Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 38.325
Filtrar
1.
J Ethnopharmacol ; 300: 115719, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36126781

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Saffron, the dried stigma of Crocus sativus L., has a long history of use in the treatment of depression in traditional Chinese medicine and Islamic medicine. The unique aroma of saffron, primarily derived from its volatile oil, has been widely used by folk to mitigate anxiety and depression via sniffing because the aroma of saffron has a pleasant and invigorating effect. AIM OF THE STUDY: This study aimed to investigate the antidepressant effect and the underlying mechanism of saffron essential oil (SEO) in mice exposed to chronic unpredictable mild stress (CUMS). MATERIALS AND METHODS: In this study, compounds of SEO were identified using gas chromatography-mass spectrometry analysis, while network pharmacology was used to predict potential active compounds, antidepressant targets, and related signaling pathways of SEO. The CUMS depression model was further used to explore the therapeutic effect and possible mechanism of SEO. During the modeling period, mice were regularly administered fluoxetine (3.6 mg/kg, i.g.) or diluted SEO (2%, 4%, and 6% SEO, inhalation). The antidepressant and neuroprotective effects of SEO were evaluated by behavior tests (the open field test, the sucrose preference test, the tail suspension test, and the forced swimming test), hematoxylin-eosin staining, and Nissl staining. The enzyme-linked immunosorbent assay kits were used to measure dopamine (DA), 5-serotonin (5-HT), brain-derived neurotrophic factor (BDNF), and γ-aminobutyric acid (GABA) levels in serum. The relative abundance of Raf1, MEK1, P-ERK1/2/ERK1/2, P-CREB1/CREB1, BDNF, and P-Trk B/Trk B in the hippocampus was determined using western blot (WB). RESULTS: According to the network pharmacology analysis, seven active SEO compounds mediated 113 targets related to depression treatment, most of which were enriched in the 5-HT synapse, calcium signaling pathway, and cAMP signaling pathway. In vivo experiments indicated that fluoxetine and SEO improved depression-like behaviors in depressed mice. The levels of 5-HT, DA, BDNF, and GABA in serum increased significantly. Histopathological examinations revealed that fluoxetine and SEO ameliorated neuronal damage in the hippocampus. WB analysis showed that the relative expressions of Raf1, MEK1, P-ERK1/2/ERK1/2, P-CREB1/CREB1, BDNF, and P-Trk B/Trk B were significantly higher in the fluoxetine and SEO groups than in the CUMS group. CONCLUSION: Overall, these findings suggest that SEO significantly alleviates the depressive symptoms in CUMS exposed mice and partially restores hippocampal neuronal damage. Meanwhile, the best efficacy was observed in 4% SEO. Furthermore, the antidepressant mechanism of SEO is primarily dependent on the regulation of the MAPK-CREB1-BDNF signaling pathway.


Assuntos
Crocus , Fármacos Neuroprotetores , Óleos Voláteis , Animais , Antidepressivos/metabolismo , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Comportamento Animal , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Crocus/metabolismo , Depressão/tratamento farmacológico , Depressão/etiologia , Depressão/metabolismo , Modelos Animais de Doenças , Dopamina/metabolismo , Amarelo de Eosina-(YS)/metabolismo , Amarelo de Eosina-(YS)/farmacologia , Fluoxetina/farmacologia , Hematoxilina/metabolismo , Hematoxilina/farmacologia , Hipocampo , Sistema de Sinalização das MAP Quinases , Camundongos , Fármacos Neuroprotetores/farmacologia , Óleos Voláteis/metabolismo , Óleos Voláteis/farmacologia , Óleos Voláteis/uso terapêutico , Serotonina/metabolismo , Transdução de Sinais , Estresse Fisiológico , Estresse Psicológico/tratamento farmacológico , Sacarose/metabolismo , Sacarose/farmacologia , Ácido gama-Aminobutírico/metabolismo
2.
J Ethnopharmacol ; 301: 115832, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36283636

RESUMO

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


Assuntos
Gastrodia , Animais , Camundongos , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Comportamento Animal , Fator Neurotrófico Derivado do Encéfalo , Depressão/tratamento farmacológico , Depressão/metabolismo , Modelos Animais de Doenças , Dopamina/metabolismo , Gastrodia/química , Monoaminoxidase/metabolismo , N-Metilaspartato , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Extratos Vegetais/química , Propano/farmacologia , Serotonina/metabolismo , Estresse Psicológico/tratamento farmacológico , Receptores de N-Metil-D-Aspartato/metabolismo
3.
Behav Brain Res ; 437: 114157, 2023 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-36241070

