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1.
Nat Genet ; 52(2): 146-159, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32060489

RESUMO

In many repeat diseases, such as Huntington's disease (HD), ongoing repeat expansions in affected tissues contribute to disease onset, progression and severity. Inducing contractions of expanded repeats by exogenous agents is not yet possible. Traditional approaches would target proteins driving repeat mutations. Here we report a compound, naphthyridine-azaquinolone (NA), that specifically binds slipped-CAG DNA intermediates of expansion mutations, a previously unsuspected target. NA efficiently induces repeat contractions in HD patient cells as well as en masse contractions in medium spiny neurons of HD mouse striatum. Contractions are specific for the expanded allele, independently of DNA replication, require transcription across the coding CTG strand and arise by blocking repair of CAG slip-outs. NA-induced contractions depend on active expansions driven by MutSß. NA injections in HD mouse striatum reduce mutant HTT protein aggregates, a biomarker of HD pathogenesis and severity. Repeat-structure-specific DNA ligands are a novel avenue to contract expanded repeats.


Assuntos
Proteína Huntingtina/genética , Doença de Huntington/genética , Naftiridinas/farmacologia , Expansão das Repetições de Trinucleotídeos/efeitos dos fármacos , Animais , Corpo Estriado/efeitos dos fármacos , DNA/metabolismo , Reparo de Erro de Pareamento de DNA/efeitos dos fármacos , Replicação do DNA/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Proteína Huntingtina/metabolismo , Doença de Huntington/tratamento farmacológico , Doença de Huntington/patologia , Masculino , Camundongos , Camundongos Transgênicos , Instabilidade de Microssatélites , Mutação , Ribonucleases/metabolismo , Proteína de Ligação a TATA-Box/genética , Transcrição Genética
2.
Science ; 367(6477): 549-555, 2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-32001651

RESUMO

Extinction learning allows animals to withhold voluntary actions that are no longer related to reward and so provides a major source of behavioral control. Although such learning is thought to depend on dopamine signals in the striatum, the way the circuits that mediate goal-directed control are reorganized during new learning remains unknown. Here, by mapping a dopamine-dependent transcriptional activation marker in large ensembles of spiny projection neurons (SPNs) expressing dopamine receptor type 1 (D1-SPNs) or 2 (D2-SPNs) in mice, we demonstrate an extensive and dynamic D2- to D1-SPN transmodulation across the striatum that is necessary for updating previous goal-directed learning. Our findings suggest that D2-SPNs suppress the influence of outdated D1-SPN plasticity within functionally relevant striatal territories to reshape volitional action.


Assuntos
Corpo Estriado/fisiologia , Neurônios Dopaminérgicos/fisiologia , Objetivos , Aprendizagem/fisiologia , Receptores de Dopamina D1/fisiologia , Receptores de Dopamina D2/fisiologia , Animais , Corpo Estriado/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nucleossomos/metabolismo , Racloprida/farmacologia , Receptores de Dopamina D1/antagonistas & inibidores
3.
Biomed Pharmacother ; 118: 109033, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31545235

RESUMO

Studies suggest that abnormal neurodevelopment of prefrontal striatal circuits is implicated in the pathogenesis of attention deficit hyperactivity disorder (ADHD). In the present study, we investigated the effect of catalpol, an active ingredient of Rehmanniae radix preparata, which is the most frequently used Chinese medicinal herb for the treatment of ADHD, on behavior and neurodevelopment in spontaneously hypertensive rats (SHR). SHR were divided into SHR group (vehicle, i.g.), methylphenidate (MPH) group (2 mg/kg/day, i.g.), and catalpol group (50 mg/kg/day i.g.), and Wistar-Kyoto (WKY) rats were used as control group (vehicle, i.g.). Open Field Test (OFT) and Morris water maze (MWM) test were performed to assess the effect of catalpol on behavior. Results revealed that both catalpol and MPH treatment decreased average speed, time spent in the central area, rearing times, and central area visits, increased the immobility time of SHR in OFT, and increased number of visits to the annulus, and time spent in target quadrant in the MWM test. Hematoxylin and eosin (H&E) staining showed that catalpol reduced irregular neuronal arrangement, ruptured nuclear membranes, and resulted in disappearance of the nucleolus in the prefrontal cortex (PFC) and striatum of SHR. Moreover, immuno-fluorescent staining of NeuN and myelin basic protein (MBP) indicated that catalpol ameliorated neuronal loss and contributed to myelination. Finally, western blot and immunostaining analysis suggested that several regulatory proteins involved in PFC development were up-regulated by catalpol treatment, such as brain-derived neurotrophic factor (BDNF), cyclin-dependent kinase 5 (Cdk5), p35, fibroblast growth factor (FGF) 21 and its receptor (FGFR)1. Taken together, catalpol can effectively ameliorate hyperactive and impulsive behavior, improve spatial learning and memory in SHR, likely through the neurodevelopmental pathways. Nonetheless, whether catalpol could attenuate inattention in SHR and the pathway by which catalpol reduces neuronal loss remain to be further studied.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Glucosídeos Iridoides/uso terapêutico , Atividade Motora/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Animais , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Estimulantes do Sistema Nervoso Central/uso terapêutico , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/patologia , Modelos Animais de Doenças , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Metilfenidato/uso terapêutico , Neurônios/efeitos dos fármacos , Neurônios/patologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/patologia , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
4.
J Biochem Mol Toxicol ; 33(10): e22389, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31468582

