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1.
Neurochem Res ; 49(9): 2535-2555, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38888830

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid-ß, leading to N-methyl-D-aspartate (NMDA) receptor-dependent synaptic depression, spine elimination, and memory deficits. Glycine transporter type 1 (GlyT1) modulates glutamatergic neurotransmission via NMDA receptors (NMDAR), presenting a potential alternative therapeutic approach for AD. This study investigates the neuroprotective potential of GlyT1 inhibition in an amyloid-ß-induced AD mouse model. C57BL/6 mice were treated with N-[3-([1,1-Biphenyl]-4-yloxy)-3-(4-fluorophenyl)propyl]-N-methylglycine (NFPS), a GlyT1 inhibitor, 24 h prior to intrahippocampal injection of amyloid-ß. NFPS pretreatment prevented amyloid-ß-induced cognitive deficits in short-term and long-term memory, evidenced by novel object recognition and spatial memory tasks. Moreover, NFPS pretreatment curbed microglial activation, astrocytic reactivity, and subsequent neuronal damage from amyloid-ß injection. An extensive label-free quantitative UPLC-MSE proteomic analysis was performed on the hippocampi of mice treated with NFPS. In proteomics, KEGG enrichment analysis revealed increased in dopaminergic synapse, purine-containing compound biosynthetic process and long-term potentiation, and a reduction in Glucose catabolic process and glycolytic process pathways. The western blot analysis confirmed that NFPS treatment elevated BDNF levels, correlating with enhanced TRKB phosphorylation and mTOR activation. Moreover, NFPS treatment reduced the GluN2B expression after 6 h, which was associated with an increase on CaMKIV and CREB phosphorylation. Collectively, these findings demonstrate that GlyT1 inhibition by NFPS activates diverse neuroprotective pathways, enhancing long-term potentiation signaling and countering amyloid-ß-induced hippocampal damage.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Proteínas da Membrana Plasmática de Transporte de Glicina , Hipocampo , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores , Animais , Doença de Alzheimer/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/prevenção & controle , Peptídeos beta-Amiloides/metabolismo , Masculino , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Camundongos , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores , Proteínas da Membrana Plasmática de Transporte de Glicina/metabolismo , Modelos Animais de Doenças , Sarcosina/análogos & derivados , Sarcosina/farmacologia , Sarcosina/uso terapêutico , Neuroproteção/efeitos dos fármacos , Neuroproteção/fisiologia
2.
Exp Brain Res ; 241(2): 451-467, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36577922

RESUMO

Schizophrenia is a neurological disorder that alters the behavior and affects the quality of life of a patient. It is characterized by hallucinations, disorganized behavior, cognitive dysfunction, hyperlocomotion, and loss of the reward system. Schizophrenia constitutes three symptoms' domains, viz. positive, negative and cognitive. Typical and atypical antipsychotics do not fully resolve all the symptoms' domains thus paving the way to the genesis of the glutamatergic hypothesis, i.e. N-methyl-D-aspartate (NMDA) receptor hypofunction in the pathophysiology of schizophrenia. Positive modulation of NMDA receptors by enhancing co-agonist, glycine effect is proposed to produce a therapeutic effect in schizophrenia. Hence, sarcosine (N-methyl glycine), natural amino acid, and a glycine transporter inhibitor (GlyT-1) which also acts on NMDA receptors were used in the present study. The present study unravels the role of sarcosine in the attenuation of ketamine-induced three symptom domains in a rat model through modulation of oxidative stress, mitochondrial dysfunction, and neuroinflammatory pathways. The animal model of schizophrenia was established by injecting ketamine intraperitoneal (ip) at a 30 mg/kg dose for 10 consecutive days, after which sarcosine (300, 600 mg/kg, ip) as a treatment was given for 7 days followed by behavioral, biochemical, molecular, and histopathological analysis. It was revealed that sarcosine reversed ketamine-induced behavioral impairments. Moreover, sarcosine ameliorated oxidative and nitrosative stress, mitochondrial dysfunction, and neuroinflammation and showed protective effects in histopathological examination by hematoxylin and eosin staining. Hence, conclusively, sarcosine was regarded to attenuate the behavioural symptoms of schizophrenia by alleviating oxidative stress, neuroinflammation, and mitochondrial dysfunction established by the ketamine.


Assuntos
Ketamina , Esquizofrenia , Ratos , Animais , Sarcosina/farmacologia , Sarcosina/uso terapêutico , Esquizofrenia/induzido quimicamente , Esquizofrenia/tratamento farmacológico , Proteínas da Membrana Plasmática de Transporte de Glicina , Ketamina/farmacologia , Ketamina/uso terapêutico , Receptores de N-Metil-D-Aspartato , Doenças Neuroinflamatórias , Qualidade de Vida
3.
Biomed Res Int ; 2022: 5467498, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36281465

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by behavioral and psychological symptoms in addition to cognitive impairment and loss of memory. The exact pathogenesis and genetic background of AD are unclear and there remains no effective treatment option. Sarcosine, an n-methyl derivative of glycine, showed a promising therapeutic strategy for some cognitive disorders. To our knowledge, the impacts of sarcosine supplementation against AD have not yet been elucidated. Therefore, we aimed to determine the neuroprotective potential of sarcosine in in vitro and in vivo AD model. In vitro studies have demonstrated that sarcosine increased the percentage of viable cells against aluminum induced neurotoxicity. In AlCl3-induced rat model of AD, the level of antioxidant capacity was significantly decreased and expression levels of APP, BACE1, TNF-α, APH1A, and PSENEN genes were elevated compared to the control group. Additionally, histopathological examinations of the hippocampus of AlCl3-induced rat brains showed the presence of neurofibrillary tangles (NFTs). However, the administration of sarcosine produced marked improvement and protection of AD-associated pathologies induced by AlCl3 in experimental rats. Therefore, this investigation may contribute to design novel therapeutic strategies using sarcosine for the management of AD pathologies.