RESUMO

Vocal communication, cognition, and affective state are key features of sustained health and wellness, and because vocalizations are often socially-motivated, social experience likely plays a role in these behaviors. The monoaminergic systems of the ventral tegmental area (VTA) and the locus coeruleus (LC) are associated with social and reward processing, vocalization production, and neurotransmitter changes in response to environmental stressors. The effect of social isolation on these complex behaviors and the underlying neural mechanisms is relatively unknown. To add to this body of literature, we randomized adult male Long-Evans rats to control (housed with a cagemate) or isolated (housed individually) conditions and assayed ultrasonic vocalizations, cognition (novel object recognition test), anxiety (elevated plus maze) and anhedonia (sucrose preference test) at 2, 4, 6, 8, and 10 months of age. At 10 months, VTA and LC samples were assayed for dopamine, norepinephrine, and serotonin using high performance liquid chromatography. We tested the hypotheses that isolation 1) diminishes vocalizations and cognition, 2) increases anxiety and depression, and 3) increases levels of dopamine, norepinephrine, and serotonin in the VTA and LC. Results showed isolation significantly reduced vocalization tonality (signal-to-noise ratio) and increased maximum frequency. There were no significant findings for cognition, anxiety, or anhedonia. Dopamine and serotonin and their respective metabolites were significantly increased in the VTA in isolated rats. These findings suggest chronic changes to social condition such as isolation affects vocalization production and levels of VTA neurotransmitters.


Assuntos
Locus Cerúleo , Ultrassom , Animais , Masculino , Ratos , Anedonia , Cognição , Dopamina/metabolismo , Neurotransmissores/metabolismo , Norepinefrina/metabolismo , Ratos Long-Evans , Serotonina/metabolismo , Isolamento Social , Área Tegmentar Ventral , Vocalização Animal/fisiologia
4.
Biochim Biophys Acta Mol Basis Dis ; 1869(1): 166569, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36243293

RESUMO

BACKGROUND: Hippocampus plays critical roles in drug addiction. Cocaine-induced modifications in dopamine receptor function and the downstream signaling are important regulation mechanisms in cocaine addiction. Rac regulates actin filament accumulation while Cdc42 stimulates the formation of filopodia and neurite outgrowth. Based on the region specific roles of small GTPases in brain, we focused on the hippocampal subregions to detect the regulation of Cdc42 signaling in long-term morphological and behavioral adaptations to cocaine. METHODS: Genetically modified mouse models of Cdc42, dopamine receptor D1 (D1R) and D2 (D2R) and expressed Cdc42 point mutants that are defective in binding to and activation of its downstream effector molecules PAK and N-WASP were generated, respectively, in CA1 or dentate gyrus (DG) subregion. RESULTS: Cocaine induced upregulation of Cdc42 signaling activity. Cdc42 knockout or mutants blocked cocaine-induced increase in spine plasticity in hippocampal CA1 pyramidal neurons, leading to a decreased conditional place preference (CPP)-associated memories and spatial learning and memory in water maze. Cdc42 knockout or mutants promoted cocaine-induced loss of neurogenesis in DG, leading to a decreased CPP-associated memories and spatial learning and memory in water maze. Furthermore, by using D1R knockout, D2R knockout, and D2R/Cdc42 double knockout mice, we found that D2R, but not D1R, regulated Cdc42 signaling in cocaine-induced neural plasticity and behavioral changes. CONCLUSIONS: Cdc42 acts downstream of D2R in the hippocampus and plays an important role in cocaine-induced neural plasticity through N-WASP and PAK-LIMK-Cofilin, and Cdc42 signaling pathway correlatively links specific brain regions (CA1, dentate gyrus) to cocaine-induced CPP behavior.


