RESUMO
STriatal-Enriched protein tyrosine Phosphatase (STEP) is a brain-specific tyrosine phosphatase that is associated with numerous neurological and neuropsychiatric disorders. STEP dephosphorylates and inactivates various kinases and phosphatases critical for neuronal function and health including Fyn, Pyk2, ERK1/2, p38, and PTPα. Importantly, STEP dephosphorylates NMDA and AMPA receptors, two major glutamate receptors that mediate fast excitatory synaptic transmission. This STEP-mediated dephosphorylation leads to their internalization and inhibits both Hebbian synaptic potentiation and homeostatic synaptic scaling. Hence, STEP has been widely accepted to weaken excitatory synaptic strength. However, emerging evidence implicates a novel role of STEP in neuronal hyperexcitability and seizure disorders. Genetic deletion and pharmacological blockade of STEP reduces seizure susceptibility in acute seizure mouse models and audiogenic seizures in a mouse model of Fragile X syndrome. Pharmacologic inhibition of STEP also decreases hippocampal activity and neuronal intrinsic excitability. Here, we will highlight the divergent roles of STEP in excitatory synaptic transmission and neuronal intrinsic excitability, present the potential underlying mechanisms, and discuss their impact on STEP-associated neurologic and neuropsychiatric disorders.
RESUMO
At the Institute of Cytology and Genetics (Novosibirsk, Russia) for over 85 generations, gray rats have been selected for high aggression toward humans (aggressive rats) or its complete absence (tame rats). Aggressive rats are an interesting model for studying fear-induced aggression. Benzopentathiepin TC-2153 exerts an antiaggressive effect on aggressive rats and affects the serotonergic system: an important regulator of aggression. The aim of this study was to investigate effects of TC-2153 on key serotonergic-system enzymes - tryptophan hydroxylase 2 (TPH2) and monoamine oxidase A (MAOA) - in the brain of aggressive and tame rats. Either TC-2153 (10 or 20 mg/kg) or vehicle was administered once intraperitoneally to aggressive and tame male rats. TPH2 and MAOA enzymatic activities and mRNA and protein levels were assessed. The selection for high aggression resulted in upregulation of Tph2 mRNA in the midbrain, of the TPH2 protein in the hippocampus, and of proteins TPH2 and MAOA in the hypothalamus, as compared to tame rats. MAO enzymatic activity was higher in the midbrain and hippocampus of aggressive rats while TPH2 activity did not differ between the strains. The single TC-2153 administration decreased TPH2 and MAO activity in the hypothalamus and midbrain, respectively. The drug affected MAOA protein levels in the hypothalamus: upregulated them in aggressive rats and downregulated them in tame ones. Thus, this study shows profound differences in the expression and activity of key serotonergic system enzymes in the brain of rats selectively bred for either highly aggressive behavior toward humans or its absence, and the effects of benzopentathiepin TC-2153 on these enzymes may point to mechanisms of its antiaggressive action.
Assuntos
Agressão , Encéfalo , Monoaminoxidase , Triptofano Hidroxilase , Animais , Triptofano Hidroxilase/metabolismo , Triptofano Hidroxilase/genética , Monoaminoxidase/metabolismo , Monoaminoxidase/genética , Ratos , Masculino , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Agressão/efeitos dos fármacos , Humanos , Serotonina/metabolismoRESUMO
The Bdnf (brain-derived neurotrophic factor) gene contains eight regulatory exons (I-VIII) alternatively spliced to the protein-coding exon IX. Only exons I, II, IV, and VI are relatively well studied. The BDNF system and brain serotonergic system are tightly interconnected and associated with aggression. The benzopentathiepine TC-2153 affects both systems and exerts antiaggressive action. Our aim was to evaluate the effects of TC-2153 on the Bdnf exons I-IX's expressions and serotonin receptors' mRNA levels in the brain of rats featuring high aggression toward humans (aggressive) or its absence (tame). Aggressive and tame adult male rats were treated once with vehicle or 10 or 20 mg/kg of TC-2153. mRNA was quantified in the cortex, hippocampus, hypothalamus, and midbrain with real-time PCR. Selective breeding for high aggression or its absence affected the serotonin receptors' and Bdnf exons' transcripts differentially, depending on the genotype (strain) and brain region. TC-2153 had comprehensive effects on the Bdnf exons' expressions. The main trend was downregulation in the hypothalamus and midbrain. TC-2153 increased 5-HT1B receptor hypothalamusc mRNA expression. For the first time, an influence of TC-2153 on the expressions of Bdnf regulatory exons and the 5-HT1B receptor was shown, as was an association between Bdnf regulatory exons and fear-induced aggression involving genetic predisposition.
