receptors mediate these electrical signals in an isolated preparation of the chicken vestibular system at three developmental stages, E15, E18, and E21. We found that the spontaneous and mechanically evoked discharges from primary afferents of the posterior semicircular canal were modulated by agonists NMDA and glycine, but not by the agonist d-serine applied near the synapses. Moreover, the individually applied by bath perfusion of three NMDA receptor antagonists (MK-801, ifenprodil, and 2-naphthoic acid) or high Mg2+ decreased the resting discharge rate, the NMDA response, and the discharge rate of mechanically evoked activity from these primary afferents. Furthermore, we found that the vestibular ganglion shows a stage-dependent increase in the expression of NMDA receptor subunits GluN1, GluN2 (A-C), and GluN3 (A-B), being greater at E21, except for GluN2D, which was inversely related to the developmental stage. However, in the crista ampullaris, the expression pattern remained constant throughout development. This could suggest the possible existence of presynaptic NMDA receptors. Our results highlight that although the NMDA receptors are functionally active at the early embryonic stages of the vestibular system, NMDA and glycine reach their mature functionality to increase NMDA responses close to hatching (E21).


Assuntos
Galinhas , Receptores de N-Metil-D-Aspartato , Animais , Receptores de N-Metil-D-Aspartato/metabolismo , Galinhas/metabolismo , N-Metilaspartato , Sistema Vestibular , Glicina
3.
Synapse ; 77(1): e22250, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36085433

RESUMO

The suprachiasmatic nucleus (SCN) is the most important circadian clock in mammals. The SCN synchronizes to environmental light via the retinohypothalamic tract (RHT), which is an axon cluster derived from melanopsin-expressing intrinsic photosensitive retinal ganglion cells. Investigations on the development of the nonimage-forming pathway and the RHT are scarce. Previous studies imply that light stimulation during postnatal development is not needed to make the RHT functional at adult stages. Here, we examined the effects of light deprivation (i.e., constant darkness (DD) rearing) during postnatal development on the expression in the ventral SCN of two crucial proteins for the synchronization of circadian rhythms to light: the presynaptic vesicular glutamate transporter type 2 (vGluT2) and the GluN2B subunit of the postsynaptic NMDA receptor. We found that animals submitted to DD conditions exhibited a transitory reduction in the expression of vGluT2 (at P12-19) and of GluN2B (at P7-9) that was compensated at older stages. These findings support the hypothesis that visual stimulation during early ages is not decisive for normal development of the RHT-SCN pathway.


Assuntos
Receptores de N-Metil-D-Aspartato , Núcleo Supraquiasmático , Proteína Vesicular 2 de Transporte de Glutamato , Animais , Ratos , Ritmo Circadiano/fisiologia , Mamíferos/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Células Ganglionares da Retina/metabolismo , Núcleo Supraquiasmático/metabolismo , Proteína Vesicular 2 de Transporte de Glutamato/metabolismo
4.
J Ethnopharmacol ; 301: 115832, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36283636

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Gastrodia elata Blume (GE) is a Chinese medicinal herb commonly used to treat central nervous system-related diseases, including headaches, dizziness, epilepsy, numbness of the limbs and depression. AIM OF THE STUDY: Microbial-based fermentation has been successfully used to increase the extract efficiency of medicinal herbs in recent years. However, no study has hitherto explored the anti-depressant-like effect of GE processed by microorganisms. Herein, this subject aimed to clarify the anti-depressant-like effect of fermented Gastrodia elata Bl. (FGE) and its active chemical constituents. MATERIALS AND METHODS: The chronic unpredictable mild stress (CUMS) model, a well-established animal model of depression, was induced in Kunming (KM) mice. The mice were administrated with FGE for 3 weeks. The sucrose preference test (SPT), open field test (OFT) and tail suspension test (TST) were conducted. Moreover, the levels of serotonin (5-HT) and dopamine (DA) in brain tissue homogenates, the concentration of Ca2+ and the activity of MAO in serum, H&E and Nissl staining in the hippocampus, and the hippocampus protein expressions of BDNF, NMDAR1, NMDAR2A and NMDAR2B relevant to depression were detected. Furthermore, chemical constituents of FGE were further isolated, and the protective activity of the obtained compounds against NMDA-induced PC-12 cell damage was assessed. RESULTS: FGE could alleviate the depression state in CUMS-induced mice and reduce apoptosis of neuronal cells in the hippocampus. Furthermore, FGE could improve the contents of 5-HT, DA and decrease the concentration of Ca2+ and MAO activity in brain tissue and serum compared with the control group. It could reverse the decreased expression of BDNF, NMDAR2A and NMDAR2B and increase NMDAR1 protein expression. Investigation of the active constituents from FGE yielded two new compounds, (4-(((4-ethoxybenzyl) oxy)methyl)-phenol 1 and 3-((4-hydroxy benzyl)oxy)propane-1,2-diol) 2, with twelve known compounds (3-14). The compounds (3-((4-hydroxybenzyl)oxy)propane-1,2-diol 2, 4, 4'-dihydroxyd iphenyl methane 3, and bungein A 4) protected against NMDA-induced PC-12 cells damage. CONCLUSION: This study demonstrated that FGE could improve the depressive behavior of CUMS-induced mice and exert a protective effect on nerve cells in the brain. Importantly, compounds 2-4 are the active components of FGE. Overall, the above findings suggest that FGE has huge prospects for application in treating depression-related diseases.