RESUMO

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.


Assuntos
Álcoois Benzílicos/uso terapêutico , Glucosídeos/uso terapêutico , Proteína HMGB1/metabolismo , Heme Oxigenase-1/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Síndrome de Tourette/tratamento farmacológico , Animais , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/enzimologia , Corpo Estriado/metabolismo , Citocinas/sangue , Citocinas/metabolismo , Ácido Glutâmico/metabolismo , Masculino , Malondialdeído/metabolismo , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase/sangue , Superóxido Dismutase/metabolismo , Síndrome de Tourette/enzimologia , Síndrome de Tourette/metabolismo , Ácido gama-Aminobutírico/metabolismo
5.
J Ethnopharmacol ; 245: 112182, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31445131

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The totally-amounted glucosides of paeony (TGP), which are made up of paeoniflorin, albiflorin, oxypaeoniflorin as well as benzoylpaeoniflorin, constitute the Baishao' actively-working component extracted from Radix Paeonia alba employed in conventional oriental medicine aiming to treat cerebrovascular disorders, such as Parkinson's disease. However, its pharmacologic mechanism is not clear. AIM OF THE STUDY: The initial investigation was made on TGP's neuroprotective effects on PD of the mouse model based on 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) as well as the identification of potential involvement of a molecular signaling pathway. MATERIALS AND METHODS: The evaluation of the behavioral damage as well as neurotoxicity in mice was made through MPTP. Spontaneous motor activity test, as well as a test of Rota-rod on mice was employed for the measurement of bradykinesia symptom. Additionally, liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS-MS) works as the determiner of the main monoamine neurotransmitters dopamine (DA) along with its metabolites 3, 4-dihydroxyphenylacetic acid (DOPAC) as well as homovanillic acid (HVA) based on mouse hippocampus connected with the anti-Parkinson's disease like effect of TGP. Besides, the measurement of the effects of TGP treatment on the expressions level of TH, DAT, a-synuclein, p-CREBS133 as well as apoptosis influence was made with the help of western-blot assay with apoptosis-related markers such as Bax and Bcl-2. RESULTS: The results showed that TGP treatment lessened the behavior-based loss shown "in the spontaneous motor activity as well as the potential of falling to rotarod test". In addition, we found that pretreatment with TGP markedly improved motor coordination, striatal dopamine and its metabolite levels. Furthermore, pretreatment of TGP conducted the protection for dopaminergic neurons with the prevented MPTP-induced reductions within the tyrosine hydroxylase (TH), substantia nigra dopaminergic transporter (DAT), as well as increasing α-synuclein protein levels with transformed dopamine catabolism as well as inhibited dopamine turnover. Besides, TGP treatment helped reversed apoptosis signaling molecules Bcl-2/Bax' reduction; meanwhile improving p-CREBS133 the factor of growth signaling in the substantia nigra' decrease. CONCLUSION: These results suggested that TGP can enhance dopaminergic neuron's cell survival in the SNpc in virtue of the activated cAMP/PKA/CREB factor of growth on inhibiting the pathway of second messenger apoptosis as well. In conclusion, the current findings indicate TGP is expected to be a new cure for PD.


Assuntos
Glucosídeos/uso terapêutico , Intoxicação por MPTP/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Paeonia , Animais , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , AMP Cíclico/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Dopamina/metabolismo , Glucosídeos/farmacologia , Ácido Homovanílico/metabolismo , Intoxicação por MPTP/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , alfa-Sinucleína/metabolismo
6.
Pharmacol Res Perspect ; 7(3): e00484, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31149340