Assuntos
Fator Neurotrófico Derivado do Encéfalo , Receptor 5-HT1B de Serotonina , Humanos , Ratos , Animais , Masculino , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Receptor 5-HT1B de Serotonina/genética , Receptor 5-HT1B de Serotonina/metabolismo , Encéfalo/metabolismo , Medo/fisiologia , RNA Mensageiro/análise , Hipocampo/metabolismo , Agressão/fisiologiaRESUMO
OBJECTIVE: STriatal-Enriched protein tyrosine Phosphatase (STEP) is a brain-specific tyrosine phosphatase. Membrane-bound STEP61 is the only isoform expressed in hippocampus and cortex. Genetic deletion of STEP enhances excitatory synaptic currents and long-term potentiation in the hippocampus. However, whether STEP61 affects seizure susceptibility is unclear. Here we investigated the effects of STEP inhibitor TC-2153 on seizure propensity in a murine model displaying kainic acid (KA)-induced status epilepticus and its effect on hippocampal excitability. METHODS: Adult male and female C57BL/6J mice received intraperitoneal injection of either vehicle (2.8% dimethylsulfoxide [DMSO] in saline) or TC-2153 (10 mg/kg) and then either saline or KA (30 mg/kg) 3 h later before being monitored for behavioral seizures. A subset of female mice was ovariectomized (OVX). Acute hippocampal slices from Thy1-GCaMP6s mice were treated with either DMSO or TC-2153 (10 µM) for 1 h, and then incubated in artificial cerebrospinal fluid (ACSF) and potassium chloride (15 mM) for 2 min prior to live calcium imaging. Pyramidal neurons in dissociated rat hippocampal culture (DIV 8-10) were pre-treated with DMSO or TC-2153 (10 µM) for 1 h before whole-cell patch-clamp recording. RESULTS: TC-2153 treatment significantly reduced KA-induced seizure severity, with greater trend seen in female mice. OVX abolished this TC-2153-induced decrease in seizure severity in female mice. TC-2153 application significantly decreased overall excitability of acute hippocampal slices from both sexes. Surprisingly, TC-2153 treatment hyperpolarized resting membrane potential and decreased firing rate, sag voltage, and hyperpolarization-induced current (Ih ) of cultured hippocampal pyramidal neurons. SIGNIFICANCE: This study is the first to demonstrate that pharmacological inhibition of STEP with TC-2153 decreases seizure severity and hippocampal activity in both sexes, and dampens hippocampal neuronal excitability and Ih . We propose that the antiseizure effects of TC-2153 are mediated by its unexpected action on suppressing neuronal intrinsic excitability.
Assuntos
Dimetil Sulfóxido , Hipocampo , Animais , Benzotiepinas , Dimetil Sulfóxido/efeitos adversos , Dimetil Sulfóxido/metabolismo , Feminino , Ácido Caínico/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Convulsões/induzido quimicamente , Convulsões/metabolismoRESUMO
Loss of dendritic spines and decline of cognitive function are hallmarks of patients with Alzheimer's disease (AD). Previous studies have shown that AD pathophysiology involves increased expression of a central nervous system-enriched protein tyrosine phosphatase called STEP (STriatal-Enriched protein tyrosine Phosphatase). STEP opposes the development of synaptic strengthening by dephosphorylating substrates, including GluN2B, Pyk2, and ERK1/2. Genetic reduction of STEP as well as pharmacological inhibition of STEP improve cognitive function and hippocampal memory in the 3×Tg-AD mouse model. Here, we show that the improved cognitive function is accompanied by an increase in synaptic connectivity in cell cultures as well as in the triple transgenic AD mouse model, further highlighting the potential of STEP inhibitors as a therapeutic agent.