Assuntos
Doença de Alzheimer , Fármacos Neuroprotetores , Animais , Ratos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Cloreto de Alumínio , Sarcosina/farmacologia , Sarcosina/uso terapêutico , Antioxidantes/farmacologia , Secretases da Proteína Precursora do Amiloide , Fator de Necrose Tumoral alfa , Alumínio/uso terapêutico , Ratos Wistar , Ácido Aspártico Endopeptidases , Doença de Alzheimer/metabolismo
4.
Psychiatr Pol ; 56(2): 217-228, 2022 Apr 30.
Artigo em Inglês, Polonês | MEDLINE | ID: mdl-35988070

RESUMO

Currently, we observe a huge number of publications describing the role of glycine transporter (GlyT1) inhibitors in schizophrenia treatment. The concept of application for these drugs derives from the glutamatergic theory of schizophrenia. This theory explains psychotic disturbances as the consequence of NMDA receptor functioning defect. The role of the mentioned receptor depends mostly on the presence of cofactors. One such cofactor is the simplest aminoacid, glycine. This amino acid affects the glycine-binding site, located on the NR1 subunit of NMDAR and enables activation of the receptor. Substances enhancing the access of glycine to the receptor could hypothetically improve neuroplasticity. Higher efficacy of these neuroplastic processes may protect from cognitive deterioration and negative symptoms in the course of schizophrenia. In this article we present a systematic review of current literature on the topic of GlyT1 inhibitors in schizophrenia treatment (the state of literature as of November 2019). Firstly, we described the preclinical reasons for glycine enhancement use. Next, we used CINAHL, EMBASE, EMCARE, Medline, PsycINFO, PubMed and Google Scholar databases to extract and analyze evidence from clinical trials. GlyT1 inhibitors seem to have a potential in searching for novel substances in the treatment of negative symptoms, but their capacity to reduce cognitive deficits is not evidenced. So far, the clinical efficacy of several substances was proven, including N-methylglycine (sarcosine), bitopertin and derivatives obtained with chemical synthesis. Some of these substances demonstrate a beneficial clinical effect, but the number of published reports in this area is disproportionate to the value of evidence.


Assuntos
Proteínas da Membrana Plasmática de Transporte de Glicina , Esquizofrenia , Glicina/metabolismo , Glicina/uso terapêutico , Proteínas da Membrana Plasmática de Transporte de Glicina/metabolismo , Humanos , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de N-Metil-D-Aspartato/uso terapêutico , Sarcosina/química , Sarcosina/uso terapêutico , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismo
5.
Nat Aging ; 2(11): 1024-1039, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-37118092

RESUMO

Alzheimer's disease (AD) is the most common form of dementia without effective clinical treatment. Here, we show that intermittent fasting (IF) improves cognitive functions and AD-like pathology in a transgenic AD mouse model (5XFAD). IF alters gut microbial composition with a significant enrichment in probiotics such as Lactobacillus. The changes in the composition of the gut microbiota affect metabolic activities and metabolite production. Metabolomic profiling analysis of cecal contents revealed IF leads to a decreased carbohydrate metabolism (for example, glucose) and an increased abundance in amino acids (for example, sarcosine and dimethylglycine). Interestingly, we found that the administration of IF-elevated sarcosine or dimethylglycine mimics the protective effects of IF in 5XFAD mice, including the amelioration of cognitive decline, amyloid-ß (Aß) burden and glial overactivation. Our findings thus demonstrate an IF regimen is a potential approach to prevent AD progression, at least through the gut-microbiota-metabolites-brain axis, and constitutes an innovative AD therapeutic avenue.


Assuntos
Doença de Alzheimer , Microbioma Gastrointestinal , Camundongos , Animais , Doença de Alzheimer/tratamento farmacológico , Microbioma Gastrointestinal/fisiologia , Jejum Intermitente , Sarcosina/uso terapêutico , Camundongos Transgênicos
6.
Curr Med Chem ; 29(15): 2632-2651, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34823458

RESUMO

Autism is a neurodevelopmental disorder belonging to the autism spectrum disorder (ASD). In ASDs, the individuals show substantial impairments in social communication, repetitive behaviours, and sensory behaviours deficits in the early stages of their life. Globally, the prevalence of autism is estimated to be less than 1%, especially in high- -income countries. In recent decades, there has been a drastic increase in the incidence of ASD, which has put ASD into the category of epidemics. Presently, two US Food and Drug Administration-approved drugs, aripiprazole and risperidone, are used to treat symptoms of agitation and irritability in autistic children. However, to date, no medication has been found to treat the core symptoms of ASD. The adverse side effects of conventional medicine and limited treatment options have led families of autistic children to turn to complementary and alternative medicine (CAM) treatments, which are perceived as relatively safe compared to conventional medicine. Recently N, N-dimethylglycine (DMG), a dietary supplement, has emerged as a useful supplement to improve the mental and physical state of children with ASD. The current review discusses ASD, the prevalence of ASD, the CAM approach, and the efficacy of CAM treatment in children with ASD. Moreover, it highlights the chemistry, pharmacological effect, and clinical studies of DMG, highlighting its potential for improving the lifestyle of children with ASD.