RESUMO

Mutations in leucine-rich repeat kinase 2 (LRRK2) gene have been pathogenically linked to Parkinson's disease, and pharmacological inhibition of LRRK2 is being pursued to tackle nigro-striatal dopaminergic neurodegeneration. However, LRRK2 kinase inhibitors may have manifold actions, affecting not only pathological mechanisms in dopaminergic neurons but also physiological functions in nondopaminergic neurons. Therefore, we investigated whether LRRK2 kinase inhibitors differentially modulate dopamine and glutamate release from the mouse striatum and cerebral cortex. Spontaneous and KCl-evoked [3H]-dopamine and glutamate release from superfused synaptosomes obtained from wild-type and LRRK2 knock-out, kinase-dead or G2019S knock-in mice was measured. Two structurally unrelated inhibitors, LRRK2-IN-1 and GSK2578215A, were tested. LRRK2, phosphoSerine1292 and phosphoSerine935 LRRK2 levels were measured in all genotypes, and target engagement was evaluated by monitoring phosphoSerine935 LRRK2. LRRK2-IN-1 inhibited striatal glutamate but not dopamine release; GSK2578215A inhibited striatal dopamine and cortical glutamate but enhanced striatal glutamate release. LRRK2-IN-1 reduced striatal and cortical phosphoSerine935 levels whereas GSK2578215A inhibited only the former. Neither LRRK2 inhibitor affected neurotransmitter release in LRRK2 knock-out and kinase-dead mice; however, they facilitated dopamine without affecting striatal glutamate in G2019S knock-in mice. GSK2578215A inhibited cortical glutamate release in G2019S knock-in mice. We conclude that LRRK2-IN-1 and GSK2578215A modulate exocytosis by blocking LRRK2 kinase activity, although their effects vary depending on the nerve terminal examined. The G2019S mutation unravels a dopamine-promoting action of LRRK2 inhibitors while blunting their effects on glutamate release, which highlights their positive potential for the treatment of PD, especially of LRRK2 mutation carriers.


Assuntos
Aminopiridinas/farmacologia , Benzamidas/farmacologia , Benzodiazepinonas/farmacologia , Corpo Estriado/citologia , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Pirimidinas/farmacologia , Córtex Visual/citologia , Animais , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Dopamina/metabolismo , Exocitose , Técnicas de Introdução de Genes , Ácido Glutâmico/metabolismo , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/antagonistas & inibidores , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/química , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Masculino , Camundongos , Fosforilação , Serina/metabolismo , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismo , Córtex Visual/efeitos dos fármacos , Córtex Visual/metabolismo
7.
Environ Toxicol ; 34(10): 1114-1120, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31231976

RESUMO

The aim of this study was designed to investigate the effects of rhynchophyllin (RH) on neuroinflammation in Tourette syndrome (TS) rats. TS model was established in rats by the injection of selective 5-HT2A/2C agonist 1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). Behavior in DOI-induced rats was tested. Inflammatory cytokines levels such as interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in serum and striatum were detected. The expression levels of janus kinase 2 (JAK2)/signal transducer and transcription activator 3 (STAT3) and nuclear factor (NF)-κB pathways in striatum were measured by Western blot. Data indicated that RH can significantly reduce the numbers of nodding experiment of TS rats. RH significantly decreased IL-6, IL-1ß, and TNF-α in serum and striatum of TS rats, with altered expression of P-JAK2, P-STAT3, P-NF-κBp65, and P-IκBα in TS rats, as evidenced by Western blot analysis and immunohistochemistry, suggesting that the regulation of JAK2/STAT3 and NF-κB pathways might be involved in the mechanism of RH on TS.


Assuntos
Corpo Estriado/imunologia , Medicamentos de Ervas Chinesas/administração & dosagem , Janus Quinase 2/imunologia , Oxindois/administração & dosagem , Síndrome de Tourette/tratamento farmacológico , Uncaria/química , Animais , Corpo Estriado/efeitos dos fármacos , Humanos , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Janus Quinase 2/genética , Masculino , NF-kappa B/genética , NF-kappa B/imunologia , Propano/efeitos adversos , Propano/análogos & derivados , Ratos , Ratos Wistar , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/imunologia , Transdução de Sinais/efeitos dos fármacos , Síndrome de Tourette/induzido quimicamente , Síndrome de Tourette/genética , Síndrome de Tourette/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
8.
Int J Neurosci ; 129(11): 1139-1144, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31234674

