RESUMEN
CHIR99021, also known as laduviglusib or CT99021, is a Glycogen-synthase kinase 3ß (GSK3ß) inhibitor, which has been reported as a promising drug for cardiomyocyte regeneration or treatment of sensorial hearing loss. Since the activation of dopamine (DA) receptors regulates dopamine synthesis and they can signal through the ß-arrestin pathway and GSK3ß, we decided to check the effect of GSK3ß inhibitors (CHIR99021, SB216763 and lithium ion) on the control of DA synthesis. Using ex vivo experiments with minces from rat brain striatum, we observed that CHIR99021, but not SB216763 or lithium, causes complete abrogation of both DA synthesis and accumulation, pointing to off-target effects of CHIR99021. This decrease can be attributed to tyrosine hydroxylase (TH) inhibition since the accumulation of l-DOPA in the presence of a DOPA decarboxylase inhibitor was similarly decreased. On the other hand, CHIR99021 caused a dramatic increase in the DOPAC/DA ratio, an indicator of DA metabolization, and hindered DA incorporation into striatum tissue. Tetrabenazine, an inhibitor of DA vesicular transport, also caused DA depletion and DOPAC/DA ratio increase to the same extent as CHIR99021. In addition, both CHIR99021 or SB216763, but not lithium, decreased TH phosphorylation in Ser19, but not in Ser31 or Ser40. These results demonstrate that CHIR99021 can lead to TH inactivation and DA depletion in brain striatum, opening the possibility of its use in DA-related disorders, and shows effects to be considered in future clinical trials. More work is needed to find the mechanism exerted by CHIR99021 on DA accumulation.
Asunto(s)
Cuerpo Estriado , Dopamina , Tirosina 3-Monooxigenasa , Animales , Ratas , Ácido 3,4-Dihidroxifenilacético/metabolismo , Cuerpo Estriado/enzimología , Dopamina/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Litio/farmacología , Tirosina 3-Monooxigenasa/antagonistas & inhibidoresRESUMEN
The canonical model of striatal function predicts that animal locomotion is associated with the opposing regulation of protein kinase A (PKA) in direct and indirect pathway striatal spiny projection neurons (SPNs) by dopamine1-7. However, the precise dynamics of PKA in dorsolateral SPNs during locomotion remain to be determined. It is also unclear whether other neuromodulators are involved. Here we show that PKA activity in both types of SPNs is essential for normal locomotion. Using two-photon fluorescence lifetime imaging8-10 of a PKA sensor10 through gradient index lenses, we measured PKA activity within individual SPNs of the mouse dorsolateral striatum during locomotion. Consistent with the canonical view, dopamine activated PKA activity in direct pathway SPNs during locomotion through the dopamine D1 receptor. However, indirect pathway SPNs exhibited a greater increase in PKA activity, which was largely abolished through the blockade of adenosine A2A receptors. In agreement with these results, fibre photometry measurements of an adenosine sensor11 revealed an acute increase in extracellular adenosine during locomotion. Functionally, antagonism of dopamine or adenosine receptors resulted in distinct changes in SPN PKA activity, neuronal activity and locomotion. Together, our results suggest that acute adenosine accumulation interplays with dopamine release to orchestrate PKA activity in SPNs and proper striatal function during animal locomotion.
Asunto(s)
Adenosina , Cuerpo Estriado , Proteínas Quinasas Dependientes de AMP Cíclico , Dopamina , Locomoción , Neuronas , Animales , Ratones , Adenosina/metabolismo , Cuerpo Estriado/citología , Cuerpo Estriado/enzimología , Cuerpo Estriado/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Dopamina/metabolismo , Locomoción/fisiología , Neuronas/enzimología , Neuronas/metabolismo , Receptores de Dopamina D1/metabolismo , Receptor de Adenosina A2A/metabolismoRESUMEN
Mutations in leucine-rich repeat kinase 2 (LRRK2) cause Parkinson's disease with a similar clinical presentation and progression to idiopathic Parkinson's disease, and common variation is linked to disease risk. Recapitulation of the genotype in rodent models causes abnormal dopamine release and increases the susceptibility of dopaminergic neurons to insults, making LRRK2 a valuable model for understanding the pathobiology of Parkinson's disease. It is also a promising druggable target with targeted therapies currently in development. LRRK2 mRNA and protein expression in the brain is highly variable across regions and cellular identities. A growing body of work has demonstrated that pathogenic LRRK2 mutations disrupt striatal synapses before the onset of overt neurodegeneration. Several substrates and interactors of LRRK2 have been identified to potentially mediate these pre-neurodegenerative changes in a cell-type-specific manner. This review discusses the effects of pathogenic LRRK2 mutations in striatal neurons, including cell-type-specific and pathway-specific alterations. It also highlights several LRRK2 effectors that could mediate the alterations to striatal function, including Rabs and protein kinase A. The lessons learned from improving our understanding of the pathogenic effects of LRRK2 mutations in striatal neurons will be applicable to both dissecting the cell-type specificity of LRRK2 function in the transcriptionally diverse subtypes of dopaminergic neurons and also increasing our understanding of basal ganglia development and biology. Finally, it will inform the development of therapeutics for Parkinson's disease.