Assuntos
Transtorno do Espectro Autista , Transtorno Autístico , Transtorno do Espectro Autista/tratamento farmacológico , Transtorno do Espectro Autista/epidemiologia , Criança , Humanos , Nutrientes , Sarcosina/análogos & derivados , Sarcosina/uso terapêutico
7.
Eur J Pharmacol ; 910: 174452, 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34480885

RESUMO

Dyskinesia and psychosis are complications encountered in advanced Parkinson's disease (PD) following long-term therapy with L-3,4-dihydroxyphenylalanine (L-DOPA). Disturbances in the glutamatergic system have been associated with both dyskinesia and psychosis, making glutamatergic modulation a potential therapeutic approach for these. Treatments thus far have sought to dampen glutamatergic transmission, for example through blockade of N-methyl-D-aspartate (NMDA) receptors or modulation of metabotropic glutamate receptors 5. In contrast, activation of the glycine-binding site on NMDA receptors is required for their physiological response. Here, we investigated whether indirectly enhancing glutamatergic transmission through inhibition of glycine re-uptake would be efficacious in diminishing both dyskinesia and psychosis-like behaviours (PLBs) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned common marmoset. Six marmosets were rendered parkinsonian by MPTP injection. Following repeated administration of L-DOPA to induce dyskinesia and PLBs, they underwent acute challenges of the glycine transporter 1 (GlyT1) inhibitor ALX-5407 (0.01, 0.1 and 1 mg/kg) or vehicle, in combination with L-DOPA, after which the severity of dyskinesia, PLBs and parkinsonian disability was evaluated. In combination with L-DOPA, ALX-5407 0.1 and 1 mg/kg significantly reduced the severity of dyskinesia, by 51% and 41% (both P < 0.001), when compared to vehicle. ALX-5407 0.01, 0.1 and 1 mg/kg also decreased the severity of global PLBs, by 25%, 51% and 38% (all P < 0.001), when compared to vehicle. The benefits on dyskinesia and PLBs were achieved without compromising the therapeutic effect of L-DOPA on parkinsonism. Our results suggest that GlyT1 inhibition may be a novel strategy to attenuate dyskinesia and PLBs in PD, without interfering with L-DOPA anti-parkinsonian action.


Assuntos
Antiparkinsonianos/farmacologia , Discinesia Induzida por Medicamentos/tratamento farmacológico , Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores , Transtornos Parkinsonianos/tratamento farmacológico , Psicoses Induzidas por Substâncias/tratamento farmacológico , Sarcosina/análogos & derivados , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Animais , Antiparkinsonianos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Callithrix , Modelos Animais de Doenças , Discinesia Induzida por Medicamentos/complicações , Feminino , Levodopa/efeitos adversos , Levodopa/farmacologia , Levodopa/uso terapêutico , Intoxicação por MPTP , Masculino , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/complicações , Psicoses Induzidas por Substâncias/complicações , Sarcosina/farmacologia , Sarcosina/uso terapêutico
8.
Hum Psychopharmacol ; 36(3): e2770, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33245168

RESUMO

OBJECTIVE: Modulation of glutamatergic neurotransmission in schizophrenia by sarcosine leads to a reduction in primary negative symptoms, while its metabolic profile is safe. In order to extend research in the area, we assessed serum levels of neuropeptide Y (NPY), a hypothalamic hormone related to anxiety and depression, also involved in mechanisms inducing weight gain. Additionally, we analyzed associations between NPY concentrations and its changes with severity of symptoms and metabolic parameters. METHODS: A prospective 6-month, randomized, double-blind placebo-controlled trial was completed by 57 subjects with chronic schizophrenia with predominant negative symptoms and stable antipsychotic treatment. The participants received 2 g of sarcosine (n = 28) or placebo (n = 29) daily. We assessed serum NPY concentrations and severity of symptoms (with the Positive and Negative Syndrome Scale [PANSS] and Calgary Depression Scale for Schizophrenia) at the beginning of the study, after 6 weeks and 6 months. RESULTS: Sarcosine did not affect NPY levels in all time points. The highest decrease in NPY concentrations was observed in the subjects who were initially depressed, who became euthymic at the last visit. We noticed an improvement in the total PANSS score, and negative symptom and general psychopathology subscales in the sarcosine group, however, without any correlation with NPY levels. CONCLUSION: The use of sarcosine does not change NPY levels. Peripheral NPY concentrations may be related to depressive symptoms in schizophrenia.