Assuntos
Transtornos Relacionados ao Uso de Cocaína , Cocaína , Camundongos , Animais , Transtornos Relacionados ao Uso de Cocaína/genética , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismo , Hipocampo/metabolismo , Cocaína/farmacologia , Cocaína/metabolismo , Dopamina/metabolismo , Camundongos Knockout
5.
Clin Neuropharmacol ; 45(6): 168-174, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36383915

RESUMO

OBJECTIVES: Parkinson disease (PD) is the second most common neurodegenerative disorder, and no disease-modifying medications are available. Ursodeoxycholic acid (UDCA) has been shown to prevent neuronal damage; however, the effect of UDCA on PD is unclear. This study aimed to the role of UDCA on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. METHODS: Mice were divided into 3 experimental groups: the control group, MPTP group, and UDCA-treat group. Mice were tested for behavioral impairments, and slices at the level of the ventral midbrain were collected to perform hematoxylin and eosin and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining and immunohistochemistry. To evaluate the levels of dopamine (DA), serotonin (5-HT), antioxidant markers, and inflammatory cytokines, enzyme-linked immunoassays were carried out. The protein (α-synuclein, p38, phospho-p38, c-Jun N-terminal kinase [JNK], and phospho-JNK) expression was examined adopting Western blot. RESULTS: We found that UDCA reduced the MPTP-induced degeneration of DA neurons, improved behavioral impairments, and decreased the protein level of α-synuclein, accompanied with increases of DA and 5-HT. In the present study, UDCA prevented DA neurons from MPTP toxicity with increased superoxide dismutase, catalase, glutathione, and decreased malondialdehyde levels. Ursodeoxycholic acid prevented DA neurons from MPTP toxicity with decreased levels of tumor necrosis factor α, interferon γ, and interleukin (IL)-1ß, IL-6, and IL-10. Our results demonstrated that UDCA inhibited the phosphorylation of JNK and p38MAPK. CONCLUSIONS: This study revealed protective effects of UDCA against oxidative stress and neuroinflammation through mitogen-activated protein kinases pathways in MPTP-induced PD, suggesting that UDCA may be a novel therapeutic candidate for PD.


Assuntos
Doença de Parkinson , Camundongos , Humanos , Animais , Doença de Parkinson/tratamento farmacológico , alfa-Sinucleína/metabolismo , alfa-Sinucleína/farmacologia , alfa-Sinucleína/uso terapêutico , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/uso terapêutico , Ácido Ursodesoxicólico/farmacologia , Ácido Ursodesoxicólico/uso terapêutico , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteínas Quinases Ativadas por Mitógeno/farmacologia , Doenças Neuroinflamatórias , Serotonina/metabolismo , Serotonina/farmacologia , Serotonina/uso terapêutico , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia
6.
J Neurosci ; 42(45): 8406-8415, 2022 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-36351826

RESUMO

Both the cerebellum and the basal ganglia are known for their roles in motor control and motivated behavior. These two systems have been classically considered as independent structures that coordinate their contributions to behavior via separate cortico-thalamic loops. However, recent evidence demonstrates the presence of a rich set of direct connections between these two regions. Although there is strong evidence for connections in both directions, for brevity we limit our discussion to the better-characterized connections from the cerebellum to the basal ganglia. We review two sets of such connections: disynaptic projections through the thalamus and direct monosynaptic projections to the midbrain dopaminergic nuclei, the VTA and the SNc. In each case, we review the evidence for these pathways from anatomic tracing and physiological recordings, and discuss their potential functional roles. We present evidence that the disynaptic pathway through the thalamus is involved in motor coordination, and that its dysfunction contributes to motor deficits, such as dystonia. We then discuss how cerebellar projections to the VTA and SNc influence dopamine release in the respective targets of these nuclei: the NAc and the dorsal striatum. We argue that the cerebellar projections to the VTA may play a role in reward-based learning and therefore contribute to addictive behavior, whereas the projection to the SNc may contribute to movement vigor. Finally, we speculate how these projections may explain many of the observations that indicate a role for the cerebellum in mental disorders, such as schizophrenia.


Assuntos
Gânglios da Base , Cerebelo , Humanos , Vias Neurais/fisiologia , Gânglios da Base/fisiologia , Cerebelo/fisiologia , Tálamo/fisiologia , Recompensa , Dopamina/metabolismo
7.
Cells ; 11(21)2022 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-36359841