Asunto(s)
Cuerpo Estriado/enzimología , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/metabolismo , Sinapsis/enzimología , Secuencia de Aminoácidos , Animales , Modelos Animales de Enfermedad , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/química , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Modelos Biológicos , Mutación/genéticaRESUMEN
Extracellular Vesicles (EVs) are implicated in the spread of pathogenic proteinsin a growing number of neurological diseases. Given this, there is rising interest in developing inhibitors of Neutral Sphingomyelinase 2 (nSMase2), an enzyme critical in EV biogenesis. Our group recently discovered phenyl(R)-(1-(3-(3,4-dimethoxyphenyl)-2,6-dimethylimidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)carbamate (PDDC), the first potent, selective, orally-available, and brain-penetrable nSMase2 inhibitor, capable of dose-dependently reducing EVs release in vitro and in vivo. Herein, using multiplexed Surface Plasmon Resonance imaging (SPRi), we evaluated which brain cell-derived EVs were affected by PDDC following acute brain injury. Mice were fed PDDC-containing chow at doses which gave steady PDDC brain exposures exceeding its nSMase2 IC50. Mice were then administered an intra-striatal IL-1ß injection and two hours later plasma and brain were collected. IL-1ß injection significantly increased striatal nSMase2 activity which was completely normalized by PDDC. Using SPRi, we found that IL-1ß-induced injury selectively increased plasma levels of CD171 + and PLP1 + EVs; this EV increase was normalized by PDDC. In contrast, GLAST1 + EVs were unchanged by IL-1ß or PDDC. IL-1ß injection selectively increased EVs released from activated versus non-activated microglia, indicated by the CD11b+/IB4 + ratio. The increase in EVs from CD11b + microglia was dramatically attenuated with PDDC. Taken together, our data demonstrate that following acute injury, brain nSMase2 activity is elevated. EVs released from neurons, oligodendrocytes, and activated microglial are increased in plasma and inhibition of nSMase2 with PDDC reduced these IL-1ß-induced changes implicating nSMase2 inhibition as a therapeutic target for acute brain injury.
Asunto(s)
Lesiones Encefálicas/enzimología , Vesículas Extracelulares/enzimología , Microglía/enzimología , Neuronas/enzimología , Oligodendroglía/enzimología , Esfingomielina Fosfodiesterasa/metabolismo , Animales , Lesiones Encefálicas/tratamiento farmacológico , Carnitina/administración & dosificación , Carnitina/análogos & derivados , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/enzimología , Vesículas Extracelulares/efectos de los fármacos , Inyecciones Intraventriculares , Interleucina-1beta/administración & dosificación , Masculino , Ratones , Ratones Transgénicos , Microglía/efectos de los fármacos , Neuronas/efectos de los fármacos , Oligodendroglía/efectos de los fármacos , Pirenos/administración & dosificación , Esfingomielina Fosfodiesterasa/antagonistas & inhibidoresRESUMEN
The 20% ethanol extract of Polygala tenuifolia, Angelica tenuissima, and Dimocarpus longan (WIN-1001X) was derived from a modified version of Korean traditional herbal formula 'Chungsimyeolda-tang' which has been used for the treatment of cerebrovascular disorders. The Parkinson's disease presents with impaired motor functions and loss of dopaminergic neurons. However, the treatment for Parkinson's disease is not established until now. This study aims to elucidate the therapeutic advantages of WIN-1001X on animal models of Parkinson's disease. WIN-1001X administration successfully relieved the Parkinsonism symptoms in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease mice tested by rota-rod and pole tests. The loss of tyrosine hydroxylase activities in substantia nigra and striatum was also attenuated by administration of WIN-1001X. In mice with sub-chronical MPTP injections, autophagy-related proteins, such as LC3, beclin-1, mTOR, and p62, were measured using the immunoblot assay. The results were favorable to induction of autophagy after the WIN-1001X administration. WIN-1001X treatment on 6-hydroxydopamine-injected rats also exhibited protective effects against striatal neuronal damage and loss of dopaminergic cells. Such protection is expected to be due to the positive regulation of autophagy by administration of WIN-1001X with confirmation both in vivo and in vitro. In addition, an active compound, onjisaponin B was isolated and identified from WIN-1001X. Onjisaponin B also showed significant autophagosome-inducing effect in human neuroblastoma cell line. Our study suggests that relief of Parkinsonism symptoms and rescue of tyrosine hydroxylase activity in dopaminergic neurons are affected by autophagy enhancing effect of WIN-1001X which the onjisaponin B is one of the major components of activity.