RESUMO

Aim: The aim of the present study is to investigate the neuroprotective effects of l-Arginine (l-arg) in the seven-day-old rat hypoxia-ischemia model. Materials and methods: L-Arginine (n = 10) or saline (n = 8) was administered intraperitoneally to seven-day-old rats before hypoxia-ischemia. In addition, 18 seven-day-old rats were given l-Arginine (n = 10) or saline (n = 8) after hypoxic-ischemic insult. Neuronal apoptosis was investigated by terminal dUDP-biotin nick end-labeling (TUNEL) following three days of recovery. The ratios of right side numerical density to the sum of right and left sides' numerical densities (right apoptosis index) were calculated for every brain region in rats receiving l-arginine and they were compared with the vehicle groups. Results: Right side apoptosis indexes of the hippocampus (mean ± SD; 35.0 ± 16.1) and striatum (41.9 ± 16.0) were significantly decreased in the l-Arginine post-treatment groups when compared to vehicles (61.0 ± 17.0 and 62.4 ± 27.0 respectively) (p < 0.05). There was no significant difference in the right apoptosis indexes of the cortex between l-Arginine post-treated group and the vehicle group. There were also no significant differences between the right side apoptosis indexes of the l-Arginine pretreatment groups and those of the vehicle group in any of the three regions (p > 0.05). Conclusions: It is concluded that neuronal apoptosis due to hypoxic-ischemic injury may likely to be reduced by post-treatment of l-Arginine in the neonatal rat model and l-Arginine provides a new possibility for neuroprotective strategies based on NO production.


Assuntos
Apoptose/efeitos dos fármacos , Arginina/farmacologia , Corpo Estriado , Hipocampo , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Hipóxia-Isquemia Encefálica/patologia , Fármacos Neuroprotetores/farmacologia , Animais , Animais Recém-Nascidos , Arginina/administração & dosagem , Corpo Estriado/citologia , Corpo Estriado/efeitos dos fármacos , Modelos Animais de Doenças , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Marcação In Situ das Extremidades Cortadas , Fármacos Neuroprotetores/administração & dosagem , Ratos , Ratos Wistar
9.
J Neuroinflammation ; 16(1): 99, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31088570

RESUMO

BACKGROUND: Osteopontin (OPN, SPP1) is upregulated in response to acute brain injury, and based on its immunoreactivity, two distinct forms have been identified: intracellular OPN within brain macrophages and small granular OPN, identified as OPN-coated degenerated neurites. This study investigates the spatiotemporal relationship between punctate OPN deposition and astroglial and microglial reactions elicited by 3-nitropropionic acid (3-NP). METHODS: Male Sprague-Dawley rats were intraperitoneally injected with mitochondrial toxin 3-NP and euthanized at 3, 7, 14, and 28 days. Quantitative and qualitative light and electron microscopic techniques were used to assess the relationship between OPN and glial cells. Statistical significance was determined by Student's t test or a one-way analysis of variance followed by Tukey's multiple comparisons test. RESULTS: Punctate OPN-immunoreactive profiles were synthesized and secreted by amoeboid-like brain macrophages in the lesion core, but not by reactive astrocytes and activated microglia with a stellate shape in the peri-lesional area. Punctate OPN accumulation was detected only in the lesion core away from reactive astrocytes in the peri-lesional area at day 3, but had direct contact with, and even overlapped with astroglial processes at day 7. The distance between the OPN-positive area and the astrocytic scar significantly decreased from days 3 to 7. By days 14 and 28 post-lesion, when the glial scar was fully formed, punctate OPN distribution mostly overlapped with the astrocytic scar. Three-dimensional reconstructions and quantitative image analysis revealed numerous granular OPN puncta inside the cytoplasm of reactive astrocytes and brain macrophages. Reactive astrocytes showed prominent expression of the lysosomal marker lysosomal-associated membrane protein 1, and ultrastructural analysis confirmed OPN-coated degenerating neurites inside astrocytes, suggesting the phagocytosis of OPN puncta by reactive astrocytes after injury. CONCLUSIONS: Punctate OPN-immunoreactive profiles corresponded to OPN-coated degenerated neurites, which were closely associated with, or completely engulfed by, the reactive astrocytes forming the astroglial scar in 3-NP lesioned striatum, suggesting that OPN may cause astrocytes to migrate towards these degenerated neurites in the lesion core to establish physical contact with, and possibly, to phagocytose them. Our results provide novel insights essential to understanding the recovery and repair of the central nervous system tissue.