RESUMO

The complexity and overall burden of Parkinson's disease (PD) require new pharmacological approaches to counteract the symptomatology while reducing the progressive neurodegeneration of affected dopaminergic neurons. Since the pathophysiological signature of PD is characterized by the loss of physiological levels of dopamine (DA) and the misfolding and aggregation of the alpha-synuclein (α-syn) protein, new proposals seek to restore the lost DA and inhibit the progressive damage derived from pathological α-syn and its impact in terms of oxidative stress. In this line, nanomedicine (the medical application of nanotechnology) has achieved significant advances in the development of nanocarriers capable of transporting and delivering basal state DA in a controlled manner in the tissues of interest, as well as highly selective catalytic nanostructures with enzyme-like properties for the elimination of reactive oxygen species (responsible for oxidative stress) and the proteolysis of misfolded proteins. Although some of these proposals remain in their early stages, the deepening of our knowledge concerning the pathological processes of PD and the advances in nanomedicine could endow for the development of potential treatments for this still incurable condition. Therefore, in this paper, we offer: (i) a brief summary of the most recent findings concerning the physiology of motor regulation and (ii) the molecular neuropathological processes associated with PD, together with (iii) a recapitulation of the current progress in controlled DA release by nanocarriers and (iv) the design of nanozymes, catalytic nanostructures with oxidoreductase-, chaperon, and protease-like properties. Finally, we conclude by describing the prospects and knowledge gaps to overcome and consider as research into nanotherapies for PD continues, especially when clinical translations take place.


Assuntos
Doença de Parkinson , Humanos , Doença de Parkinson/metabolismo , Nanomedicina , Neurônios Dopaminérgicos/metabolismo , Dopamina/metabolismo , Sistemas de Liberação de Medicamentos
8.
Transl Psychiatry ; 12(1): 464, 2022 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-36344514

RESUMO

Dopamine (DA) is a major monoamine neurotransmitter in the brain and has essential roles in higher functions of the brain. Malfunctions of dopaminergic signaling have been implicated in various mental disorders such as addiction, attention deficit/hyperactivity disorder, Huntington's disease, Parkinson's disease (PD), and schizophrenia. The pathogenesis of PD and schizophrenia involves the interplay of mitochondrial defect and DA metabolism abnormalities. This article focuses on this issue in schizophrenia. It started with the introduction of metabolism, behavioral action, and physiology of DA, followed by reviewing evidence for malfunctions of dopaminergic signaling in patients with schizophrenia. Then it provided an overview of multiple facets of mitochondrial physiology before summarizing mitochondrial defects reported in clinical studies with schizophrenia patients. Finally, it discussed the interplay between DA metabolism abnormalities and mitochondrial defects and outlined some clinical studies showing effects of combination therapy of antipsychotics and antioxidants in treating patients with schizophrenia. The update and integration of these lines of information may advance our understanding of the etiology, pathogenesis, phenomenology, and treatment of schizophrenia.


Assuntos
Antipsicóticos , Doença de Parkinson , Esquizofrenia , Humanos , Esquizofrenia/metabolismo , Dopamina/metabolismo , Antipsicóticos/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Mitocôndrias/metabolismo
9.
Int J Mol Sci ; 23(21)2022 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-36361717

RESUMO

Recent studies implicate a key role of dopamine signaling in lifespan regulation. Our previous study found that quetiapine, an atypical antipsychotic drug that has antagonistic activity on dopamine D2-like receptors (D2Rs), shortened the lifespan of Caenorhabditis elegans (C. elegans). However, the detailed mechanism of this effect was not clear. In the present study, we evaluate the effect of quetiapine on aging and explore its underlying molecular mechanism. The results show that quetiapine shortened healthspan in C. elegans. The lifespan-shortening effect is dependent on DOP-2, a D2R expressed in worms. Quetiapine shortens lifespan through the C. elegans insulin and IGF-1 receptor DAF-2, but not the downstream Akt pathway. Quetiapine-induced lifespan reduction is dependent on RSKS-1, a key protein kinase that functions in mTOR signaling. In addition, the quetiapine effect is also related to mitochondrial function. These findings further support the key role of dopamine signaling in lifespan regulation and promote our insight into the mechanism of action of antipsychotic drugs.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Caenorhabditis elegans/metabolismo , Longevidade , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Fumarato de Quetiapina/farmacologia , Fumarato de Quetiapina/metabolismo , Dopamina/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Insulina/metabolismo , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo
10.
Int J Mol Sci ; 23(21)2022 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-36361716