Assuntos
Antipsicóticos , Esquizofrenia , Antipsicóticos/uso terapêutico , DEAE-Dextrano/uso terapêutico , Método Duplo-Cego , Quimioterapia Combinada , Humanos , Neuropeptídeo Y/uso terapêutico , Estudos Prospectivos , Escalas de Graduação Psiquiátrica , Sarcosina/uso terapêutico , Esquizofrenia/tratamento farmacológico , Resultado do Tratamento
9.
Toxicology ; 446: 152613, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33086094

RESUMO

Toluene intoxication produces deleterious effects on cognitive function, which has been associated with the inhibition of N-methyl-d-aspartate receptor (NMDAR). The present study determined whether N,N-dimethylglycine (DMG), a nutrient supplement and a partial agonist for NMDAR glycine binding site, could counteract recognition memory deficits and hippocampal synaptic dysfunction after acute toluene exposure. Male ICR mice were treated with toluene (250-750 mg/kg) for monitoring the sociability and social novelty in three-chamber test and long-term potentiation (LTP) of hippocampal synaptic transmission. Moreover, the combined effects of DMG (30-100 mg/kg) pretreatment with toluene (750 mg/kg) on three-chamber test, novel location and object recognition test and synaptic function were determined. Toluene decreased the sociability, preference for social novelty, hippocampal synaptic transmission and LTP in a dose-dependent manner. DMG pretreatment significantly reduced the toluene-induced memory impairment in social recognition, object location and object recognition and synaptic dysfunction. Furthermore, NMDAR glycine binding site antagonist, 7-chlorokynurenic acid, abolished the protective effects of DMG. These results indicate that DMG could prevent toluene-induced recognition memory deficits and synaptic dysfunction and its beneficial effects might be associated with modulation of NMDAR. These findings suggest that DMG supplementation might be an effective approach to prevent memory problems for the workers at risk of high-level toluene exposure or toluene abusers.


Assuntos
Transtornos da Memória/induzido quimicamente , Transtornos da Memória/prevenção & controle , Plasticidade Neuronal/efeitos dos fármacos , Reconhecimento Psicológico/efeitos dos fármacos , Sarcosina/análogos & derivados , Tolueno/toxicidade , Animais , Relação Dose-Resposta a Droga , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Masculino , Transtornos da Memória/psicologia , Camundongos , Camundongos Endogâmicos ICR , Plasticidade Neuronal/fisiologia , Reconhecimento Psicológico/fisiologia , Sarcosina/farmacologia , Sarcosina/uso terapêutico , Solventes/toxicidade
10.
Chin Med J (Engl) ; 132(3): 311-318, 2019 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-30681497

RESUMO

BACKGROUND: The clinical trials emerged centromere protein E inhibitor GSK923295 as a promising anticancer drug, but its function in hepatocellular carcinoma (HCC) remain needs to be fully elucidated, especially as chemotherapy after hepatectomy for liver tumors. We aimed to describe anti-HCC activities of GSK923295 and compare its antiproliferative effects on liver regeneration after partial hepatectomy (PH). METHODS: All subjects were randomized to treatment with either vehicle or GSK923295. Antitumor activity of GSK923295 was assessed by xenograft growth assays. The C57BL/6 mice were subjected to 70% PH and the proliferation was calculated by liver coefficient, further confirmed by immunohistochemistry. The proliferation and cell cycle analysis of liver cell AML12 and HCC cells LM3, HUH7, and HepG2 were investigated using the cell counting kit-8 assay and Flow Cytometry. The chromosome misalignment and segregation in AML12 cells were visualized by immunofluorescence. RESULTS: Treatment with GSK923295 induced antiproliferation in HCC cell lines. It also caused delay on HCC tumor growth instead of regression both in a HCC cell line xenograft model and patient-derived tumor xenograft model. With microarray analysis, CENtromere Protein E was gradually increased in mouse liver after PH. Exposure of liver cells to GSK923295 resulted in delay on a cell cycle in mitosis with a phenotype of misaligned chromosomes and chromosomes clustered. In 70% PH mouse model, GSK923295 treatment also remarkably reduced liver regeneration in later stage, in parallel with the mitotic marker phospho-histone H3 elevation. CONCLUSION: The anticancer drug GSK923295 causes a significant delay on HCC tumor growth and liver regeneration after PH in later stage.


Assuntos
Antineoplásicos/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/cirurgia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/cirurgia , Sarcosina/análogos & derivados , Animais , Western Blotting , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Proteínas Cromossômicas não Histona/antagonistas & inibidores , Eletroforese em Gel de Poliacrilamida , Feminino , Imunofluorescência , Humanos , Imuno-Histoquímica , Regeneração Hepática/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Reação em Cadeia da Polimerase em Tempo Real , Sarcosina/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Hum Psychopharmacol ; 33(2): e2652, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29417623

RESUMO

OBJECTIVE: Augmentation of sarcosine, a natural inhibitor of the glycine transporter type I, normalizes glutamatergic neurotransmission, having beneficial impact on primary negative symptoms in schizophrenia and may also influence immune system and interleukin 6 (IL-6) levels. AIM: Finding a relationship between initial IL-6 serum concentrations or its changes and severity of symptoms as a result of sarcosine addition to stable antipsychotic treatment. METHOD: Fifity-eight individuals with schizophrenia with predominantly negative symptoms completed a 6-month randomized, double-blind placebo-controlled prospective study. Patients received 2 g of sarcosine (n = 29) or placebo (n = 30) daily per os. We measured IL-6 levels and severity of symptoms at the beginning, after 6 weeks and 6 months. As main clinical tools, we used Positive and Negative Syndrome Scale (PANSS) and Calgary depression scale for schizophrenia (CDSS). RESULTS: Augmentation with sarcosine had no effect on IL-6 serum levels in all time points. We noted significant improvements in negative symptoms, general psychopathology, and total PANSS score in the sarcosine group. We found correlation of initial serum IL-6 with severity of positive symptoms and negative association between IL-6 levels reduction and positive symptoms reduction. CONCLUSIONS: Sarcosine does not significantly affect IL-6 concentrations but IL-6 may be involved in mechanisms related to the presence of positive symptoms.