Assuntos
Gastrodia , Animais , Camundongos , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Comportamento Animal , Fator Neurotrófico Derivado do Encéfalo , Depressão/tratamento farmacológico , Depressão/metabolismo , Modelos Animais de Doenças , Dopamina/metabolismo , Gastrodia/química , Monoaminoxidase/metabolismo , N-Metilaspartato , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Extratos Vegetais/química , Propano/farmacologia , Serotonina/metabolismo , Estresse Psicológico/tratamento farmacológico , Receptores de N-Metil-D-Aspartato/metabolismo
5.
Commun Biol ; 5(1): 1168, 2022 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-36329137

RESUMO

Active recall of short-term memory (STM) is known to last for a few hours, but whether STM has long-term functions is unknown. Here we show that STM can be optogenetically retrieved at a time point during which natural recall is not possible, uncovering the long-term existence of an STM engram. Moreover, re-training within 3 days led to natural long-term recall, indicating facilitated consolidation. Inhibiting offline CA1 activity during non-rapid eye movement (NREM) sleep, N-methyl-D-aspartate receptor (NMDAR) activity, or protein synthesis after first exposure to the STM-forming event impaired the future re-exposure-facilitated consolidation, which highlights a role of protein synthesis, NMDAR and NREM sleep in the long-term storage of an STM trace. These results provide evidence that STM is not completely lost within hours and demonstrates a possible two-step STM consolidation, first long-term storage as a behaviorally inactive engram, then transformation into an active state by recurrence within 3 days.


Assuntos
Consolidação da Memória , Memória de Curto Prazo , Animais , Camundongos , Rememoração Mental , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Hipocampo/metabolismo
6.
Folia Neuropathol ; 60(3): 308-315, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36382483

RESUMO

INTRODUCTION: This study investigated the specific mechanism of N-methyl-D-aspartate (NMDA) receptor-mediated spinal cord ischemia-reperfusion by comparing the protective effects of the voltage-gated Ca2+ channel blocker nimodipine and the NMDA receptor blocker K-1024 on the spinal cord. MATERIAL AND METHODS: In this study, 42 SD rats were divided randomly into four groups: non-blocking (n = 6), normal saline (n = 12), K-1024 (n = 12) and nimodipine (n = 12). The rats in three groups (saline, K-1024, nimodipine) received an intraperitoneal injection 30 minutes before ischemia. In these three groups, 6 out of 12 rats were selected randomly to have their thoracic aorta blocked with a balloon to induce spinal cord ischemia for 10 minutes. Then, the spinal cord tissues were collected. The remaining six rats were evaluated for nerve function at 1, 2, 4 and 8 hours after reperfusion. The lumbar spinal cord was removed for histological examination. The release of neurotransmitter amino acids was observed by high-pressure liquid chromatography, and the protein expression level of neuronal nitric oxide synthase (nNOS) in the spinal cord was determined by immunohistochemistry. RESULTS: All the animals in the normal saline group and five in the nimodipine group were paralysed after ischemia. Compared with the normal saline and nimodipine groups, the rats in the K-1024 group had more normal motor neurons and better behavioural scores. In addition, the histopathology of the rats in the K-1024 group was significantly better than in the normal saline and nimodipine groups. After 10 minutes of ischemia, there was no significant difference in glutamate concentration in each group. The protein expression level of nNOS in the K-1024 group was significantly downregulated compared with the saline and nimodipine groups. At 8 hours after reperfusion, the protein expression level of nNOS in the K-1024 group was significantly upregulated compared with the normal saline group. CONCLUSIONS: The specific mechanism of the NMDA receptor blocker K-1024 in protection against spinal cord ischemia-reperfusion injury is related closely to the inhibition of NMDA receptors and the downregulation of the protein expression level of nNOS.