Asunto(s)
Angelica/química , Autofagia/efectos de los fármacos , Fármacos Neuroprotectores/uso terapéutico , Trastornos Parkinsonianos/tratamiento farmacológico , Fitoterapia , Extractos Vegetales/uso terapéutico , Polygala/química , Sapindaceae/química , Animales , Apomorfina/farmacología , Línea Celular Tumoral , Cuerpo Estriado/enzimología , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/enzimología , Evaluación Preclínica de Medicamentos , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Estructura Molecular , Neuroblastoma/patología , Fármacos Neuroprotectores/farmacología , Oxidopamina/toxicidad , Extractos Vegetales/farmacología , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Prueba de Desempeño de Rotación con Aceleración Constante , Saponinas/química , Saponinas/farmacología , Saponinas/uso terapéutico , Sustancia Negra/enzimología , Triterpenos/química , Triterpenos/farmacología , Triterpenos/uso terapéutico , Tirosina 3-Monooxigenasa/análisisRESUMEN
The current opioid epidemic necessitates a better understanding of human addiction neurobiology to develop efficacious treatment approaches. Here, we perform genome-wide assessment of chromatin accessibility of the human striatum in heroin users and matched controls. Our study reveals distinct neuronal and non-neuronal epigenetic signatures, and identifies a locus in the proximity of the gene encoding tyrosine kinase FYN as the most affected region in neurons. FYN expression, kinase activity and the phosphorylation of its target Tau are increased by heroin use in the post-mortem human striatum, as well as in rats trained to self-administer heroin and primary striatal neurons treated with chronic morphine in vitro. Pharmacological or genetic manipulation of FYN activity significantly attenuates heroin self-administration and responding for drug-paired cues in rodents. Our findings suggest that striatal FYN is an important driver of heroin-related neurodegenerative-like pathology and drug-taking behavior, making FYN a promising therapeutic target for heroin use disorder.
Asunto(s)
Cromatina/metabolismo , Cuerpo Estriado/enzimología , Dependencia de Heroína/enzimología , Terapia Molecular Dirigida , Proteínas Proto-Oncogénicas c-fyn/metabolismo , Animales , Secuencia de Bases , Conducta Animal/efectos de los fármacos , Señales (Psicología) , Genoma , Células HEK293 , Heroína/efectos adversos , Humanos , Masculino , Neuronas/metabolismo , Fosforilación/efectos de los fármacos , Regiones Promotoras Genéticas/genética , Proteínas Proto-Oncogénicas c-fyn/antagonistas & inhibidores , Ratas Long-Evans , Autoadministración , Transcripción Genética/efectos de los fármacos , Proteínas tau/metabolismoRESUMEN
Nandrolone decanoate (ND) belongs to the class II of anabolic-androgenic steroids (AAS), which is composed of 19-nor-testosterone-derivatives. AAS represent a group of synthetic testosterone that is used in clinical treatment. However, these drugs are widely abused among individuals as a means of promoting muscle growth or enhancing athletic performance. AAS in general and ND in particular have been associated with several behavioral disturbances, such as anxiety, aggressiveness and depression. A factor that contributes to the development of depression is the brain activation of indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme of kynurenine pathway (KP). In the present study, we examined the involvement of KP in depressive phenotype induced by a ND treatment (10 mg/kg/day/s.c., for 28 days) that mimics human abuse system (e.g. supraphysiological doses) in C57B/6J mice. Our results showed that ND caused depressive like-behavior in the tail suspension test and anhedonic-like state measured in the sucrose preference test. ND administration decreased the levels of brain-derived neurotrophic factor and neurotrophin-3 and reduced Na+,K+-ATPase activity in the hippocampus, striatum and prefrontal cortex. We also found that ND elicited KP activation, as reflected by the increase of IDO activity and kynurenine levels in these brain regions. Moreover, ND decreased serotonin levels and increased 5-hydroxyindoleacetic acid levels in the brain. Treatment with IDO inhibitor 1-methyl-dl-trypthophan (1 mg/kg/i.p.) reversed the behavioral and neurochemical alterations induced by ND. These results indicate for the first time that KP plays a key role in depressive-like behavior and neurotoxicity induced by supraphysiologicaldoses of ND in mice.
Asunto(s)
Anabolizantes/administración & dosificación , Conducta Animal/efectos de los fármacos , Depresión/psicología , Quinurenina/metabolismo , Nandrolona Decanoato/administración & dosificación , Animales , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/enzimología , Cuerpo Estriado/metabolismo , Depresión/inducido químicamente , Relación Dosis-Respuesta a Droga , Hipocampo/efectos de los fármacos , Hipocampo/enzimología , Hipocampo/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/enzimología , Corteza Prefrontal/metabolismo , Triptófano/administración & dosificación , Triptófano/análogos & derivadosRESUMEN
Protein kinase A (PKA) are tetramers of two catalytic and two regulatory subunits, docked at precise intracellular sites to provide localized phosphorylating activity, triggered by cAMP binding to regulatory subunits and subsequent dissociation of catalytic subunits. It is unclear whether in the brain PKA dissociated subunits may also be found. PKA catalytic subunit was examined in various mouse brain areas using immunofluorescence, equilibrium binding and western blot, to reveal its location in comparison to regulatory subunits type RI and RII. In the cerebral cortex, catalytic subunits colocalized with clusters of RI, yet not all RI clusters were bound to catalytic subunits. In stria terminalis, catalytic subunits were in proximity to RI but separated from them. Catalytic subunits clusters were also present in the corpus striatum, where RII clusters were detected, whereas RI clusters were absent. Upon cAMP addition, the distribution of regulatory subunits did not change, while catalytic subunits were completely released from regulatory subunits. Unpredictably, catalytic subunits were not solubilized; instead, they re-targeted to other binding sites within the tissue, suggesting local macromolecular reorganization. Hence, the interactions between catalytic and regulatory subunits of protein kinase A consistently vary in different brain areas, supporting the idea of multiple interaction patterns.