Assuntos
Antipsicóticos/uso terapêutico , Interleucina-6/sangue , Sarcosina/uso terapêutico , Esquizofrenia/sangue , Esquizofrenia/tratamento farmacológico , Adolescente , Adulto , Antropometria , Composição Corporal , Método Duplo-Cego , Sinergismo Farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Fatores de Tempo , Adulto Jovem
12.
Behav Brain Res ; 316: 1-10, 2017 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-27555541

RESUMO

Sarcosine, an N-methyl-d-aspartate receptor enhancer, can improve depression-like behavior in rodent models and depression in humans. We found that a single dose of sarcosine exerted antidepressant-like effects with rapid concomitant increases in the mammalian target of rapamycin (mTOR) signaling pathway activation and enhancement of α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor (AMPAR) membrane insertion. Sarcosine may play a crucial role in developing novel therapy for depression. For a detailed understanding of sarcosine, this study examined the effects of long-term sarcosine treatment on the forced swim test (FST), mTOR signaling, and AMPAR membrane insertion in rats. The effects of long-term sarcosine treatment were examined in naive rats and rats exposed to chronic unpredictable stress (CUS). Long-term sarcosine treatment (560mg/kg/d for 21 d) significantly ameliorated the increased immobility induced by CUS in the FST, reaffirming the potential role of sarcosine as an antidepressant for depressed patients. The same long-term treatment exhibited no such effect in naive rats despite increased mTOR activation and AMPAR membrane insertion in both groups. Our findings clearly show CUS-exposed rats are sensitive to long-term sarcosine treatment in FST and the response at the same dose is absent in naïve rats. Nevertheless, the distinct sensitivity to long-term sarcosine treatment in rats with or without CUS is not associated with the activated mTOR signaling pathway or increased AMPAR membrane insertion. Additionally, understanding the behavioral and molecular basis of distinct responses is vital important for developing personalized treatment programs to increase the probability of success when treating depression.


Assuntos
Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Depressão/etiologia , Sarcosina/uso terapêutico , Estresse Psicológico/complicações , Animais , Modelos Animais de Doenças , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores de AMPA/metabolismo , Natação/psicologia , Serina-Treonina Quinases TOR/metabolismo , Fatores de Tempo , Regulação para Cima/efeitos dos fármacos
13.
J Psychopharmacol ; 30(10): 976-82, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27443598

RESUMO

Methylphenidate, a stimulant that activates dopaminergic and noradrenergic function, is an important agent in the treatment of attention deficit hyperactivity disorder (ADHD). Sarcosine, a glycine transporter-1 inhibitor, may also play a role in treating ADHD by modulating the glutamatergic neurotransmission system through activating N-methyl-D-aspartate type glutamate receptors. This study aimed to assess the efficacy of sarcosine in treating children with ADHD. We conducted a six-week, randomized, double-blind, placebo-controlled clinical trial. The primary outcome measures were those on the Inattention, Hyperactivity/impulsivity, and oppositional defiant disorder (ODD) subscales of the Swanson, Nolan, and Pelham, version IV scale. Efficacy and safety were measured bi-weekly. A total of 116 children with ADHD were enrolled. Among them, 48 (83%) of the 58 sarcosine recipients and 44 (76%) of the 58 placebo recipients returned for the first post-treatment visit. The missing data values were imputed by the last observation carry forward method. From a multiple linear regression analysis, using the generalized estimating equation approach, and an intention to treat analysis, the efficacy of sarcosine marginally surpassed that of placebo at weeks 2, 4, and 6, with p-values=0.01, 0.026, and 0.012, respectively, although only for ODD symptoms. Treatment of ADHD by sarcosine (0.03 g/kg/day) was well tolerated. Sarcosine could possibly be a novel agent for managing ODD symptoms in the context of ADHD. However, future larger-scale studies are warranted to optimize its dosage.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/tratamento farmacológico , Sarcosina/uso terapêutico , Estimulantes do Sistema Nervoso Central/uso terapêutico , Criança , Método Duplo-Cego , Feminino , Humanos , Masculino , Metilfenidato/uso terapêutico , Resultado do Tratamento
14.
Int J Mol Sci ; 17(7)2016 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-27409603

RESUMO

AIM: Find changes in matrix metallopeptidase-9 (MMP-9) levels during augmentation of antipsychotic treatment with sarcosine and a relationship between schizophrenia symptoms severity and initial level of MMP-9. METHOD: Fifty-eight patients with diagnosis of schizophrenia with predominant negative symptoms participated in a six-month prospective RCT (randomized controlled trial). The patients received two grams of sarcosine (n = 28) or placebo (n = 30) daily. At the beginning, after six weeks and after six months MMP-9 levels were measured. Severity of symptomatology was assessed with the Positive and Negative Syndrome Scale (PANSS) and Calgary Depression Scale for Schizophrenia (CDSS). RESULTS: MMP-9 serum levels were stable after six weeks and six months in both groups. We noted improvement in negative symptoms, general psychopathology and total PANSS score in sarcosine group compared to placebo; however, there was no correlations between serum MMP-9 concentrations and PANSS scores in all assessments. Initial serum MMP-9 concentrations cannot be used as an improvement predictor acquired during sarcosine augmentation. CONCLUSIONS: Our results indicate that either MMP-9 is not involved in the N-methyl-d-aspartate (NMDA)-dependent mechanism of sarcosine action in terms of clinical parameters or sarcosine induced changes in peripheral MMP-9 concentrations cannot be detected in blood assessments.