Assuntos
Traumatismo por Reperfusão , Isquemia do Cordão Espinal , Ratos , Animais , Receptores de N-Metil-D-Aspartato/metabolismo , Nimodipina/farmacologia , Nimodipina/metabolismo , Solução Salina/metabolismo , Solução Salina/farmacologia , Ratos Sprague-Dawley , Isquemia do Cordão Espinal/metabolismo , Isquemia do Cordão Espinal/patologia , Medula Espinal/patologia , Traumatismo por Reperfusão/metabolismo
7.
Pharm Biol ; 60(1): 2145-2154, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36373991

RESUMO

CONTEXT: Veratramine may have a potential therapeutic effect for diabetic peripheral neuropathy (DPN). OBJECTIVE: To evaluate whether veratramine ameliorates neuropathic pain in a rat diabetic model. MATERIALS AND METHODS: Sprague-Dawley rats were used for a diabetic model induced by a streptozotocin + high-fat diet. Two months after the induction of the diabetic model, the rats with DPN were screened according to the mechanical pain threshold. The rats with DPN were divided into a model group (n = 12) and a treated group (n = 12). Rats with diabetes, but without peripheral neuropathy, were used in the vehicle group (n = 9). The treatment group received 50 µg/kg veratramine via the tail vein once a day for 4 weeks. During modelling and treatment, rats in all three groups were fed a high-fat diet. RESULTS: The mechanical withdrawal threshold increased from 7.5 ± 1.9 N to 17.9 ± 2.6 N in DPN rats treated with veratramine. The tolerance time of the treated group to hot and cold ectopic pain increased from 11.8 ± 4.2 s and 3.4 ± 0.8 s to 20.4 ± 4.1 s and 5.9 ± 1.7 s, respectively. Veratramine effectively alleviated L4-L5 spinal cord and sciatic nerve pathological injury. Veratramine inhibited the expression of SIGMAR1 and the phosphorylation of the N-methyl-d-aspartate receptor (NMDAR) Ser896 site in spinal cord tissue, as well as inhibited the formation of SIGMAR1-NMDAR and NMDAR-CaMKII complexes. DISCUSSION AND CONCLUSIONS: Veratramine may alleviate the occurrence of pain symptoms in rats with DPN by inhibiting activation of the SIGMAR1-NMDAR pathway.


Assuntos
Diabetes Mellitus , Neuropatias Diabéticas , Neuralgia , Traumatismos dos Nervos Periféricos , Ratos , Animais , Neuropatias Diabéticas/tratamento farmacológico , Ratos Sprague-Dawley , NAD/metabolismo , Neuralgia/tratamento farmacológico , Receptores de N-Metil-D-Aspartato/metabolismo
8.
Rom J Morphol Embryol ; 63(2): 307-322, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36374137

RESUMO

The article is a review of the latest meta-analyses regarding the genetic spectrum in schizophrenia, discussing the risks given by the disrupted-in-schizophrenia 1 (DISC1), catechol-O-methyltransferase (COMT), monoamine oxidases-A∕B (MAO-A∕B), glutamic acid decarboxylase 67 (GAD67) and neuregulin 1 (NRG1) genes, and dysbindin-1 protein. The DISC1 polymorphism significantly increases the risk of schizophrenia, as well injuries from the prefrontal cortex that affect connectivity. NRG1 is one of the most important proteins involved. Its polymorphism is associated with the reduction of areas in the corpus callosum, right uncinate, inferior lateral fronto-occipital fascicle, right external capsule, fornix, right optic tract, gyrus. NRG1 and the ErbB4 receptor (tyrosine kinase receptor) are closely related to the N-methyl-D-aspartate receptor (NMDAR) (glutamate receptor). COMT is located on chromosome 22 and together with interleukin-10 (IL-10) have an anti-inflammatory and immunosuppressive function that influences the dopaminergic system. MAO gene methylation has been associated with mental disorders. MAO-A is a risk gene in the onset of schizophrenia, more precisely a certain type of single-nucleotide polymorphism (SNP), at the gene level, is associated with schizophrenia. In schizophrenia, we find deficits of the γ-aminobutyric acid (GABA)ergic neurotransmitter, the dysfunctions being found predominantly at the level of the substantia nigra. In schizophrenia, missing an allele at GAD67, caused by a SNP, has been correlated with decreases in parvalbumin (PV), somatostatin receptor (SSR), and GAD ribonucleic acid (RNA). Resulting in the inability to mature PV and SSR neurons, which has been associated with hyperactivity.