Assuntos
Doença de Alzheimer , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Animais , Modelos Animais de Doenças , Hipocampo , Memória , Camundongos , Camundongos Endogâmicos C57BL , Camundongos TransgênicosRESUMO
Tyrosine phosphatase STEP (striatal-enriched tyrosine protein phosphatase) is a brain-specific protein phosphatase and is involved in the pathogenesis of many neurodegenerative diseases. Here, we examined the impact of STEP on the development of age-related macular degeneration (AMD)-like pathology in senescence-accelerated OXYS rats. Using OXYS and Wistar rats (control), we for the first time demonstrated age-dependent changes in Ptpn5 mRNA expression, STEP46 and STEP61 protein levels, and their phosphatase activity in the retina. The increases in STEP protein levels and the decrease of total and STEP phosphatase activities in the retina (as compared with Wistar rats) preceded the manifestation of clinical signs of AMD in OXYS rats (age 20 days). There were no differences in these retinal parameters between 13-month-old Wistar rats and OXYS rats with pronounced signs of AMD. Inhibition of STEP with TC-2153 during progressive AMD-like retinopathy (from 9 to 13 months of age) reduced the thickness of the retinal inner nuclear layer, as evidenced by a decreased amount of parvalbumin-positive amacrine neurons. Prolonged treatment with TC-2153 had no effect on Ptpn5 mRNA expression, STEP46 and STEP61 protein levels, and their phosphatase activity in the OXYS retina. Thus, TC-2153 may negatively affect the retina through mechanisms unrelated to STEP.
Assuntos
Envelhecimento/metabolismo , Regulação da Expressão Gênica/genética , Degeneração Macular/metabolismo , Proteínas Tirosina Fosfatases não Receptoras/metabolismo , Retina/metabolismo , Doenças Retinianas/metabolismo , Envelhecimento/genética , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Benzotiepinas/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Senescência Celular/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Degeneração Macular/patologia , Masculino , Fator de Crescimento Neural/metabolismo , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Proteínas Tirosina Fosfatases não Receptoras/antagonistas & inibidores , Proteínas Tirosina Fosfatases não Receptoras/genética , Ratos , Ratos Wistar , Doenças Retinianas/enzimologia , Doenças Retinianas/genéticaRESUMO
Cocaine self-administration in rats results in dysfunctional neuroadaptations in the prelimbic (PrL) cortex during early abstinence. Central to these adaptations is decreased phospho-extracellular signal-regulated kinase (p-ERK), which plays a key role in cocaine seeking. Normalizing ERK phosphorylation in the PrL cortex immediately after cocaine self-administration decreases subsequent cocaine seeking. The disturbance in ERK phosphorylation is accompanied by decreased phosphorylation of striatal-enriched protein tyrosine phosphatase (STEP), indicating increased STEP activity. STEP is a well-recognized ERK phosphatase but whether STEP activation during early abstinence mediates the decrease in p-ERK and is involved in relapse is unknown. Here, we show that a single intra-PrL cortical microinfusion of the selective STEP inhibitor, TC-2153, immediately after self-administration suppressed post-abstinence context-induced relapse under extinction conditions and cue-induced reinstatement, but not cocaine prime-induced drug seeking or sucrose seeking. Moreover, an intra-PrL cortical TC-2153 microinfusion immediately after self-administration prevented the cocaine-induced decrease in p-ERK within the PrL cortex during early abstinence. Interestingly, a systemic TC-2153 injection at the same timepoint failed to suppress post-abstinence context-induced relapse or cue-induced reinstatement, but did suppress cocaine prime-induced reinstatement. These data indicate that the STEP-induced ERK dephosphorylation in the PrL cortex during early abstinence is a critical neuroadaptation that promotes relapse to cocaine seeking and that systemic versus intra-PrL cortical inhibition of STEP during early abstinence differentially suppresses cocaine seeking.