Assuntos
Metaloproteinase 9 da Matriz/sangue , Sarcosina/uso terapêutico , Esquizofrenia/tratamento farmacológico , Adolescente , Adulto , Antipsicóticos/uso terapêutico , Método Duplo-Cego , Esquema de Medicação , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Efeito Placebo , Estudos Prospectivos , Receptores de N-Metil-D-Aspartato/metabolismo , Esquizofrenia/metabolismo , Esquizofrenia/patologia , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto Jovem
15.
Artigo em Inglês | MEDLINE | ID: mdl-27296677

RESUMO

Ketamine, a dissociative anesthetic, produces rapid and sustained antidepressant effects at subanesthtic doses. However, it still inevitably induces psychotomimetic side effects. N,N-dimethylglycine (DMG) is a derivative of the amino acid glycine and is used as a dietary supplement. Recently, DMG has been found acting at glycine binding site of the N-methyl-d-aspartate receptor (NMDAR). As blockade of NMDARs is one of the main mechanisms responsible for the action of ketamine on central nervous system, DMG might modulate the behavioral responses to ketamine. The present study determined the effects of DMG on the ketamine-induced psychotomimetic, anesthetic and antidepressant-like effects in mice. DMG pretreatment reversed the ketamine-induced locomotor hyperactivity and impairment in the rotarod performance, novel location and novel object recognition tests, and prepulse inhibition. In addition, DMG alone exhibited antidepressant-like effects in the forced swim test and produced additive effects when combined with ketamine. However, DMG did not affect ketamine-induced anesthesia. These results reveal that DMG could antagonize ketamine's psychotomimetic effects, yet produce additive antidepressant-like effects with ketamine, suggesting that DMG might have antipsychotic potential and be suitable as an add-on therapy to ketamine for patients with treatment-resistant depression.


Assuntos
Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Ketamina/efeitos adversos , Ketamina/farmacologia , Sarcosina/análogos & derivados , Estimulação Acústica , Animais , Antidepressivos/farmacologia , Depressão/fisiopatologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Antagonistas de Aminoácidos Excitatórios/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Medo/efeitos dos fármacos , Medo/psicologia , Hipercinese/induzido quimicamente , Hipercinese/tratamento farmacológico , Resposta de Imobilidade Tônica/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Masculino , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Camundongos , Camundongos Endogâmicos ICR , Inibição Pré-Pulso/efeitos dos fármacos , Sarcosina/farmacologia , Sarcosina/uso terapêutico
16.
Nutrients ; 7(10): 8767-82, 2015 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-26506383

RESUMO

Dysfunction of the glutamatergic system, the main stimulating system in the brain, has a major role in pathogenesis of schizophrenia. The frontal white matter (WM) is partially composed of axons from glutamatergic pyramidal neurons and glia with glutamatergic receptors. The natural amino acid sarcosine, a component of a normal diet, inhibits the glycine type 1 transporter, increasing the glycine level. Thus, it modulates glutamatergic transmission through the glutamatergic ionotropic NMDA (N-methyl-d-aspartate) receptor, which requires glycine as a co-agonist. To evaluate the concentrations of brain metabolites (NAA, N-acetylaspartate; Glx, complex of glutamate, glutamine, and γ-aminobutyric acid (GABA); mI, myo-inositol; Cr, creatine; Cho, choline) in the left frontal WM, Proton Nuclear Magnetic Resonance (¹H-NMR) spectroscopy was used. Twenty-five patients randomly chosen from a group of fifty with stable schizophrenia (DSM-IV-TR) and dominant negative symptoms, who were receiving antipsychotic therapy, were administered 2 g of sarcosine daily for six months. The remaining 25 patients received placebo. Assignment was double blinded. ¹H-NMR spectroscopy (1.5 T) was performed twice: before and after the intervention. NAA, Glx and mI were evaluated as Cr and Cho ratios. All patients were also assessed twice with the Positive and Negative Syndrome Scale (PANSS). Results were compared between groups and in two time points in each group. The sarcosine group demonstrated a significant decrease in WM Glx/Cr and Glx/Cho ratios compared to controls after six months of therapy. In the experimental group, the final NAA/Cr ratio significantly increased and Glx/Cr ratio significantly decreased compared to baseline values. Improvement in the PANSS scores was significant only in the sarcosine group. In patients with schizophrenia, sarcosine augmentation can reverse the negative effect of glutamatergic system overstimulation, with a simultaneous beneficial increase of NAA/Cr ratio in the WM of the left frontal lobe. Our results further support the glutamatergic hypothesis of schizophrenia.