Assuntos
Corpo Estriado/metabolismo , Mitocôndrias/metabolismo , Neuroglia/metabolismo , Nitrocompostos/toxicidade , Osteopontina/metabolismo , Fagocitose/fisiologia , Propionatos/toxicidade , Animais , Corpo Estriado/química , Corpo Estriado/efeitos dos fármacos , Masculino , Mitocôndrias/química , Mitocôndrias/efeitos dos fármacos , Neuroglia/química , Neuroglia/efeitos dos fármacos , Osteopontina/análise , Fagocitose/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Fatores de Tempo
10.
J Pharm Pharmacol ; 71(8): 1271-1281, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31144300

RESUMO

OBJECTIVE: To investigate the effect of desferrioxamine (DFO) and dextromethorphan (DXM) combination in animal model of Parkinson's disease (PD). METHODS: The PD was induced in rats through intracerebroventricular administration of 6-hydroxydopamine (6-OHDA) using stereotaxic apparatus. The animals were subjected to behavioural assessments and neurobiochemicals estimation followed by immunohistochemistry staining of neuron specific enolase (NSE) in striatum. KEY FINDINGS: Desferrioxamine and DXM combination has significantly reversed the catalepsy behaviour and elevated the antioxidant enzymes (SOD, CAT, GSH) and dopamine levels. Interestingly, the level of glutamate, nitric oxide, cytokines (IL-1ß, TNF-α) and NSE expressions were found to be decreased in striatum region of 6-OHDA-administered rats. The combination of DFO and DXM has shown synergism in most of the parameters studied, when compared to per se treatment. CONCLUSIONS: The reversal of catalepsy behaviour represents the protective effect of above combination on dopamine neurons in striatum from 6-OHDA toxicity. The mechanism of DFO and DXM combination might be attributed through attenuation of glutamate-induced excitotoxicity in neurons through ameliorating the reactive oxygen species and pro-inflammatory cytokines release. Treatment with DFO and DXM combination could control the multiple events in the pathogenesis of PD.


Assuntos
Catalepsia/tratamento farmacológico , Corpo Estriado/efeitos dos fármacos , Desferroxamina/farmacologia , Dextrometorfano/farmacologia , Ácido Glutâmico/metabolismo , Hidroxidopaminas/farmacologia , Animais , Antioxidantes/farmacologia , Catalepsia/metabolismo , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Combinação de Medicamentos , Sinergismo Farmacológico , Masculino , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Ratos , Ratos Wistar
11.
Nat Neurosci ; 22(7): 1122-1131, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31133689

RESUMO

A remarkable feature of motor control is the ability to coordinate movements across distinct body parts into a consistent, skilled action. To reach and grasp an object, 'gross' arm and 'fine' dexterous movements must be coordinated as a single action. How the nervous system achieves this coordination is currently unknown. One possibility is that, with training, gross and fine movements are co-optimized to produce a coordinated action; alternatively, gross and fine movements may be modularly refined to function together. To address this question, we recorded neural activity in the primary motor cortex and dorsolateral striatum during reach-to-grasp skill learning in rats. During learning, the refinement of fine and gross movements was behaviorally and neurally dissociable. Furthermore, inactivation of the primary motor cortex and dorsolateral striatum had distinct effects on skilled fine and gross movements. Our results indicate that skilled movement coordination is achieved through emergent modular neural control.


Assuntos
Corpo Estriado/fisiologia , Modelos Neurológicos , Córtex Motor/fisiologia , Destreza Motora/fisiologia , Desempenho Psicomotor/fisiologia , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Condicionamento Operante , Corpo Estriado/efeitos dos fármacos , Membro Anterior/fisiologia , Trombose Intracraniana/fisiopatologia , Aprendizagem/fisiologia , Muscimol/farmacologia , Técnicas de Patch-Clamp , Ratos
12.
Neuropharmacology ; 155: 89-97, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31121177

RESUMO

Alcohol consumption alters glutamatergic transmission in many brain regions, including the dorsomedial striatum (DMS); this aberrant plasticity is thought to be responsible for alcohol-seeking behavior. Recent studies reported that alcohol induced such plasticity specifically in direct pathway spiny projection neurons (dSPNs) of the DMS. However, it is unknown how this specific change contributes to alcohol-seeking behavior and relapse. Here, we first demonstrated that operant alcohol self-administration increased NMDA receptor activity in DMS dSPNs. Next, we found that optogenetic inhibition of dSPNs reversibly decreased operant lever presses for alcohol and alcohol intake. Furthermore, optogenetic stimulation of corticostriatal inputs at low and moderate frequencies induced reliable LTD in DMS slices. Surprisingly, in vivo delivery of the LTD-inducing protocol increased operant alcohol self-administration; this effect was blocked by a D2R antagonist. Importantly, LTD induction in the presence of both D1 and D2 receptor antagonists produced a long-lasting decrease in operant alcohol self-administration. Our results suggest that suppressing DMS dSPNs activity and their cortical inputs represents a novel treatment mechanism for alcohol use disorder.