Assuntos
Benzotiepinas/farmacologia , Cocaína/administração & dosagem , Inibidores da Captação de Dopamina/administração & dosagem , Comportamento de Procura de Droga/efeitos dos fármacos , Proteínas Tirosina Fosfatases não Receptoras/antagonistas & inibidores , Animais , MAP Quinases Reguladas por Sinal Extracelular , Masculino , Fosfoproteínas , Córtex Pré-Frontal , Ratos , Ratos Sprague-Dawley , AutoadministraçãoRESUMO
We compared the effect of a new potential antidepressant 8-trifluoromethyl 1,2,3,4,5-benzopentathiepine-6-amine hydrochloride (TC-2153) and classical antidepressant fluoxetine in a dose of 0.25 mg/liter on the behavior of Danio rerio in the "novel tank" test and content of biogenic amines and their metabolites in the brain. Fluoxetine alone and TC-2153 alone significantly increased the time spent in the upper part of the tank and insignificantly reduced motor activity. Combined exposure of fishes in the solution containing potential and classical antidepressants potentiated their effects on both parameters. The compounds did not affect brain contents of serotonin, dopamine, and norepinephrine. At the same time, fluoxetine, but not TC-2153, reduced brain content of the main serotonin metabolite 5-hydroxyindole acetic acid.
Assuntos
Antidepressivos/farmacologia , Benzotiepinas/farmacologia , Aminas Biogênicas/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Fluoxetina/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Dopamina/metabolismo , Norepinefrina/metabolismo , Serotonina/metabolismo , Peixe-ZebraRESUMO
Striatal-enriched protein tyrosine phosphatase (STEP) is a signal transduction protein involved in the pathogenesis of neuropathologies. A STEP inhibitor (TC-2153) has antipsychotic and antidepressant effects. Here, we evaluated the role of STEP in fear-induced aggression using Norway rats selectively bred for 90 generations for either high aggression toward humans (aggressive rats) or its absence (tame rats). We studied the effects of acute administration of TC-2153 on behavior and STEP expression in the brain of these animals and the influence of chronic treatment with TC-2153 on the behavior and STEP expression in aggressive rats in comparison with classic antidepressant fluoxetine, which is known to exert antiaggressive action. Acute TC-2153 administration decreased the aggressive reaction to humans in aggressive rats, while having no impact on the friendly behavior of tame rats. Moreover, in the elevated plus-maze test, the drug had an anxiolytic effect on both aggressive and tame rats. Aggressive rats demonstrated elevated levels of a STEP isoform (STEP46) as compared to tame animals, whereas acute TC-2153 administration significantly reduced STEP46 protein concentration in the brain of aggressive rats. Chronic treatment of aggressive rats with either TC-2153 or fluoxetine attenuated fear-induced aggression. Chronic administration of fluoxetine enhanced the exploratory activity in the elevated plus-maze test and decreased the STEP46 protein level in aggressive rats' hippocampus, whereas chronic TC-2153 administration did not affect these parameters. Thus, STEP46 can play an important role in the mechanisms of aggression and may mediate antiaggressive effects of TC-2153 and fluoxetine.
Assuntos
Agressão/efeitos dos fármacos , Ansiolíticos/farmacologia , Benzotiepinas/farmacologia , Encéfalo/efeitos dos fármacos , Medo/efeitos dos fármacos , Proteínas Tirosina Fosfatases não Receptoras/antagonistas & inibidores , Animais , Comportamento Animal/efeitos dos fármacos , Fluoxetina/farmacologia , Hipocampo/efeitos dos fármacos , Masculino , RatosRESUMO
Autism spectrum disorders (ASDs) are highly prevalent childhood illnesses characterized by impairments in communication, social behavior, and repetitive behaviors. Studies have found aberrant synaptic plasticity and neuronal connectivity during the early stages of brain development and have suggested that these contribute to an increased risk for ASD. STEP is a protein tyrosine phosphatase that regulates synaptic plasticity and is implicated in several cognitive disorders. Here we test the hypothesis that STEP may contribute to some of the aberrant behaviors present in the VPA-induced mouse model of ASD. In utero VPA exposure of pregnant dams results in autistic-like behavior in the pups, which is associated with a significant increase in the STEP expression in the prefrontal cortex. The elevated STEP protein levels are correlated with increased dephosphorylation of STEP substrates GluN2B, Pyk2 and ERK, suggesting upregulated STEP activity. Moreover, pharmacological inhibition of STEP rescues the sociability, repetitive and abnormal anxiety phenotypes commonly associated with ASD. These data suggest that STEP may play a role in the VPA model of ASD and STEP inhibition may have a potential therapeutic benefit in this model.