RESUMO

Parkinson's disease (PD) is a multisystem alpha-synucleinopathic neurodegenerative disease and the most prevalent neurodegenerative disorder after Alzheimer's disease with a high incidence rate in the elderly population. PD is highly multifactorial in etiology and has complex and wide-ranging pathogenic mechanisms. Environmental exposures and genetic predisposition are prominent risk factors. However, current evidence suggests that an intimate link may exist between the risk factor of sleep disturbance and PD pathogenesis. PD is characterized by the pathological hallmarks of alpha-synuclein aggregations and dopaminergic neuron degeneration in the substantia nigra. The loss of dopamine-producing neurons results in both motor and non-motor symptoms, most commonly, bradykinesia, tremor, rigidity, psychiatric disorders, sleep disorders and gastrointestinal problems. Factors that may exacerbate alpha-synuclein accumulation and dopamine neuron loss include neuroinflammation and glymphatic system impairment. Extracellular alpha-synuclein can induce an inflammatory response which can lead to neural cell death and inhibition of neurogenesis. The glymphatic system functions most optimally to remove extracellular brain solutes during sleep and therefore sleep disruption may be a crucial progression factor as well as a risk factor. This literature review interprets and analyses data from experimental and epidemiological studies to determine the recent advances in establishing a relationship between glymphatic system dysfunction, sleep disturbance, and PD pathogenesis and progression. This review addresses current limitations surrounding the ability to affirm a causal link between improved glymphatic clearance by increased sleep quality in PD prevention and management. Furthermore, this review proposes potential therapeutic approaches that could utilize the protective mechanism of sleep, to promote glymphatic clearance that therefore may reduce disease progression as well as symptom severity in PD patients.


Assuntos
Sistema Glinfático , Doenças Neurodegenerativas , Doença de Parkinson , Transtornos do Sono-Vigília , Humanos , Idoso , alfa-Sinucleína/metabolismo , Doença de Parkinson/metabolismo , Sistema Glinfático/metabolismo , Doenças Neurodegenerativas/metabolismo , Transtornos do Sono-Vigília/complicações , Transtornos do Sono-Vigília/metabolismo , Sono , Degeneração Neural/patologia , Dopamina/metabolismo
11.
Molecules ; 27(21)2022 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-36363986

RESUMO

BACKGROUND: Europinidin is a derivative of delphinidin obtained from the plants Plumbago Europea and Ceratostigma plumbaginoides. This herb has wide medicinal applications in treating various diseases but there are very few studies available on this bioactive compound. Considering this background, the present study is designed for the evaluation of Europinidin against Parkinson's disease. AIM: The investigation aims to assess the effect of Europinidin in the rotenone-activated Parkinson's paradigm. METHODS: To evaluate neuroprotective activity, rotenone (1.5 mg/kg s.c) and europinidin (10 mg/kg and 20 mg/kg) was administered in rats for 21 days. The behavioural parameters were performed before sacrificing the rats. On the 22nd day, all the rats were assessed for biochemical markers (SOD, GSH, MDA, Catalase), neurotransmitter levels (Dopamine, 5-HIAA, DOPAC, and HVA levels), and neuroinflammatory markers (IL-6, IL-1ß and TNF-α). RESULTS: It was found that rotenone produced significant (p < 0.001) oxidative damage, a cholinergic deficit, dopaminergic loss, and a rise in neuroinflammatory markers in rats. CONCLUSION: The study concludes that europinidin possesses anti-oxidant and anti-inflammatory properties. The results suggest the therapeutic role of europinidin against rotenone-activated behavioural, biochemical, and neuroinflammatory alterations in rats.


Assuntos
Fármacos Neuroprotetores , Doença de Parkinson , Animais , Ratos , Rotenona , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Peroxidação de Lipídeos , Citocinas/metabolismo , Roedores/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo , Dopamina/metabolismo , Modelos Animais de Doenças
12.
Molecules ; 27(21)2022 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-36364268

RESUMO

Tetrahydroisoquinoline (THIQ) alkaloids and their derivatives have a structural similarity to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a well-known neurotoxin. THIQs seem to present a broad range of actions in the brain, critically dependent on their catechol moieties and metabolism. These properties make it reasonable to assume that an acute or chronic exposure to some THIQs might lead to neurodegenerative diseases including essential tremor (ET). We developed a method to search for precursor carbonyl compounds produced during the Maillard reaction in overcooked meats to study their reactivity with endogenous amines and identify the reaction products. Then, we predicted in silico their pharmacokinetic and toxicological properties toward the central nervous system. Finally, their possible neurological effects on a novel in vitro 3D neurosphere model were assessed. The obtained data indicate that meat is an alkaloid precursor, and we identified the alkaloid 1-benzyl-1,2,3,4-tetrahydroisoquinoline-6,7-diol (1-benz-6,7-diol THIQ) as the condensation product of phenylacetaldehyde with dopamine; in silico study of 1-benz-6,7-diol-THIQ reveals modulation of dopamine receptor D1 and D2; and in vitro study of 1-benz-6,7-diol-THIQ for cytotoxicity and oxidative stress induction does not show any difference after 24 h contact for all tested concentrations. To conclude, our in vitro data do not support an eventual neurotoxic effect for 1-benz-6,7-diol-THIQ.