Asunto(s)
Encéfalo/enzimología , Proteína Quinasa Tipo II Dependiente de AMP Cíclico/metabolismo , Proteína Quinasa Tipo I Dependiente de AMP Cíclico/metabolismo , Animales , Corteza Cerebral/enzimología , Cuerpo Estriado/enzimología , AMP Cíclico/metabolismo , Proteína Quinasa Tipo I Dependiente de AMP Cíclico/genética , Proteína Quinasa Tipo II Dependiente de AMP Cíclico/genética , Femenino , Masculino , Ratones , Especificidad de Órganos , Núcleos Septales/enzimologíaRESUMEN
Parkinson's disease (PD) is a devastating neurodegenerative disease that leads to motor deficits and selective destruction of nigrostriatal dopaminergic neurons. PD is typically treated by dopamine replacement agents; however, dopamine replacement loses effectiveness in the later stages of the disease. Here, we describe the neuroprotective effects of the omega-3 fatty acid docosahexaenoic acid (DHA) in the medial forebrain bundle 6-hydroxydopamine (6-OHDA) model of advanced-stage PD in rats. We show that daily administration of DHA protects against core symptoms of PD, including deficits in postural stability, gait integrity, and dopamine neurochemistry in motor areas of the striatum. Our results also demonstrate that DHA increases striatal dopamine synthesis via phosphorylation of the rate-limiting catecholamine synthesizing enzyme tyrosine hydroxylase, in a manner dependent on the second messenger-linked protein kinases PKA and PKC. We also show that DHA specifically reverses dopamine loss in the nigrostriatal pathway, with no effect in the mesolimbic or mesocortical pathways. This suggests that DHA is unlikely to produce pharmacotherapeutic or adverse effects that depend on dopamine pathways other than the nigrostriatal pathway. To our knowledge, previous reports have not examined the effects of DHA in such an advanced-stage model, documented that the dopamine synthesizing effects of DHA in vivo are mediated through the activation of protein kinases and regulation of TH activity, or demonstrated specificity to the nigrostriatal pathway. These novel findings corroborate the beneficial effects of omega-3 fatty acids seen in PD patients and suggest that DHA provides a novel means of protecting patients for dopamine neurodegeneration.
Asunto(s)
Cuerpo Estriado/enzimología , Ácidos Docosahexaenoicos/uso terapéutico , Dopamina/biosíntesis , Trastornos Parkinsonianos/enzimología , Trastornos Parkinsonianos/prevención & control , Proteínas Quinasas/biosíntesis , Animales , Cuerpo Estriado/efectos de los fármacos , Ácidos Docosahexaenoicos/farmacología , Masculino , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Oxidopamina/toxicidad , Trastornos Parkinsonianos/inducido químicamente , Distribución Aleatoria , Ratas , Ratas Sprague-DawleyRESUMEN
Sleep complaints are an early clinical symptom of neurodegenerative disorders. Patients with Parkinson's disease (PD) experience sleep disruption (SD). The objective of this study was to determine if preexisting, chronic SD leads to a greater loss of tyrosine hydroxylase (TH) within the striatum and the substantia nigra following chronic/progressive exposure with the neurotoxin, 1-methyl-2-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Male mice underwent chronic SD for 4 weeks, then injected with vehicle (VEH) or increasing doses of MPTP for 4 weeks. There was a significant decrease in the plasma corticosterone levels in the MPTP group, an increase in the SD group, and a return to the VEH levels in the SD+MPTP group. Protein expression levels for TH in the striatum (terminals) and substantia nigra pars compacta (dopamine [DA] cell counts) revealed up to a 78% and 38% decrease, respectively, in the MPTP and SD+MPTP groups compared to their relevant VEH and SD groups. DA transporter protein expression increased in the striatum in the MPTP versus VEH group and in the SN/midbrain between the SD+MPTP and the VEH group. There was a main effect of MPTP on various gait measures (e.g., braking) relative to the SD or VEH groups. In the SD+MPTP group, there were no differences compared to the VEH group. Thus, SD, prior to administration of MPTP, has effects on serum corticosterone and gait but more importantly does not potentiate greater loss of TH within the nigrostriatal pathway compared to the MPTP group, suggesting that in PD patients with SD, there is no exacerbation of the DA cell loss.