Assuntos
Transtorno do Espectro Autista/fisiopatologia , Proteínas Tirosina Fosfatases não Receptoras/metabolismo , Animais , Transtorno do Espectro Autista/tratamento farmacológico , Transtorno Autístico/tratamento farmacológico , Comportamento Animal , Modelos Animais de Doenças , Comportamento Exploratório/fisiologia , Feminino , Inibição Psicológica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/fisiologia , Córtex Pré-Frontal , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Proteínas Tirosina Fosfatases/metabolismo , Proteínas Tirosina Fosfatases/fisiologia , Proteínas Tirosina Fosfatases não Receptoras/fisiologia , Comportamento Social , Comportamento Estereotipado/fisiologia , Ácido Valproico/efeitos adversosRESUMO
Significance: Sulfur has a critical role in protein structure/function and redox status/signaling in all living organisms. Although hydrogen sulfide (H2S) and sulfane sulfur (SS) are now recognized as central players in physiology and pathophysiology, the full scope and depth of sulfur metabolome's impact on human health and healthy longevity has been vastly underestimated and is only starting to be grasped. Since many pathological conditions have been related to abnormally low levels of H2S/SS in blood and/or tissues, and are amenable to treatment by H2S supplementation, development of safe and efficacious H2S donors deserves to be undertaken with a sense of urgency; these prodrugs also hold the promise of becoming widely used for disease prevention and as antiaging agents. Recent Advances: Supramolecular tuning of the properties of well-known molecules comprising chains of sulfur atoms (diallyl trisulfide [DATS], S8) was shown to lead to improved donors such as DATS-loaded polymeric nanoparticles and SG1002. Encouraging results in animal models have been obtained with SG1002 in heart failure, atherosclerosis, ischemic damage, and Duchenne muscular dystrophy; with TC-2153 in Alzheimer's disease, schizophrenia, age-related memory decline, fragile X syndrome, and cocaine addiction; and with DATS in brain, colon, gastric, and breast cancer. Critical Issues: Mode-of-action studies on allyl polysulfides, benzyl polysulfides, ajoene, and 12 ring-substituted organic disulfides and thiosulfonates led several groups of researchers to conclude that the anticancer effect of these compounds is not mediated by H2S and is only modulated by reactive oxygen species, and that their central model of action is selective protein S-thiolation. Future Directions: SG1002 is likely to emerge as the H2S donor of choice for acquiring knowledge on this gasotransmitter's effects in animal models, on account of its unique ability to efficiently generate H2S without byproducts and in a slow and sustained mode that is dose independent and enzyme independent. Efficient tuning of H2S donation characteristics of DATS, dibenzyl trisulfide, and other hydrophobic H2S prodrugs for both oral and parenteral administration will be achieved not only by conventional structural modification of a lead molecule but also through the new "supramolecular tuning" paradigm.
Assuntos
Sulfeto de Hidrogênio/química , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Compostos de Enxofre/química , Compostos de Enxofre/farmacologia , Animais , Fenômenos Químicos , Ensaios Clínicos como Assunto , Suplementos Nutricionais , Relação Dose-Resposta a Droga , Desenvolvimento de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Humanos , Imunomodulação/efeitos dos fármacos , Estrutura Molecular , Pró-Fármacos/uso terapêutico , Espécies Reativas de Oxigênio , Células-Tronco/efeitos dos fármacos , Relação Estrutura-Atividade , Sulfetos , Compostos de Enxofre/uso terapêuticoRESUMO
Fragile X syndrome (FXS) is the leading cause of inherited intellectual disability, with additional symptoms including attention deficit and hyperactivity, anxiety, impulsivity, and repetitive movements or actions. The majority of FXS cases are attributed to a CGG expansion that leads to transcriptional silencing and diminished expression of fragile X mental retardation protein (FMRP). FMRP, an RNA binding protein, regulates the synthesis of dendritically-translated mRNAs by stalling ribosomal translation. Loss of FMRP leads to increased translation of some of these mRNAs, including the CNS-specific tyrosine phosphatase STEP (STriatal-Enriched protein tyrosine Phosphatase). Genetic reduction of STEP in Fmr1 KO mice have diminished audiogenic seizures and a reversal of social and non-social anxiety-related abnormalities. This study investigates whether a newly discovered STEP inhibitor (TC-2153) could attenuate the behavioral and synaptic abnormalities in Fmr1 KO mice. TC-2153 reversed audiogenic seizure incidences, reduced hyperactivity, normalized anxiety states, and increased sociability in Fmr1 KO mice. Moreover, TC-2153 reduced dendritic spine density and improved synaptic aberrations in Fmr1 KO neuronal cultures as well as in vivo. TC-2153 also reversed the mGluR-mediated exaggerated LTD in brain slices derived from Fmr1 KO mice. These studies suggest that STEP inhibition may have therapeutic benefit in FXS.