Assuntos
Consumo de Bebidas Alcoólicas/metabolismo , Corpo Estriado/metabolismo , Comportamento de Procura de Droga/fisiologia , Rede Nervosa/metabolismo , Optogenética/métodos , Consumo de Bebidas Alcoólicas/psicologia , Animais , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Corpo Estriado/química , Corpo Estriado/efeitos dos fármacos , Comportamento de Procura de Droga/efeitos dos fármacos , Etanol/administração & dosagem , Masculino , Rede Nervosa/química , Rede Nervosa/efeitos dos fármacos , Ratos , Ratos Long-Evans , Autoadministração
13.
Cell Biol Int ; 43(7): 809-819, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31050073

RESUMO

Our research group has developed a cell-penetrating peptide-based delivery system that includes the Asn194Lys mutation in the rabies virus glycoprotein-9R peptide (mRVG-9R). This system has the capacity to deliver DNA in astrocytes and SH-SY5Y cells. The aim of this study was to evaluate the ability of the mRVG-9R peptide to deliver DNA molecules to murine brain cells. The mRVG-9R peptide, a karyophilic peptide (KP) and a plasmid encoding green fluorescent protein (GFP) were bound by electrostatic charges to form the mRVG-9R complex. mRVG-9R complex was injected into the cerebral cortex, striatum and hippocampus of C57BL/6 mice by stereotactic surgery. After 2, 4, and 20 days, the animals were sacrificed and their brains were prepared for quantitative reverse-transcription polymerase chain reaction and histological analysis. We detected the GFP expression in neurons and glial cells in the cerebral cortex, striatum, and hippocampus of the murine brain. The results suggest that the mRVG-9R peptide has the ability to deliver DNA molecules to murine brain cells. Also, the expression of the reporter gene is maintained at least up to 20 days after injection in neurons, astrocytes, oligodendrocytes, and microglia cells. Thus, the in vivo transfection ability of the mRVG-9R peptide, makes it a promising candidate as a therapeutic gene delivery vector to the central nervous system cells.


Assuntos
Peptídeos Penetradores de Células/farmacologia , Corpo Estriado/efeitos dos fármacos , Portadores de Fármacos/farmacologia , Glicoproteínas/farmacologia , Proteínas de Fluorescência Verde/metabolismo , Hipocampo/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Proteínas Virais/farmacologia , Animais , Astrócitos/citologia , Astrócitos/efeitos dos fármacos , Corpo Estriado/citologia , Genes Reporter , Vetores Genéticos/uso terapêutico , Proteínas de Fluorescência Verde/genética , Hipocampo/citologia , Camundongos , Camundongos Endogâmicos C57BL , Microglia/citologia , Neurônios/citologia , Neurônios/efeitos dos fármacos , Oligodendroglia/citologia , Oligodendroglia/efeitos dos fármacos , Transfecção/métodos
14.
Elife ; 82019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-31099753

RESUMO

The medial thalamus (MThal), anterior cingulate cortex (ACC) and striatum play important roles in affective-motivational pain processing and reward learning. Opioids affect both pain and reward through uncharacterized modulation of this circuitry. This study examined opioid actions on glutamate transmission between these brain regions in mouse. Mu-opioid receptor (MOR) agonists potently inhibited MThal inputs without affecting ACC inputs to individual striatal medium spiny neurons (MSNs). MOR activation also inhibited MThal inputs to the pyramidal neurons in the ACC. In contrast, delta-opioid receptor (DOR) agonists disinhibited ACC pyramidal neuron responses to MThal inputs by suppressing local feed-forward GABA signaling from parvalbumin-positive interneurons. As a result, DOR activation in the ACC facilitated poly-synaptic (thalamo-cortico-striatal) excitation of MSNs by MThal inputs. These results suggest that opioid effects on pain and reward may be shaped by the relative selectivity of opioid drugs to the specific circuit components.


Assuntos
Analgésicos Opioides/metabolismo , Corpo Estriado/efeitos dos fármacos , Giro do Cíngulo/efeitos dos fármacos , Rede Nervosa/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Tálamo/efeitos dos fármacos , Animais , Aprendizagem/efeitos dos fármacos , Camundongos , Dor , Receptores Opioides delta/agonistas , Receptores Opioides mu/agonistas
15.
Neuroscience ; 410: 76-96, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31078685