Asunto(s)
Cuerpo Estriado/enzimología , Trastornos Neurológicos de la Marcha/etiología , Trastornos Parkinsonianos/complicaciones , Trastornos Intrínsecos del Sueño/etiología , Estrés Fisiológico , Sustancia Negra/enzimología , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Animales , Cuerpo Estriado/patología , Corticosterona/sangre , Modelos Animales de Enfermedad , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/análisis , Trastornos Neurológicos de la Marcha/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas del Tejido Nervioso/análisis , Oxidopamina/toxicidad , Trastornos Parkinsonianos/metabolismo , Método Simple Ciego , Trastornos Intrínsecos del Sueño/sangre , Trastornos Intrínsecos del Sueño/fisiopatología , Sustancia Negra/patología , Tirosina 3-Monooxigenasa/análisis , Proteínas de Transporte Vesicular de Monoaminas/análisisRESUMEN
The aim is to study the effects of gastrodin (GA) on striatal inflammation and oxidative stress in rats with Tourette syndrome (TS). The rat model of TS was induced by 3,3'-iminodipropionitrile. Behavioral tests were carried out by stereotype experiment. The concentrations of amino acid transmitters glutamic acid (Glu) and γ-aminobutyric acid (GABA) in striatum were determined by high-performance liquid chromatography. Superoxide dismutase (SOD) and malondialdehyde (MDA) in serum and striatum were detected by commercial kits. Cytokines in serum and striatum were detected by enzyme-linked immunosorbent assay kits. Western blot analysis was used to detect striatum nuclear erythroid factor 2-related factor 2 (Nrf-2)/heme oxygenase-1 (HO-1)/high mobility group box 1 protein (HMGB1)/nuclear factor-кB (NF-кB) pathway-related proteins. The expressions of Nrf-2 and P-NF-кBp65 in striatum were detected by immunohistochemistry. Compared with the control group, the stereotype scores of rats in the model group significantly increased, and the contents of Glu and GABA in striatum obviously increased. GA significantly reduced the stereotype scores and decreased the contents of Glu and GABA. The levels of SOD in serum and striatum were decreased and the content of MDA in serum and striatum were increased compared with the control group, while GA significantly restored the changes. GA significantly adjusted Nrf-2/HO-1/HMGB1/NF-кB pathway-related proteins changes consistent with immunohistochemical changes. GA may protect striatum of rats with TS by regulating Nrf-2/HO-1/HMGB1/NF-кB pathway protein changes in striatum.
Asunto(s)
Alcoholes Bencílicos/uso terapéutico , Glucósidos/uso terapéutico , Proteína HMGB1/metabolismo , Hemo-Oxigenasa 1/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , Síndrome de Tourette/tratamiento farmacológico , Animales , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/enzimología , Cuerpo Estriado/metabolismo , Citocinas/sangre , Citocinas/metabolismo , Ácido Glutámico/metabolismo , Masculino , Malondialdehído/metabolismo , Ratas , Ratas Sprague-Dawley , Superóxido Dismutasa/sangre , Superóxido Dismutasa/metabolismo , Síndrome de Tourette/enzimología , Síndrome de Tourette/metabolismo , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Inhibition of monoamine oxidase (MAO)-A/B can ameliorate depressive- and anxiety-related symptoms via increase of monoamine extracellular levels. However, such inhibition can also instigate hypertensive response following exposure to dietary tyramine (i.e., "the cheese effect"). Novel herbal treatment (NHT) is an herbal formula that has been demonstrated to reduce depressive- and anxiety-like symptoms in pre-clinical studies. The aim of the current study was to examine whether the therapeutic potential of NHT is underlain by inhibition of MAO-A/B and whether NHT poses a risk for tyramine hyper-potentiation. Unpredictable chronic mild stress (UCMS)-exposed mice and naïve mice were treated for 3 weeks with NHT (30 mg/kg; i.p.), the selective serotonin reuptake inhibitor (SSRI) escitalopram (15 mg/kg; i.p.), or saline. Subsequently, MAO-A/B activities in the hypothalamus, striatum, and prefrontal cortex (PFC) were assessed. Exposure to UCMS led to significant increases in both MAO-A and MAO-B activities in the hypothalamus (p < 0.001) and in the PFC (p < 0.01 for MAO-A; p < 0.001 for MAO-B). Neither NHT nor escitalopram had any notable effects. Treatment with NHT was supported as safe in terms of risk for inducing a hypertensive response. The antidepressant- and anxiolytic-like effects of NHT are mediated via pathways other than MAO-A/B inhibition.
Asunto(s)
Antidepresivos/uso terapéutico , Cuerpo Estriado/efectos de los fármacos , Depresión/tratamiento farmacológico , Hipotálamo/efectos de los fármacos , Monoaminooxidasa/análisis , Proteínas del Tejido Nervioso/análisis , Fitoterapia , Preparaciones de Plantas/uso terapéutico , Corteza Prefrontal/efectos de los fármacos , Animales , Ansiolíticos/farmacología , Ansiolíticos/uso terapéutico , Antidepresivos/farmacología , Citalopram/uso terapéutico , Cuerpo Estriado/enzimología , Crataegus , Depresión/etiología , Evaluación Preclínica de Medicamentos , Hipotálamo/enzimología , Lilium , Ratones , Ratones Endogámicos ICR , Monoaminooxidasa/biosíntesis , Corteza Prefrontal/enzimología , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Estrés Psicológico/psicología , Triticum , Tiramina/metabolismo , ZiziphusRESUMEN
The caudal part of the striatum, also named the tail of the striatum (TS), defines a fourth striatal domain. Determining whether rewarding, aversive and salient stimuli regulate the activity of striatal spiny projections neurons (SPNs) of the TS is therefore of paramount importance to understand its functions, which remain largely elusive. Taking advantage of genetically encoded biosensors (A-kinase activity reporter 3) to record protein kinase A signals and by analyzing the distribution of dopamine D1R- and D2R-SPNs in the TS, we characterized three subterritories: a D2R/A2aR-lacking, a D1R/D2R-intermingled and a D1R/D2R-SPNs-enriched area (corresponding to the amygdalostriatal transition). In addition, we provide evidence that the distribution of D1R- and D2R-SPNs in the TS is evolutionarily conserved (mouse, rat, gerbil). The in vivo analysis of extracellular signal-regulated kinase (ERK) phosphorylation in these TS subterritories in response to distinct appetitive, aversive and pharmacological stimuli revealed that SPNs of the TS are not recruited by stimuli triggering innate aversive responses, fasting, satiety, or palatable signals whereas a reduction in ERK phosphorylation occurred following learned avoidance. In contrast, D1R-SPNs of the intermingled and D2R/A2aR-lacking areas were strongly activated by both D1R agonists and psychostimulant drugs (d-amphetamine, cocaine, 3,4-methyl enedioxy methamphetamine, or methylphenidate), but not by hallucinogens. Finally, a similar pattern of ERK activation was observed by blocking selectively dopamine reuptake. Together, our results reveal that the caudal TS might participate in the processing of specific reward signals and discrete aversive stimuli. Cover Image for this issue: doi: 10.1111/jnc.14526. Open Science: This manuscript was awarded with the Open Materials Badge For more information see: https://cos.io/our-services/open-science-badges/.