Assuntos
Potenciais Pós-Sinápticos Excitadores/genética , Proteína do X Frágil da Deficiência Intelectual/metabolismo , Síndrome do Cromossomo X Frágil/complicações , Síndrome do Cromossomo X Frágil/patologia , Proteínas Tirosina Fosfatases não Receptoras/metabolismo , Sinapses/patologia , Adaptação Ocular/efeitos dos fármacos , Adaptação Ocular/genética , Animais , Animais Recém-Nascidos , Ansiedade/tratamento farmacológico , Ansiedade/etiologia , Benzotiepinas/farmacologia , Comportamento de Escolha/efeitos dos fármacos , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/genética , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Epilepsia Reflexa/tratamento farmacológico , Epilepsia Reflexa/etiologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Comportamento Exploratório/efeitos dos fármacos , Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Hipocampo/patologia , Hipocampo/ultraestrutura , Camundongos , Camundongos TransgênicosRESUMO
The serotoninergic 5-HT2A receptor is involved in the mechanism of depression and antidepressant drugs action. Earlier we showed that striatal-enriched protein tyrosine phosphatase (STEP) inhibitor - 8-(trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine hydrochloride (TC-2153) affects both the brain serotoninergic system and the brain-derived neurotropic factor that are known to be involved in the psychopathology of depression. In the present study we investigated the effects of chronic TC-2153 administration on behavior in the standard battery of tests as well as the effects of acute and chronic TC-2153 treatment on the brain 5-HT2A receptors in mice. We obtained a prominent antidepressant-like effect of chronic TC-2153 treatment in the forced swim test without any adverse side effects on locomotor activity, anxiety, exploration, motor skill and obsessive-compulsive-like behavior. Moreover, both acute and chronic TC-2153 administration inhibited the functional activity of 5-HT2A receptors estimated by the number of 2,5-dimethoxy-4-iodoamphetamine (DOI, agonist of 5-HT2A receptors)-induced head-twitches. TC-2153 treatment also attenuated the DOI-induced c-fos expression in cortical and hippocampal neurons and reduced the 5-HT2A receptor protein level in the hippocampus and frontal cortex, but not in the striatum. Taken together, our combined data demonstrate that the antidepressant effect of STEP inhibitor TC-2153 could be mediated by its inhibitory properties towards the 5-HT2A receptor-mediated signaling.
Assuntos
Antidepressivos/administração & dosagem , Benzotiepinas/administração & dosagem , Encéfalo/efeitos dos fármacos , Depressão/tratamento farmacológico , Proteínas Tirosina Fosfatases não Receptoras/antagonistas & inibidores , Receptor 5-HT2A de Serotonina/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismoRESUMO
Striatal-enriched tyrosine protein phosphatase (STEP) is expressed mainly in the brain. Its dysregulation is associated with Alzheimer's and Huntington's diseases, schizophrenia, fragile X syndrome, drug abuse and stroke/ischemia. However, an association between STEP and depressive disorders is still obscure. The review discusses the theoretical foundations and experimental facts concerning possible relationship between STEP dysregulation and depression risk. STEP dephosphorylates and inactivates several key neuronal signaling proteins such as extracellular signal-regulating kinase 1 and 2 (ERK1/2), stress activated protein kinases p38, the Src family tyrosine kinases Fyn, Pyk2, NMDA and AMPA glutamate receptors. The inactivation of these proteins decreases the expression of brain derived neurotrophic factor (BDNF) necessary for neurogenesis and neuronal survival. The deficit of BDNF results in progressive degeneration of neurons in the hippocampus and cortex and increases depression risk. At the same time, a STEP inhibitor, 8-(trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine hydrochloride (TC-2153), increases BDNF expression in the hippocampus and attenuated the depressivelike behavior in mice. Thus, STEP is involved in the mechanism of depressive disorders and it is a promising molecular target for atypical antidepressant drugs of new generation.