RESUMO

Parkinson's disease (PD) is a neurodegenerative illness presenting motor and non-motor symptoms due to the loss of dopaminergic terminals in basal ganglia, most importantly, the striatum. L-DOPA relieves many motor signs. Unfortunately, in the long term, L-DOPA use causes motor disabilities by itself and does not act in comorbid conditions such as depression. These deficiencies have led to search for drugs such as dopamine (DA) receptor agonists (DA-agonists) that allow the reduction of L-DOPA dose. Previously, we have identified the attributes of non-stimulated (resting) and cortical stimulated (active) striatal microcircuits following the activity of dozens of neurons simultaneously using calcium imaging in brain slices. We also have characterized the changes that take place in DA-depleted microcircuits in vitro. In control conditions, there is low spontaneous activity. After cortical stimulation (CtxS) sequences and alternation of neuronal ensembles activity occur, including reverberations. In contrast, DA-deprived circuits exhibit high spontaneous activity at rest, and a highly recurrent ensemble curtails alternation. Interestingly, CtxS briefly relieves these Parkinsonian signs in DA-depleted tissue. Here we compare the actions of some DA-agonists used in PD therapeutics on the pathological dynamics of DA-depleted microcircuits at rest and with CtxS; taking L-DOPA as reference. D2-class agonists better reduce the excessive spontaneous activity of DA-depleted microcircuits. All DA-agonists tend to maintain ensemble alternation seen in control circuits after CtxS. However, quantitative analyses suggest differences in their actions: in general, DA-agonists only approximate L-DOPA actions. Nonetheless no treatment, including L-DOPA, completely restores microcircuit dynamics to control conditions.


Assuntos
Corpo Estriado/metabolismo , Agonistas de Dopamina/farmacologia , Dopamina/metabolismo , Levodopa/farmacologia , Rede Nervosa/metabolismo , Animais , Corpo Estriado/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Rede Nervosa/efeitos dos fármacos , Técnicas de Cultura de Órgãos
16.
Neuroscience ; 409: 180-194, 2019 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-31029732

RESUMO

Standard treatment for Parkinson's disease (PD) is L-DOPA, but with chronic administration the majority of patients develop L-DOPA-induced dyskinesia (LID). Emerging evidence implicates the cholinergic system in PD and LID. Muscarinic acetylcholine receptors (mAChR) are known to modulate movement and of late have been implicated as possible targets for LID. Therefore the current study investigated the role of M1 and M4 mAChRs in LID, on motor performance following L-DOPA treatment, and sought to identify brain sites through which these receptors were acting. We first administered M1R-preferring antagonist trihexyphenidyl (0, 0.1, and 1.0 mg/kg, i.p.) or the M4R-preferring antagonist tropicamide (0, 10, and 30 mg/kg, i.p.) before L-DOPA, after which LID and motor performance were evaluated. Both compounds worsened and extended the time course of LID, while M1R blockade improved motor performance. We then evaluated the effects of tropicamide and trihexyphenidyl on dyskinesia induced by D1R agonist SKF81297 or D2R agonist quinpirole. Surprisingly, both M1R and M4R antagonists reduced D1R agonist-induced dyskinesia but not D2R agonist-induced dyskinesia, suggesting that mAChR blockade differentially affects MSN firing in the absence of postsynaptic DA. Finally, we evaluated effects of striatum- or PPN-targeted tropicamide microinfusion on LID and motor performance. Despite prior evidence, M4R blockade in either site alone did not affect the severity of LID via local striatal or PPN infusions. Taken together, these data suggest M4R as a promising therapeutic target for reducing LID using more selective compounds.


Assuntos
Discinesia Induzida por Medicamentos/tratamento farmacológico , Antagonistas Muscarínicos/uso terapêutico , Doença de Parkinson Secundária/tratamento farmacológico , Receptor Muscarínico M1/antagonistas & inibidores , Receptor Muscarínico M4/antagonistas & inibidores , Animais , Antiparkinsonianos/efeitos adversos , Antiparkinsonianos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Levodopa/efeitos adversos , Levodopa/uso terapêutico , Masculino , Antagonistas Muscarínicos/farmacologia , Oxidopamina , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento , Triexifenidil/farmacologia , Triexifenidil/uso terapêutico , Tropicamida/farmacologia , Tropicamida/uso terapêutico
17.
Sensors (Basel) ; 19(7)2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30978990

RESUMO

The neuroimaging techniques such as dopaminergic imaging using Single Photon Emission Computed Tomography (SPECT) with 99mTc-TRODAT-1 have been employed to detect the stages of Parkinson's disease (PD). In this retrospective study, a total of 202 99mTc-TRODAT-1 SPECT imaging were collected. All of the PD patient cases were separated into mild (HYS Stage 1 to Stage 3) and severe (HYS Stage 4 and Stage 5) PD, according to the Hoehn and Yahr Scale (HYS) standard. A three-dimensional method was used to estimate six features of activity distribution and striatal activity volume in the images. These features were skewness, kurtosis, Cyhelsky's skewness coefficient, Pearson's median skewness, dopamine transporter activity volume, and dopamine transporter activity maximum. Finally, the data were modeled using logistic regression (LR) and support vector machine (SVM) for PD classification. The results showed that SVM classifier method produced a higher accuracy than LR. The sensitivity, specificity, PPV, NPV, accuracy, and AUC with SVM method were 0.82, 1.00, 0.84, 0.67, 0.83, and 0.85, respectively. Additionally, the Kappa value was shown to reach 0.68. This claimed that the SVM-based model could provide further reference for PD stage classification in medical diagnosis. In the future, more healthy cases will be expected to clarify the false positive rate in this classification model.