Assuntos
Esquizofrenia , Humanos , Esquizofrenia/genética , Esquizofrenia/metabolismo , Catecol O-Metiltransferase/genética , Catecol O-Metiltransferase/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Polimorfismo de Nucleotídeo Único , Monoaminoxidase/genética , Monoaminoxidase/metabolismo
9.
Int J Mol Sci ; 23(21)2022 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-36362260

RESUMO

Data on the long-term consequences of a single episode of generalized seizures in infants are inconsistent. In this study, we examined the effects of pentylenetetrazole-induced generalized seizures in three-week-old rats. One month after the seizures, we detected a moderate neuronal loss in several hippocampal regions: CA1, CA3, and hilus, but not in the dentate gyrus. In addition, long-term synaptic potentiation (LTP) was impaired. We also found that the mechanism of plasticity induction was altered: additional activation of metabotropic glutamate receptors (mGluR1) is required for LTP induction in experimental rats. This disturbance of the plasticity induction mechanism is likely due to the greater involvement of perisynaptic NMDA receptors compared to receptors located in the core part of the postsynaptic density. This hypothesis is supported by experiments with selective blockades of core-located NMDA receptors by the use-dependent blocker MK-801. MK-801 had no effect on LTP induction in experimental rats and suppressed LTP in control animals. The weakening of the function of core-located NMDA receptors may be due to the disturbed clearance of glutamate from the synaptic cleft since the distribution of the astrocytic glutamate transporter EAAT2 in experimental animals was found to be altered.


Assuntos
Pentilenotetrazol , Receptores de N-Metil-D-Aspartato , Animais , Ratos , Maleato de Dizocilpina , Hipocampo/metabolismo , Plasticidade Neuronal , Pentilenotetrazol/farmacologia , Receptores de N-Metil-D-Aspartato/metabolismo , Convulsões/induzido quimicamente
10.
J Pharmacol Sci ; 150(4): 233-243, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36344045

RESUMO

N-Methyl-D-aspartate receptors (NMDARs) in the brain are influenced by psychoactive drugs such as 2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one (ketamine) and its analog 2-(ethylamino)-2-(3-methoxyphenyl)-cyclohexanone (methoxetamine). The recreational methoxetamine use can cause several toxicities and methoxetamine-related deaths have also been reported. Therefore, it has been banned in many countries. Since 2020, methoxetamine derivatives, 2-(ethylamino)-2-(m-tolyl)cyclohexan-1-one (deoxymethoxetamine) and 2-(isopropylamino)-2-(3-methoxyphenyl)cyclohexan-1-one (methoxisopropamine), have been sold online as designer drugs. However, how deoxymethoxetamine and methoxisopropamine act on NMDARs remains unknown. In this study, we first performed in silico docking studies of NMDARs, and deoxymethoxetamine and methoxisopropamine in addition to the major methoxetamine metabolites, 2-amino-2-(3-methoxyphenyl)-cyclohexanone (N-desethyl methoxetamine) and 2-(ethylamino)-2-(3-hydroxyphenyl)-cyclohexanone (O-desmethyl methoxetamine). The docking study suggested each compound interacts with NMDARs. We also determined the half-maximal inhibitory concentration (IC50s) of the methoxetamine-related compounds for NMDARs using NMDAR-expressing cartwheel interneurons of mice and patch-clamp recordings. We found that the IC50s of methoxetamine, deoxymethoxetamine, methoxisopropamine, N-desethyl methoxetamine, and O-desmethyl methoxetamine for NMDARs were 0.524, 0.679, 0.661, 1.649, and 0.227 µM, respectively. These results indicate that the methoxetamine-related compounds act as potent NMDAR blockers. Thus, deoxymethoxetamine and methoxisopropamine, both of which may cause damage by blocking NMDARs, are serious concerns. N-Desethyl methoxetamine and O-desmethyl methoxetamine may cause several adverse effects when methoxetamine is metabolized.