Assuntos
Suplementos Nutricionais , Lobo Frontal/efeitos dos fármacos , Sarcosina/uso terapêutico , Esquizofrenia/tratamento farmacológico , Substância Branca/efeitos dos fármacos , Adulto , Aminoácidos/metabolismo , Antipsicóticos/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Masculino , Espectroscopia de Prótons por Ressonância Magnética , Sarcosina/metabolismo , Sarcosina/farmacologia , Esquizofrenia/metabolismo
17.
Int J Mol Sci ; 16(10): 24475-89, 2015 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-26501260

RESUMO

The glutamatergic system is a key point in pathogenesis of schizophrenia. Sarcosine (N-methylglycine) is an exogenous amino acid that acts as a glycine transporter inhibitor. It modulates glutamatergic transmission by increasing glycine concentration around NMDA (N-methyl-d-aspartate) receptors. In patients with schizophrenia, the function of the glutamatergic system in the prefrontal cortex is impaired, which may promote negative and cognitive symptoms. Proton nuclear magnetic resonance (¹H-NMR) spectroscopy is a non-invasive imaging method enabling the evaluation of brain metabolite concentration, which can be applied to assess pharmacologically induced changes. The aim of the study was to evaluate the influence of a six-month course of sarcosine therapy on the concentration of metabolites (NAA, N-acetylaspartate; Glx, complex of glutamate, glutamine and γ-aminobutyric acid (GABA); mI, myo-inositol; Cr, creatine; Cho, choline) in the left dorso-lateral prefrontal cortex (DLPFC) in patients with stable schizophrenia. Fifty patients with schizophrenia, treated with constant antipsychotics doses, in stable clinical condition were randomly assigned to administration of sarcosine (25 patients) or placebo (25 patients) for six months. Metabolite concentrations in DLPFC were assessed with 1.5 Tesla ¹H-NMR spectroscopy. Clinical symptoms were evaluated with the Positive and Negative Syndrome Scale (PANSS). The first spectroscopy revealed no differences in metabolite concentrations between groups. After six months, NAA/Cho, mI/Cr and mI/Cho ratios in the left DLPFC were significantly higher in the sarcosine than the placebo group. In the sarcosine group, NAA/Cr, NAA/Cho, mI/Cr, mI/Cho ratios also significantly increased compared to baseline values. In the placebo group, only the NAA/Cr ratio increased. The addition of sarcosine to antipsychotic therapy for six months increased markers of neurons viability (NAA) and neurogilal activity (mI) with simultaneous improvement of clinical symptoms. Sarcosine, two grams administered daily, seems to be an effective adjuvant in the pharmacotherapy of schizophrenia.


Assuntos
Antipsicóticos/uso terapêutico , Córtex Pré-Frontal/metabolismo , Sarcosina/uso terapêutico , Esquizofrenia/tratamento farmacológico , Adulto , Antipsicóticos/farmacologia , Feminino , Humanos , Masculino , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Espectroscopia de Prótons por Ressonância Magnética , Sarcosina/farmacologia
18.
Neurosci Lett ; 606: 7-12, 2015 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-26306650

RESUMO

Glutamatergic system, the main stimulating system of the brain, plays an important role in the pathogenesis of schizophrenia. Hippocampus, a structure crucial for memory and cognitive functions and rich in glutamatergic neurons, is a natural object of interest in studies on psychoses. Sarcosine, a glycine transporter (GlyT-1) inhibitor influences the function of NMDA receptor and glutamate-dependent transmission. The aim of the study was to assess the effects of sarcosine on metabolism parameters in the left hippocampus in patients with schizophrenia. Assessments were performed using proton nuclear magnetic resonance ((1)H NMR) spectroscopy (1.5T). Fifty patients diagnosed with schizophrenia (DSM-IV-TR), with dominant negative symptoms, in stable clinical condition and stable antipsychotics doses were treated either with sarcosine (n=25) or placebo (n=25). Spectroscopic parameters were evaluated within groups and between two groups before and after 6-month intervention. All patients were also assessed with the Positive and Negative Syndrome Scale (PANSS). In the sarcosine group, after 6-month treatment, we found significant decrease in hippocampal Glx/Cr (Glx-complex of glutamate, glutamine and GABA, Cr-creatine) and Glx/Cho (Cho-choline), while N-acetylaspartate (NAA), myo-inositol (mI), Cr and Cho parameters remained stable along the study and also did not differ significantly between both groups. This is the first study showing that a pharmacological intervention in schizophrenia, particularly augmentation of the antypsychotic treatment with sarcosine, may reverse the pathological increase in glutamatergic transmission in the hippocampus. The results confirm involvement of glutamatergic system in the pathogenesis of schizophrenia and demonstrate beneficial effects of GlyT-1 inhibitor on the metabolism in the hippocampus and symptoms of schizophrenia.


Assuntos
Antipsicóticos/uso terapêutico , Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores , Sarcosina/uso terapêutico , Esquizofrenia/tratamento farmacológico , Adolescente , Adulto , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Colina/metabolismo , Creatina/metabolismo , Método Duplo-Cego , Feminino , Ácido Glutâmico/metabolismo , Glutamina/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Inositol/metabolismo , Masculino , Pessoa de Meia-Idade , Esquizofrenia/metabolismo , Adulto Jovem , Ácido gama-Aminobutírico/metabolismo
19.
Curr Pharm Des ; 21(17): 2291-303, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25578890