Asunto(s)
Reacción de Prevención/fisiología , Cuerpo Estriado/enzimología , Sistema de Señalización de MAP Quinasas/fisiología , Recompensa , Estimulación Acústica/efectos adversos , Animales , Reacción de Prevención/efectos de los fármacos , Cocaína/farmacología , Cuerpo Estriado/efectos de los fármacos , Dopamina/farmacología , Inhibidores de Captación de Dopamina/farmacología , Activación Enzimática/efectos de los fármacos , Activación Enzimática/fisiología , Gerbillinae , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Técnicas de Cultivo de Órganos , Ratas , Ratas Sprague-DawleyRESUMEN
Emerging findings suggest that Parkinson's disease (PD) pathology (α-synuclein accumulation) and neuronal dysfunction may occur first in peripheral neurons of the autonomic nervous system including the enteric branches of the vagus nerve. The risk of PD increases greatly in people over the age of 65, a period of life in which chronic inflammation is common in many organ systems including the gut. Here we report that chronic mild focal intestinal inflammation accelerates the age of disease onset in α-synuclein mutant PD mice. Wild-type and PD mice treated with 0.5% dextran sodium sulfate (DSS) in their drinking water for 12 weeks beginning at 3 months of age exhibited histological and biochemical features of mild gut inflammation. The age of onset of motor dysfunction, evaluated using a rotarod test, gait analysis, and grip strength measurements, was significantly earlier in DSS-treated PD mice compared to control PD mice. Levels of the dopaminergic neuron marker tyrosine hydroxylase in the striatum and numbers of dopaminergic neurons in the substantia nigra were reduced in PD mice with gut inflammation. Levels of total and phosphorylated α-synuclein were elevated in enteric and brain neurons in DSS-treated PD mice, suggesting that mild gut inflammation accelerates α-synuclein pathology. Markers of inflammation in the colon and brain, but not in the blood, were elevated in DSS-treated PD mice, consistent with retrograde transneuronal propagation of α-synuclein pathology and neuroinflammation from the gut to the brain. Our findings suggest that interventions that reduce gut inflammation may prove beneficial in the prevention and treatment of PD.
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Encéfalo/patología , Colitis/complicaciones , Enteritis/complicaciones , Trastornos Parkinsonianos/etiología , Sinucleinopatías/etiología , alfa-Sinucleína/deficiencia , Animales , Colitis/inducido químicamente , Colon/patología , Cuerpo Estriado/enzimología , Cuerpo Estriado/patología , Citocinas/sangre , Sulfato de Dextran/toxicidad , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/patología , Enteritis/inducido químicamente , Femenino , Trastornos Neurológicos de la Marcha/etiología , Fuerza de la Mano , Humanos , Intestino Delgado/patología , Masculino , Ratones , Ratones Noqueados , Mutación Missense , Proteínas del Tejido Nervioso/análisis , Trastornos Parkinsonianos/genética , Trastornos Parkinsonianos/patología , Prueba de Desempeño de Rotación con Aceleración Constante , Sustancia Negra/enzimología , Sustancia Negra/patología , Sinucleinopatías/genética , Sinucleinopatías/patología , Tirosina 3-Monooxigenasa/análisis , alfa-Sinucleína/genéticaRESUMEN
BACKGROUND: During excitotoxic damage, neuronal death results from the increase in intracellular calcium, the induction of oxidative stress, and a subsequent inflammatory response. NADPH oxidases (NOX) are relevant sources of reactive oxygen species (ROS) during excitotoxic damage. NADPH oxidase-2 (NOX-2) has been particularly related to neuronal damage and death, as well as to the resolution of the subsequent inflammatory response. As ROS are crucial components of the regulation of inflammatory response, in this work, we evaluated the role of NOX-2 in the progression of inflammation resulting from glutamate-induced excitotoxic damage of the striatum in an in vivo model. METHODS: The striata of wild-type C57BL/6 J and NOX-2 KO mice (gp91Cybbtm1Din/J) were stereotactically injected with monosodium glutamate either alone or in combination with IL-4 or IL-10. The damage was evaluated in histological sections stained with cresyl violet and Fluoro-Jade B. The enzymatic activity of caspase-3 and NOX were also measured. Additionally, the cytokine profile was identified by ELISA and motor activity was verified by the tests of the cylinder, the adhesive tape removal, and the inverted grid. RESULTS: Our results show a neuroprotective effect in mice with a genetic inhibition of NOX-2, which is partially due to a differential response to excitotoxic damage, characterized by the production of anti-inflammatory cytokines. In NOX-2 KO animals, the excitotoxic condition increased the production of interleukin-4, which could contribute to the production of interleukin-10 that decreased neuronal apoptotic death and the magnitude of striatal injury. Treatment with interleukin-4 and interleukin-10 protected from excitotoxic damage in wild-type animals. CONCLUSIONS: The release of proinflammatory cytokines during the excitotoxic event promotes an additional apoptotic death of neurons that survived the initial damage. During the subsequent inflammatory response to excitotoxic damage, ROS generated by NOX-2 play a decisive role in the extension of the lesion and consequently in the severity of the functional compromise, probably by regulating the anti-inflammatory cytokines production.