Assuntos
Cicloexanonas , Receptores de N-Metil-D-Aspartato , Cicloexanonas/farmacologia , Receptores de N-Metil-D-Aspartato/metabolismo , Cicloexilaminas/farmacologia
11.
Elife ; 112022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-36317872

RESUMO

Social deficit is a major feature of neuropsychiatric disorders, including autism spectrum disorders, schizophrenia, and attention-deficit/hyperactivity disorder, but its neural mechanisms remain unclear. Here, we examined neuronal discharge characteristics in the medial prefrontal cortex (mPFC) of IRSp53/Baiap2-mutant mice, which show social deficits, during social approach. We found a decrease in the proportion of IRSp53-mutant excitatory mPFC neurons encoding social information, but not that encoding non-social information. In addition, the firing activity of IRSp53-mutant neurons was less differential between social and non-social targets. IRSp53-mutant excitatory mPFC neurons displayed an increase in baseline neuronal firing, but decreases in the variability and dynamic range of firing as well as burst firing during social and non-social target approaches compared to wild-type controls. Treatment of memantine, an NMDA receptor antagonist that rescues social deficit in IRSp53-mutant mice, alleviates the reduced burst firing of IRSp53-mutant pyramidal mPFC neurons. These results suggest that suppressed neuronal activity dynamics and burst firing may underlie impaired cortical encoding of social information and social behaviors in IRSp53-mutant mice.


Assuntos
Neurônios , Esquizofrenia , Animais , Camundongos , Neurônios/fisiologia , Células Piramidais/metabolismo , Córtex Pré-Frontal/fisiologia , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo
12.
Eur J Pharmacol ; 934: 175316, 2022 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-36209926

RESUMO

Huntington disease (HD), an autosomal dominant neurodegenerative disorder characterized by involuntary choreatic movements with cognitive and behavioral disturbances. HD striatum has increased conversion of kynurenine to quinolinic acid (QA) which activates NMDA receptors leading to activation of microglia and increased levels of nuclear factor kappa B (NF-κB) leading to elevated transcription of inducible nitric oxide synthase (iNOS) and various cytokines causing neuronal death via neuroinflammation, oxidative stress, mitochondrial dysfunction and apoptosis. Therefore, inhibiting IKK-NF-κB pathway induced excitotoxicity, oxidative stress and neuroinflammation could be a potential intervention in slowing down the disease progression. QA injection intrastriatally (IS-QA) produce damage mimicking HD where neuroinflammation, oxidative stress and mitochondrial dysfunction play crucial role. Ellagic acid (EA) and vanillic acid (VA) are well reported to possess antioxidant and NF-κB inhibiting effect. Hence, in present study, rats administered IS-QA were treated with EA and VA for 21 days to explore their neuroprotective effects. Behavioral studies, biochemical estimations for oxidative stress and acetylcholinesterase assay were performed. Mitochondrial function was determined by estimating mitochondrial enzyme complexes; inflammatory markers like TNF-α, IL-6, NF-κB by ELISA and apoptosis by caspase-3 levels. Brain damage was determined by histopathology which revealed their neuroprotective effects. Various doses of EA and VA produced improved motor and cognitive functions, oxidative stress and neuroinflammation were also reduced and mitochondrial functioning was improved. In a nutshell, these results signify improved motor and cognitive functions by EA and VA in QA model of HD, along with declined oxidative stress, mitochondrial dysfunction and neuroinflammation.


Assuntos
Doença de Huntington , Fármacos Neuroprotetores , Animais , Ratos , Ácido Quinolínico/efeitos adversos , Doença de Huntington/induzido quimicamente , Doença de Huntington/tratamento farmacológico , Doença de Huntington/metabolismo , NF-kappa B/metabolismo , Caspase 3/metabolismo , Ácido Elágico/farmacologia , Ácido Elágico/uso terapêutico , Ácido Vanílico/farmacologia , Ácido Vanílico/uso terapêutico , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Óxido Nítrico Sintase Tipo II/metabolismo , Acetilcolinesterase/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Antioxidantes/farmacologia , Receptores de N-Metil-D-Aspartato/metabolismo , Interleucina-6/metabolismo , Cinurenina/metabolismo , Estresse Oxidativo , Anti-Inflamatórios/farmacologia
13.
Sci Rep ; 12(1): 17114, 2022 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-36224339