RESUMO

We have synthesized a novel series of N-substituted sarcosines, analogues of NFPS (N-[3-(biphenyl-4- yloxy)-3-(4-fluorophenyl)propyl]-N-methylglycine), as type-1 glycine transporter (GlyT-1) inhibitors. Several compounds incorporated a diazine ring inhibited recombinant hGlyT-1b expressed permanently in CHO cells and GlyT-1 in rat brain synaptosomal preparations. A structure-activity relationship for the newly synthesized compounds was obtained and discussed on the ground of their GlyT-1 inhibitory potencies. Replacement of the biphenyl-4-yloxy moiety in NFPS with a 5-pyridazinylphenoxy moiety (compounds 3, 4, 5, and 6) or a 2-phenyl-5- pyridazinyloxy moiety (compounds 10, 11, and 12) afforded compounds exhibiting potent inhibition on GlyT-1 activity. The GlyT-1 inhibitory properties of NFPS analogues, in which sarcosine was closed into a ring forming (methylamino)pyridazine-3-(2H)-one, were markedly reduced (compounds 13 and 14). The pyridazine-containing GlyT-1 inhibitors with in vitro GlyT-1 inhibitory potency also enhanced extracellular glycine concentrations in conscious rat striatum as was measured by microdialysis technique. In contrast to NFPS, sarcosine-based pyridazine containing GlyT-1 inhibitors failed to evoke compulsive running behavior whereas they inhibited phencyclidine- induced hypermotility in mice. It is believed that increase of extracellular concentrations of glycine by inhibition of its reuptake may probably influence positively glutamate N-methyl-D-aspartate (NMDA)-type ionotropic receptors in the central nervous system. This may have importance in the treatment of neuropsychiatric disorders associated with hypofunctional NMDA receptor-mediated glutamatergic neurochemical transmission. Thus, impaired NMDA receptor functions have been shown to be involved in the development of the negative symptoms and the cognitive deficit of schizophrenia and the treatment of these symptoms is the possible clinical indication of GlyT-1 inhibitors including those containing pyridazine moiety.


Assuntos
Desenho de Fármacos , Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores , Piridazinas/química , Sarcosina/química , Sarcosina/uso terapêutico , Esquizofrenia/tratamento farmacológico , Animais , Células CHO , Cricetulus , Relação Dose-Resposta a Droga , Humanos , Masculino , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , Ratos , Ratos Wistar , Sarcosina/síntese química , Sarcosina/farmacologia , Relação Estrutura-Atividade
20.
Eur J Pharmacol ; 746: 252-7, 2015 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-25435080

RESUMO

Several studies have shown that glycine transporter 1 (GlyT1) inhibitors have anxiolytic actions. There are two types of glycine receptor: the strychnine-sensitive glycine receptor (GlyA) and the strychnine-insensitive glycine receptor (GlyB); however, which receptor is the main contributor to the anxiolytic actions of GlyT1 inhibitors is yet to be determined. Here, we clarified which glycine receptor is the main contributor to the anxiolytic effects of GlyT1 inhibitors by using maternal separation-induced ultrasonic vocalization (USV) by rat pups as an index of anxiety. We confirmed that administration of the benzodiazepine diazepam or the selective serotonin reuptake inhibitor escitaloplam, which are both clinically proven anxiolytics, or the GlyT1 inhibitor SSR504734 (2-chloro-N-[(S)-phenyl[(2S)-piperidin-2-yl] methyl]-3-trifluoromethyl benzamide), decreases USV in rat pups. In addition, we showed that another GlyT1 inhibitor, ALX5407 ((R)-N-[3-(4'-fluorophenyl)-3(4'-phenylphenoxy)propyl]sarcosine) also decreases USV in rat pups. SSR504734- or ALX5407-induced decreases in USV were dose-dependently reversed by administration of the GlyA antagonist strychnine, whereas the diazepam- or escitalopram-induced decreases in USV were not. Furthermore, GlyT1-induced decreases in USV were not reversed by administration of the GlyB antagonist L-687,414. Together, these results suggest that GlyA activation is the main contributor to the anxiolytic actions of GlyT1 inhibitors and that the anxiolytic actions of diazepam and escitalopram cannot be attributed to GlyA activation. Our findings provide new insights into the importance of the activation of GlyA in the anxiolytic effects of GlyT1 inhibitors.


Assuntos
Ansiolíticos/uso terapêutico , Ansiedade de Separação/tratamento farmacológico , Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores , Privação Materna , Moduladores de Transporte de Membrana/uso terapêutico , Receptores de Glicina/agonistas , Vocalização Animal/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Ansiolíticos/administração & dosagem , Ansiolíticos/efeitos adversos , Ansiolíticos/química , Ansiedade de Separação/etiologia , Benzamidas/administração & dosagem , Benzamidas/efeitos adversos , Benzamidas/antagonistas & inibidores , Benzamidas/uso terapêutico , Temperatura Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Interações Medicamentosas , Proteínas da Membrana Plasmática de Transporte de Glicina/metabolismo , Moduladores de Transporte de Membrana/administração & dosagem , Moduladores de Transporte de Membrana/efeitos adversos , Moduladores de Transporte de Membrana/química , Terapia de Alvo Molecular , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Piperidinas/antagonistas & inibidores , Piperidinas/uso terapêutico , Pirrolidinonas/uso terapêutico , Ratos Sprague-Dawley , Receptores de Glicina/antagonistas & inibidores , Receptores de Glicina/metabolismo , Sarcosina/administração & dosagem , Sarcosina/efeitos adversos , Sarcosina/análogos & derivados , Sarcosina/antagonistas & inibidores , Sarcosina/uso terapêutico , Estricnina/farmacologia , Ultrassom
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