Assuntos
Alcaloides , Tetra-Hidroisoquinolinas , Tetra-Hidroisoquinolinas/toxicidade , Dopamina/metabolismo , Alcaloides/toxicidade , Encéfalo/metabolismo
13.
Cell Mol Life Sci ; 79(12): 599, 2022 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-36409355

RESUMO

BACKGROUND: Parkinson's disease (PD) is characterized by selective and progressive dopamine (DA) neuron loss in the substantia nigra and other brain regions, with the presence of Lewy body formation. Most PD cases are sporadic, whereas monogenic forms of PD have been linked to multiple genes, including Leucine kinase repeat 2 (LRRK2) and PTEN-induced kinase 1 (PINK1), two protein kinase genes involved in multiple signaling pathways. There is increasing evidence to suggest that endogenous DA and DA-dependent neurodegeneration have a pathophysiologic role in sporadic and familial PD. METHODS: We generated patient-derived dopaminergic neurons and human midbrain-like organoids (hMLOs), transgenic (TG) mouse and Drosophila models, expressing both mutant and wild-type (WT) LRRK2 and PINK1. Using these models, we examined the effect of LRRK2 and PINK1 on tyrosine hydroxylase (TH)-DA pathway. RESULTS: We demonstrated that PD-linked LRRK2 mutations were able to modulate TH-DA pathway, resulting in up-regulation of DA early in the disease which subsequently led to neurodegeneration. The LRRK2-induced DA toxicity and degeneration were abrogated by wild-type (WT) PINK1 (but not PINK1 mutations), and early treatment with a clinical-grade drug, α-methyl-L-tyrosine (α-MT), a TH inhibitor, was able to reverse the pathologies in human neurons and TG Drosophila models. We also identified opposing effects between LRRK2 and PINK1 on TH expression, suggesting that functional balance between these two genes may regulate the TH-DA pathway. CONCLUSIONS: Our findings highlight the vital role of the TH-DA pathway in PD pathogenesis. LRRK2 and PINK1 have opposing effects on the TH-DA pathway, and its balance affects DA neuron survival. LRRK2 or PINK1 mutations can disrupt this balance, promoting DA neuron demise. Our findings provide support for potential clinical trials using TH-DA pathway inhibitors in early or prodromic PD.


Assuntos
Proteínas de Drosophila , Doença de Parkinson , Camundongos , Animais , Humanos , Dopamina/metabolismo , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismo , Doença de Parkinson/metabolismo , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Camundongos Transgênicos , Drosophila/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo
14.
Mol Brain ; 15(1): 90, 2022 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-36397051

RESUMO

Dopamine (DA) plays a vital role in brain physiology and pathology such as learning and memory, motor control, neurological diseases, and psychiatric diseases. In neurons, it has been well established that DA increases or decreases intracellular cyclic AMP (cAMP) through D1-like or D2-like dopamine receptors, respectively. In contrast, it has been elusive how astrocytes respond to DA via Ca2+ signaling and regulate synaptic transmission and reward systems. Previous studies suggest various molecular targets such as MAO-B, D1R, or D1R-D2R heteromer to modulate astrocytic Ca2+ signaling. However, which molecular target is utilized under what physiological condition remains unclear. Here, we show that DA-induced astrocytic Ca2+ signaling pathway switches during development: MAO-B is the major player at a young age (5-6 weeks), whereas DA receptors (DARs) are responsible for the adult period (8-12 weeks). DA-mediated Ca2+ response in the adult period was decreased by either D1R or D2R blockers, which are primarily known for cyclic AMP signaling (Gs and Gi pathway, respectively), suggesting that this Ca2+ response might be mediated through Gq pathway by D1R-D2R heterodimer. Moreover, DAR-mediated Ca2+ response was not blocked by TTX, implying that this response is not a secondary response caused by neuronal activation. Our study proposes an age-specific molecular target of DA-induced astrocytic Ca2+ signaling: MAO-B in young mice and DAR in adult mice.