RESUMO

Studies suggest that the scaffolding protein, postsynaptic density protein-95 (PSD-95), is involved in multiple neurological dysfunctions. However, the role of PSD-95 in the anterior cingulate cortex (ACC) in neuropathic pain (NP) has not been investigated. The current study addressed the role of PSD-95 in the ACC in NP and its modulating profile with NMDA receptor subunit 2B (NR2B). The NP model was established by chronic constriction injury (CCI) of the sciatic nerve, and mechanical and thermal tests were used to evaluate behavioral hyperalgesia. Protein expression and distribution were evaluated using immunohistochemistry and western blotting. The results showed that PSD-95 and NR2B were co-localized in neurons in the ACC. After CCI, both PSD-95 and NR2B were upregulated in the ACC. Inhibiting NR2B with Ro 25-6981 attenuated pain hypersensitivity and decreased the over-expression of PSD-95 induced by CCI. Furthermore, intra-ACC administration of PSD-95 antisense oligonucleotide not only attenuated pain hypersensitivity but also downregulated the NR2B level and the phosphorylation of cyclic AMP response element-binding protein. These results demonstrated that PSD-95 in the ACC contributes to NP by interdependent activation of NR2B.


Assuntos
Neuralgia , Receptores de N-Metil-D-Aspartato/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteína 4 Homóloga a Disks-Large/metabolismo , Giro do Cíngulo , Humanos , Hiperalgesia , Neuralgia/metabolismo , Oligonucleotídeos Antissenso/metabolismo
14.
Nat Commun ; 13(1): 6037, 2022 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-36229429

RESUMO

During early ischemic brain injury, glutamate receptor hyperactivation mediates neuronal death via osmotic cell swelling. Here we show that ischemia and excess NMDA receptor activation cause actin to rapidly and extensively reorganize within the somatodendritic compartment. Normally, F-actin is concentrated within dendritic spines. However, <5 min after bath-applied NMDA, F-actin depolymerizes within spines and polymerizes into stable filaments within the dendrite shaft and soma. A similar actinification occurs after experimental ischemia in culture, and photothrombotic stroke in mouse. Following transient NMDA incubation, actinification spontaneously reverses. Na+, Cl-, water, and Ca2+ influx, and spine F-actin depolymerization are all necessary, but not individually sufficient, for actinification, but combined they induce activation of the F-actin polymerization factor inverted formin-2 (INF2). Silencing of INF2 renders neurons vulnerable to cell death and INF2 overexpression is protective. Ischemia-induced dendritic actin reorganization is therefore an intrinsic pro-survival response that protects neurons from death induced by cell edema.


Assuntos
Actinas , N-Metilaspartato , Citoesqueleto de Actina/metabolismo , Actinas/metabolismo , Animais , Espinhas Dendríticas/metabolismo , Forminas , Isquemia/metabolismo , Camundongos , N-Metilaspartato/metabolismo , Neurônios/metabolismo , Receptores de Glutamato/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Água/metabolismo
15.
Cells ; 11(19)2022 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-36231023

RESUMO

N-methyl-D-aspartate receptors (NMDARs) are important postsynaptic receptors that contribute to normal synaptic function and cell survival; however, when overactivated, as in Huntington's disease (HD), NMDARs cause excitotoxicity. HD-affected striatal neurons show altered NMDAR currents and augmented ratio of surface to internal GluN2B-containing NMDARs, with augmented accumulation at extrasynaptic sites. Fyn protein is a member of the Src kinase family (SKF) with an important role in NMDARs phosphorylation and synaptic localization and function; recently, we demonstrated that Fyn is reduced in several HD models. Thus, in this study, we aimed to explore the impact of HD-mediated altered Fyn levels at post-synaptic density (PSD), and their role in distorted NMDARs function and localization, and intracellular neuroprotective pathways in YAC128 mouse primary striatal neurons. We show that reduced synaptic Fyn levels and activity in HD mouse striatal neurons is related to decreased phosphorylation of synaptic GluN2B-composed NMDARs; this occurs concomitantly with augmented extrasynaptic NMDARs activity and currents and reduced cAMP response element-binding protein (CREB) activation, along with induction of cell death pathways. Importantly, expression of a constitutive active form of SKF reestablishes NMDARs localization, phosphorylation, and function at PSD in YAC128 mouse neurons. Enhanced SKF levels and activity also promotes CREB activation and reduces caspase-3 activation in YAC128 mouse striatal neurons. This work supports, for the first time, a relevant role for Fyn protein in PSD modulation, controlling NMDARs synaptic function in HD, and favoring neuroprotective pathways and cell survival. In this respect, Fyn Tyr kinase constitutes an important potential HD therapeutic target directly acting at PSD.