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Cuerpo Estriado/enzimología , Cuerpo Estriado/patología , Inflamación/enzimología , Inflamación/patología , NADPH Oxidasa 2/metabolismo , Animales , Cuerpo Estriado/inmunología , Progresión de la Enfermedad , Ácido Glutámico/toxicidad , Inflamación/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
The extracellular signal-regulated kinase (ERK) is enriched in the central nervous system, including the dopamine responsive regions such as the striatum and medial prefrontal cortex (mPFC). The kinase is sensitive to changing cellular and synaptic input and is implicated in the regulation of synaptic transmission and plasticity. In this study, the role of a Gαi/o protein-coupled adenosine A1 receptor in the regulation of ERK1/2 was investigated in the rat brain in vivo. We found that an A1 agonist CPA after an intraperitoneal injection reduced ERK1/2 phosphorylation in the nucleus accumbens (NAc) and mPFC. In contrast, a single dose of an A1 antagonist DPCPX induced a rapid and transient increase in ERK1/2 phosphorylation in the caudate putamen (CPu), NAc, and mPFC. Pretreatment with a dopamine D1 receptor antagonist SCH23390 abolished the DPCPX-induced ERK1/2 phosphorylation in the striatum and mPFC. Coadministration of DPCPX and a D1 agonist SKF81297 at a low dose induced a greater elevation of ERK1/2 phosphorylation. Activation or blockade of A1 receptors had no effect on total ERK1/2 expression in the striatum and mPFC. These results reveal an existence of an inhibitory linkage from adenosine A1 receptors to ERK1/2 in striatal and mPFC neurons. This inhibitory linkage seems to form a dynamic balance with positive dopamine D1 receptor signaling to control the ERK1/2 pathway.
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Agonistas del Receptor de Adenosina A1/farmacología , Antagonistas del Receptor de Adenosina A1/farmacología , Cuerpo Estriado/efectos de los fármacos , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Corteza Prefrontal/efectos de los fármacos , Receptor de Adenosina A1/metabolismo , Adenosina/análogos & derivados , Adenosina/farmacología , Animales , Benzazepinas/farmacología , Cuerpo Estriado/enzimología , Sinergismo Farmacológico , Masculino , Núcleo Accumbens/metabolismo , Fosforilación/efectos de los fármacos , Corteza Prefrontal/enzimología , Ratas , Xantinas/antagonistas & inhibidores , Xantinas/farmacologíaRESUMEN
Highly specific and sensitive biomarkers for pathologies related to dysfunctions in the basal ganglia circuit are of great value to assess therapeutic efficacy not only clinically to establish an early diagnosis, but also in terms of monitoring the efficacy of therapeutic interventions and decelerated neurodegeneration. The phosphodiesterase 10A (PDE10A) enzyme plays a central role in striatal signaling and is implicated in several neuropsychiatric disorders involving striatal pathology, such as Huntingtons disease (HD) and schizophrenia. Inhibition of PDE10A activates the neurons in the striatum and consequently leads to alteration of behavioral aspects modulated by the striatal circuit. [18F]MNI-659, (2-(2-(3-(4-(2-[18F]fluoroethoxy)phenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione), is a newly developed PET radioligand that shows a high binding to PDE10A in the human brain in vivo. In the present study, we examined the in vitro binding of [18F]MNI-659 in human postmortem brain to gain a better understanding of the presence, density, disease-related alterations and therapy related to changes in PDE10A expression. The results show high specific binding of [18F]MNI-659 in the caudate nucleus, putamen and the hippocampal formation. Low specific [18F]MNI-659 binding was detected in nucleus accumbens in comparison to the caudate nucleus and putamen. In vitro binding studies with [18F]MNI-659 will facilitate in elucidating better understanding of the role of PDE10A activity in health and disease that may lead to new diagnostic opportunities in HD.