Assuntos
Astrócitos , Sinalização do Cálcio , Dopamina , Animais , Camundongos , Astrócitos/metabolismo , AMP Cíclico/metabolismo , Dopamina/metabolismo , Monoaminoxidase/metabolismo , Receptores Dopaminérgicos/metabolismo
15.
JCI Insight ; 7(21)2022 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-36345942

RESUMO

Dopamine acts on neurons in the arcuate nucleus (ARC) of the hypothalamus, which controls homeostatic feeding responses. Here we demonstrate a differential enrichment of dopamine receptor 1 (Drd1) expression in food intake-promoting agouti related peptide (AgRP)/neuropeptide Y (NPY) neurons and a large proportion of Drd2-expressing anorexigenic proopiomelanocortin (POMC) neurons. Owing to the nature of these receptors, this translates into a predominant activation of AgRP/NPY neurons upon dopamine stimulation and a larger proportion of dopamine-inhibited POMC neurons. Employing intersectional targeting of Drd2-expressing POMC neurons, we reveal that dopamine-mediated POMC neuron inhibition is Drd2 dependent and that POMCDrd2+ neurons exhibit differential expression of neuropeptide signaling mediators compared with the global POMC neuron population, which manifests in enhanced somatostatin responsiveness of POMCDrd2+ neurons. Selective chemogenetic activation of POMCDrd2+ neurons uncovered their ability to acutely suppress feeding and to preserve body temperature in fasted mice. Collectively, the present study provides the molecular and functional characterization of POMCDrd2+ neurons and aids our understanding of dopamine-dependent control of homeostatic energy-regulatory neurocircuits.


Assuntos
Dopamina , Pró-Opiomelanocortina , Animais , Camundongos , Proteína Relacionada com Agouti/metabolismo , Temperatura Corporal , Dopamina/metabolismo , Neurônios/metabolismo , Neuropeptídeo Y/metabolismo , Pró-Opiomelanocortina/metabolismo
16.
Front Neural Circuits ; 16: 983323, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36389179

RESUMO

Opioids are the most common medications for moderate to severe pain. Unfortunately, they also have addictive properties that have precipitated opioid misuse and the opioid epidemic. In the present study, we examined the effects of acute administration of oxycodone, a µ-opioid receptor (MOR) agonist, on Ca2+ transient activity of medium-sized spiny neurons (MSNs) in freely moving animals. Ca2+ imaging of MSNs in dopamine D1-Cre mice (expressing Cre predominantly in the direct pathway) or adenosine A2A-Cre mice (expressing Cre predominantly in the indirect pathway) was obtained with the aid of miniaturized microscopes (Miniscopes) and a genetically encoded Cre-dependent Ca2+ indicator (GCaMP6f). Systemic injections of oxycodone (3 mg/kg) increased locomotor activity yet, paradoxically, reduced concomitantly the number of active MSNs. The frequency of Ca2+ transients was significantly reduced in MSNs from A2A-Cre mice but not in those from D1-Cre mice. For comparative purposes, a separate group of mice was injected with a non-Cre dependent Ca2+ indicator in the cerebral cortex and the effects of the opioid also were tested. In contrast to MSNs, the frequency of Ca2+ transients in cortical pyramidal neurons was significantly increased by oxycodone administration. Additional electrophysiological studies in brain slices confirmed generalized inhibitory effects of oxycodone on MSNs, including membrane hyperpolarization, reduced excitability, and decreased frequency of spontaneous excitatory and inhibitory postsynaptic currents. These results demonstrate a dissociation between locomotion and striatal MSN activity after acute administration of oxycodone.


Assuntos
Cálcio , Oxicodona , Camundongos , Animais , Cálcio/metabolismo , Oxicodona/farmacologia , Oxicodona/metabolismo , Corpo Estriado/metabolismo , Neurônios/metabolismo , Dopamina/metabolismo
17.
Nat Commun ; 13(1): 6662, 2022 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-36333323

RESUMO

Hippocampal place cells support reward-related spatial memories by forming a cognitive map that over-represents reward locations. The strength of these memories is modulated by the extent of reward expectation during encoding. However, the circuit mechanisms underlying this modulation are unclear. Here we find that when reward expectation is extinguished in mice, they remain engaged with their environment, yet place cell over-representation of rewards vanishes, place field remapping throughout the environment increases, and place field trial-to-trial reliability decreases. Interestingly, Ventral Tegmental Area (VTA) dopaminergic axons in CA1 exhibit a ramping reward-proximity signal that depends on reward expectation and inhibiting VTA dopaminergic neurons largely replicates the effects of extinguishing reward expectation. We conclude that changing reward expectation restructures CA1 cognitive maps and determines map reliability by modulating the dopaminergic VTA-CA1 reward-proximity signal. Thus, internal states of high reward expectation enhance encoding of spatial memories by reinforcing hippocampal cognitive maps associated with reward.