Assuntos
Doença de Huntington , Proteínas Proto-Oncogênicas c-fyn/metabolismo , Receptores de N-Metil-D-Aspartato , Animais , Caspase 3/metabolismo , Corpo Estriado/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Doença de Huntington/metabolismo , Camundongos , Receptores de N-Metil-D-Aspartato/metabolismo
16.
Int J Mol Sci ; 23(19)2022 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-36232433

RESUMO

Spasticity impacts the quality of life of patients suffering spinal cord injury and impedes the recovery of locomotion. At the cellular level, spasticity is considered to be primarily caused by the hyperexcitability of spinal α-motoneurons (MNs) within the spinal stretch reflex circuit. Here, we hypothesized that after a complete spinal cord transection in rats, fast adaptive molecular responses of lumbar MNs develop in return for the loss of inputs. We assumed that early loss of glutamatergic afferents changes the expression of glutamatergic AMPA and NMDA receptor subunits, which may be the forerunners of the developing spasticity of hindlimb muscles. To better understand its molecular underpinnings, concomitant expression of GABA and Glycinergic receptors and serotoninergic and noradrenergic receptors, which regulate the persistent inward currents crucial for sustained discharges in MNs, were examined together with voltage-gated ion channels and cation-chloride cotransporters. Using quantitative real-time PCR, we showed in the tracer-identified MNs innervating extensor and flexor muscles of the ankle joint multiple increases in transcripts coding for AMPAR and 5-HTR subunits, along with a profound decrease in GABAAR, GlyR subunits, and KCC2. Our study demonstrated that both MNs groups similarly adapt to a more excitable state, which may increase the occurrence of extensor and flexor muscle spasms.


Assuntos
Traumatismos da Medula Espinal , Simportadores , Animais , Cloretos/metabolismo , Neurônios Motores/metabolismo , Espasticidade Muscular/metabolismo , Fenótipo , Qualidade de Vida , Ratos , Receptores de N-Metil-D-Aspartato/metabolismo , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/genética , Traumatismos da Medula Espinal/metabolismo , Simportadores/metabolismo , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/metabolismo , Ácido gama-Aminobutírico/metabolismo
17.
Sci Rep ; 12(1): 17908, 2022 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-36284170

RESUMO

In Alzheimer's disease pathology, several neuronal processes are dysregulated by excitotoxicity including neuroinflammation and oxidative stress (OS). New therapeutic agents capable of modulating such processes are needed to foster neuroprotection. Here, the effect of an optimised NMDA receptor antagonist, UB-ALT-EV and memantine, as a gold standard, have been evaluated in 5XFAD mice. Following treatment with UB-ALT-EV, nor memantine, changes in the calcineurin (CaN)/NFAT pathway were detected. UB-ALT-EV increased neurotropic factors (Bdnf, Vgf and Ngf) gene expression. Treatments reduced astrocytic and microglial reactivity as revealed by glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter molecule 1 (Iba-1) quantification. Interestingly, only UB-ALT-EV was able to reduce gene expression of Trem2, a marker of microglial activation and NF-κB. Pro-inflammatory cytokines Il-1ß, Ifn-γ, Ccl2 and Ccl3 were down-regulated in UB-ALT-EV-treated mice but not in memantine-treated mice. Interestingly, the anti-inflammatory markers of the M2-migroglial phenotype, chitinase-like 3 (Ym1) and Arginase-1 (Arg1), were up-regulated after treatment with UB-ALT-EV. Since iNOS gene expression decreased after UB-ALT-EV treatment, a qPCR array containing 84 OS-related genes was performed. We found changes in Il-19, Il-22, Gpx6, Ncf1, Aox1 and Vim gene expression after UB-ALT-EV. Hence, our results reveal a robust effect on neuroinflammation and OS processes after UB-ALT-EV treatment, surpassing the memantine effect in 5XFAD.