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Encéfalo/enzimología , Hidrolasas Diéster Fosfóricas/metabolismo , Ftalimidas , Tomografía de Emisión de Positrones/métodos , Quinazolinonas , Adulto , Anciano , Ganglios Basales/enzimología , Ganglios Basales/metabolismo , Encéfalo/diagnóstico por imagen , Cadáver , Cuerpo Estriado/enzimología , Cuerpo Estriado/metabolismo , Femenino , Radioisótopos de Flúor , Humanos , Masculino , Persona de Mediana Edad , Neostriado/enzimología , Neostriado/metabolismo , RadiofármacosRESUMEN
Previous research indicates that the subchronic administration of NG-nitro-L-arginine (L-NOARG) produces tolerance to haloperidol-induced catalepsy in Swiss mice. The present study aimed to further investigate whether intermittent subchronic systemic administration of L-NOARG induces tolerance to the cataleptic effects of haloperidol as well as olanzapine or clozapine (Clz) in C57Bl mice after subchronic administration for 5 consecutive days. Striatal FosB protein expression was measured in an attempt to gain further insights into striatal mechanisms in antipsychotic-induced extrapyramidal symptoms side effects. An nicotinamide-adenine-dinucleotide phosphate-diaphorase histochemical reaction was also used to investigate whether tolerance could induce changes in the number of nitric oxide synthase-active neurons. Subchronic administration of all antipsychotics produced catalepsy, but cross-tolerance was observed only between L-NOARG (15 mg/kg, intraperitoneally) and Clz (20 mg/kg, intraperitoneally). This cross-tolerance effect was accompanied by decreased FosB protein expression in the dorsal striatum and the nucleus accumbens shell region, and reduced icotinamide-adenine-dinucleotide phosphate-diaphorase activity in the dorsal and ventral lateral striatum. Overall, these results suggest that interference with the formation of nitric oxide, mainly in the dorsal and ventral lateral-striatal regions, appears to improve the cataleptic effects induced by antipsychotics acting as antagonists of low-affinity dopamine D2 receptor, such as Clz.
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Antipsicóticos/farmacología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/enzimología , Inhibidores Enzimáticos/farmacología , NADPH Deshidrogenasa/metabolismo , Niacinamida/metabolismo , Análisis de Varianza , Animales , Catalepsia/inducido químicamente , Catalepsia/tratamiento farmacológico , Haloperidol/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , NADP/metabolismo , Óxido Nítrico Sintasa , Nitroarginina/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismoRESUMEN
Non-ketotic hyperglycinemia (NKH) is a severe neurological disorder caused by defects in glycine (GLY) catabolism and characterized by a high cerebrospinal fluid/plasma GLY ratio. Treatment is often ineffective and limited to the control of symptoms and detoxification of GLY. In the present work, we investigated the in vivo effects of GLY intracerebroventricular administration on oxidative stress parameters in rat striatum, cerebral cortex, and hippocampus. In vitro effects of GLY were also evaluated in striatum. The effects of bezafibrate (BEZ), a potential neuroprotective agent, on the possible alterations caused by GLY administration were further evaluated. Our in vivo results showed that GLY increased the activities of the antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), and glucose-6-phosphate dehydrogenase (G6PDH) in striatum. Furthermore, GLY decreased the concentrations of total glutathione and reduced glutathione (GSH), as well as GSH/oxidized glutathione ratio in vivo in hippocampus. In vitro data also showed that GLY induced lipid peroxidation and decreased GSH in striatum. Regarding the effects of BEZ, we found that GLY-induced increase of GPx, SOD, and GR activities was attenuated or prevented by this compound. However, BEZ did not alter GLY-induced decrease of GSH in hippocampus. We hypothesize that GLY-induced increase of the activities of antioxidant enzymes in striatum occurs as a mechanism to avoid accumulation of reactive oxygen species and consequent oxidative damage. Furthermore, since BEZ prevented GLY-induced alterations, it might be considered as an adjuvant therapy for NKH.
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Antioxidantes/metabolismo , Bezafibrato/farmacología , Cuerpo Estriado/enzimología , Glicina/toxicidad , Animales , Cuerpo Estriado/efectos de los fármacos , Glutatión/metabolismo , Glicina/administración & dosificación , Inyecciones Intraventriculares , Malondialdehído/metabolismo , Ratas WistarRESUMEN
Increased levels of proinflammatory cytokines have been implicated in schizophrenia; however, their pathophysiological roles in abnormal brain dysfunctions remain unclear. We evaluated the effect of proinflammatory cytokines on a high-fat diet (HFD)-induced prepulse inhibition (PPI) deficits in the acoustic startle response. Eight-week-old male C57BL/6J mice were fed a HFD for 3 weeks and then PPI was examined. HFD significantly induced PPI deficits and increased plasma IL-6, but not TNFα, levels. Interestingly, MR16-1 administration during the HFD period ameliorated PPI deficits. Further, in the striatum of HFD-fed mice, phosphorylation of GSK3ß, but not GSK3α, was significantly increased; this increase was attenuated by MR16-1, although the protein levels of GSK3α and ß were not altered. There were no significant differences in either phosphorylation or protein levels of GSK3α, ß in the PFC during the HFD period. These results suggest that increased IL-6 levels during HFD may induce sensorimotor gating deficits, likely through the alteration of striatal GSK3ß phosphorylation. MR16-1 might have a beneficial effect on such HFD-induced sensorimotor gating deficits.