Assuntos
Motivação , Recompensa , Camundongos , Animais , Reprodutibilidade dos Testes , Área Tegmentar Ventral/fisiologia , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo
18.
Nature ; 611(7937): 762-768, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36352228

RESUMO

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.


Assuntos
Proteínas Quinases Dependentes de AMP Cíclico , Dopamina , Camundongos , Animais , Dopamina/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Adenosina/metabolismo , Receptores de Dopamina D1/metabolismo , Corpo Estriado/fisiologia , Neurônios/metabolismo , Locomoção
19.
Proc Natl Acad Sci U S A ; 119(46): e2207545119, 2022 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-36343236

RESUMO

The neurobiological understanding of obsessive-compulsive disorder (OCD) includes dysregulated frontostriatal circuitry and altered monoamine transmission. Repetitive stereotyped behavior (e.g., grooming), a featured symptom in OCD, has been proposed to be associated with perturbed dopamine (DA) signaling. However, the precise brain circuits participating in DA's control over this behavioral phenotype remain elusive. Here, we identified that DA neurons in substantia nigra pars compacta (SNc) orchestrate ventromedial striatum (VMS) microcircuits as well as lateral orbitofrontal cortex (lOFC) during self-grooming behavior. SNc-VMS and SNc-lOFC dopaminergic projections modulate grooming behaviors and striatal microcircuit function differentially. Specifically, the activity of the SNc-VMS pathway promotes grooming via D1 receptors, whereas the activity of the SNc-lOFC pathway suppresses grooming via D2 receptors. SNc DA neuron activity thus controls the OCD-like behaviors via both striatal and cortical projections as dual gating. These results support both pharmacological and brain-stimulation treatments for OCD.


Assuntos
Neurônios Dopaminérgicos , Transtorno Obsessivo-Compulsivo , Animais , Neurônios Dopaminérgicos/metabolismo , Corpo Estriado/fisiologia , Dopamina/metabolismo , Mesencéfalo/metabolismo , Substância Negra/metabolismo
20.
Mol Brain ; 15(1): 94, 2022 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-36414974

RESUMO

Calcineurin (Cn), a phosphatase important for synaptic plasticity and neuronal development, has been implicated in the etiology and pathophysiology of neuropsychiatric disorders, including schizophrenia, intellectual disability, autism spectrum disorders, epilepsy, and Alzheimer's disease. Forebrain-specific conditional Cn knockout mice have been known to exhibit multiple behavioral phenotypes related to these disorders. In this study, we investigated whether Cn mutant mice show pseudo-immaturity of the dentate gyrus (iDG) in the hippocampus, which we have proposed as an endophenotype shared by these disorders. Expression of calbindin and GluA1, typical markers for mature DG granule cells (GCs), was decreased and that of doublecortin, calretinin, phospho-CREB, and dopamine D1 receptor (Drd1), markers for immature GC, was increased in Cn mutants. Phosphorylation of cAMP-dependent protein kinase (PKA) substrates (GluA1, ERK2, DARPP-32, PDE4) was increased and showed higher sensitivity to SKF81297, a Drd1-like agonist, in Cn mutants than in controls. While cAMP/PKA signaling is increased in the iDG of Cn mutants, chronic treatment with rolipram, a selective PDE4 inhibitor that increases intracellular cAMP, ameliorated the iDG phenotype significantly and nesting behavior deficits with nominal significance. Chronic rolipram administration also decreased the phosphorylation of CREB, but not the other four PKA substrates examined, in Cn mutants. These results suggest that Cn deficiency induces pseudo-immaturity of GCs and that cAMP signaling increases to compensate for this maturation abnormality. This study further supports the idea that iDG is an endophenotype shared by certain neuropsychiatric disorders.


Assuntos
Calcineurina , Dopamina , Animais , Camundongos , Calcineurina/metabolismo , Rolipram/metabolismo , Modelos Animais de Doenças , Dopamina/metabolismo , Camundongos Knockout , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Hipocampo/metabolismo , Giro Denteado/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...