Assuntos
Doença de Alzheimer , Quitinases , Animais , Camundongos , Doença de Alzheimer/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Arginase/metabolismo , Memantina/metabolismo , NF-kappa B/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Calcineurina/metabolismo , Cálcio/metabolismo , Fator de Crescimento Neural/metabolismo , Modelos Animais de Doenças , Microglia/metabolismo , Estresse Oxidativo , Citocinas/metabolismo , Quitinases/metabolismo
18.
Elife ; 112022 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-36301074

RESUMO

N-methyl-D-aspartate receptors (NMDARs) uniquely require binding of two different neurotransmitter agonists for synaptic transmission. D-serine and glycine bind to one subunit, GluN1, while glutamate binds to the other, GluN2. These agonists bind to the receptor's bi-lobed ligand-binding domains (LBDs), which close around the agonist during receptor activation. To better understand the unexplored mechanisms by which D-serine contributes to receptor activation, we performed multi-microsecond molecular dynamics simulations of the GluN1/GluN2A LBD dimer with free D-serine and glutamate agonists. Surprisingly, we observed D-serine binding to both GluN1 and GluN2A LBDs, suggesting that D-serine competes with glutamate for binding to GluN2A. This mechanism is confirmed by our electrophysiology experiments, which show that D-serine is indeed inhibitory at high concentrations. Although free energy calculations indicate that D-serine stabilizes the closed GluN2A LBD, its inhibitory behavior suggests that it either does not remain bound long enough or does not generate sufficient force for ion channel gating. We developed a workflow using pathway similarity analysis to identify groups of residues working together to promote binding. These conformation-dependent pathways were not significantly impacted by the presence of N-linked glycans, which act primarily by interacting with the LBD bottom lobe to stabilize the closed LBD.


Assuntos
Ácido Glutâmico , Receptores de N-Metil-D-Aspartato , Receptores de N-Metil-D-Aspartato/metabolismo , Ácido Glutâmico/metabolismo , Conformação Molecular , Simulação de Dinâmica Molecular , Serina
19.
Int J Mol Sci ; 23(20)2022 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-36293063

RESUMO

This article presents a mechanism of action hypothesis to explain the rapid antidepressant effects of esmethadone (REL-1017) and other uncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonists and presents a corresponding mechanism of disease hypothesis for major depressive disorder (MDD). Esmethadone and other uncompetitive NMDAR antagonists may restore physiological neural plasticity in animal models of depressive-like behavior and in patients with MDD via preferential tonic block of pathologically hyperactive GluN2D subtypes. Tonic Ca2+ currents via GluN2D subtypes regulate the homeostatic availability of synaptic proteins. MDD and depressive behaviors may be determined by reduced homeostatic availability of synaptic proteins, due to upregulated tonic Ca2+ currents through GluN2D subtypes. The preferential activity of low-potency NMDAR antagonists for GluN2D subtypes may explain their rapid antidepressant effects in the absence of dissociative side effects.


Assuntos
Transtorno Depressivo Maior , Animais , Transtorno Depressivo Maior/tratamento farmacológico , Receptores de N-Metil-D-Aspartato/metabolismo , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Plasticidade Neuronal , Comunicação Celular
20.
Int J Mol Sci ; 23(20)2022 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-36293077

RESUMO

Prolonged neonatal febrile seizures (FSs) often lead to cognitive decline and increased risk of psychopathology in adulthood. However, the neurobiological mechanisms underlying the long-term adverse effects of FSs remain unclear. In this study, we exposed rat pups to hyperthermia and induced FSs lasting at least 15 min. We investigated the short-term (one day) and delayed (11-13 and 41-45 days) effects of FSs on some parameters of morphological and functional maturation in the hippocampus. We noticed that FSs altered the developmental pattern of glial fibrillary acidic protein (GFAP) immunoreactivity. In rats aged 21-23 days, GFAP-positive astrocytes covered a smaller area, and their morphological characteristics resembled those of rats at 11 days of age. In post-FS rats, the magnitude of long-term synaptic potentiation was reduced compared to control animals of the same age. Applying the gliotransmitter D-serine, an agonist of the glycine site of NMDA receptors, restored LTP to control values. A decrease in LTP amplitude was correlated with impaired spatial learning and memory in the Barnes maze task in post-FS rats. Our data suggest that impaired neuron-glia interactions may be an essential mechanism of the adverse effects of FS on the developing brain.


Assuntos
Epilepsia , Convulsões Febris , Estado Epiléptico , Ratos , Animais , Proteína Glial Fibrilar Ácida/metabolismo , Astrócitos/metabolismo , Convulsões Febris/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Hipocampo/metabolismo , Plasticidade Neuronal , Estado Epiléptico/metabolismo , Epilepsia/metabolismo , Serina/metabolismo , Glicina/farmacologia
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