Assuntos
Corpo Estriado/diagnóstico por imagem , Doença de Parkinson/diagnóstico por imagem , Máquina de Vetores de Suporte , Tomografia Computadorizada de Emissão de Fóton Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/patologia , Dopamina/química , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/química , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Compostos de Organotecnécio/administração & dosagem , Doença de Parkinson/classificação , Doença de Parkinson/diagnóstico , Doença de Parkinson/patologia , Estudos Retrospectivos , Tropanos/administração & dosagem
18.
Molecules ; 24(7)2019 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-30959762

RESUMO

Serotonin (5-HT) plays a crucial role in modulating the afferent fiber discharge rate in the inferior colliculus, auditory cortex, and other nuclei of the ascending auditory system. Resveratrol, a natural polyphenol phytoalexin, can inhibit serotonin transporters (SERT) to increase synaptic 5-HT levels. In this study, we investigated the effects of resveratrol on noise-induced damage in the serotonergic system. Male Sprague-Dawley rats were anaesthetized and exposed to an 8-kHz tone at 116 dB for 3.5 h. Resveratrol (30 mg/kg, intraperitoneal injection [IP]) and citalopram (20 mg/kg, IP), a specific SERT inhibitor used as a positive control, were administered once a day for four consecutive days, with the first treatment occurring 2 days before noise exposure. Auditory brainstem response testing and positron emission tomography (PET) with N,N-dimethyl-2-(2-amino-4-[18F]fluorophenylthio)benzylamine (4-[18F]-ADAM, a specific radioligand for SERT) were used to evaluate functionality of the auditory system and integrity of the serotonergic system, respectively, before and after noise exposure. Finally, immunohistochemistry was performed 1 day after the last PET scan. Our results indicate that noise-induced serotonergic fiber loss occurred in multiple brain regions including the midbrain, thalamus, hypothalamus, striatum, auditory cortex, and frontal cortex. This noise-induced damage to the serotonergic system was ameliorated in response to treatment with resveratrol and citalopram. However, noise exposure increased the hearing threshold in the rats regardless of drug treatment status. We conclude that resveratrol has protective effects against noise-induced loss of SERT.


Assuntos
Resveratrol/administração & dosagem , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores de Captação de Serotonina/administração & dosagem , Serotonina/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Radioisótopos de Flúor/administração & dosagem , Radioisótopos de Flúor/química , Humanos , Imuno-Histoquímica , Tomografia por Emissão de Pósitrons , Ratos , Serotonina/química , Proteínas da Membrana Plasmática de Transporte de Serotonina/efeitos dos fármacos , Distribuição Tecidual/efeitos dos fármacos
19.
Neuropharmacology ; 151: 1-12, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30940536

RESUMO

Huntington's disease (HD) is an inherited progressive neurodegenerative disease characterized by motor, cognitive, and behavioural changes. One of the earliest changes to occur in HD is a reduction in cannabinoid 1 receptor (CB1) levels in the striatum, which is strongly correlated with HD pathogenesis. CB1 positive allosteric modulators (PAM) enhance receptor affinity for, and efficacy of activation by, orthosteric ligands, including the endocannabinoids anandamide and 2-arachidonoylglycerol. The goal of this study was to determine whether the recently characterized CB1 allosteric modulators GAT211 (racemic), GAT228 (R-enantiomer), and GAT229 (S-enantiomer), affected the signs and symptoms of HD. GAT211, GAT228, and GAT229 were evaluated in normal and HD cell models, and in a transgenic mouse model of HD (7-week-old male R6/2 mice, 10 mg/kg/d, 21 d, i.p.). GAT229 was a CB1 PAM that improved cell viability in HD cells and improved motor coordination, delayed symptom onset, and normalized gene expression in R6/2 HD mice. GAT228 was an allosteric agonist that did not enhance endocannabinoid signaling or change symptom progression in R6/2 mice. GAT211 displayed intermediate effects between its enantiomers. The compounds used here are not drugs, but probe compounds used to determine the potential utility of CB1 PAMs in HD. Changes in gene expression, and not protein, were quantified in R6/2 HD mice because HD pathogenesis is associated with dysregulation of mRNA levels. The data presented here provide the first proof of principle for the use of CB1 PAMs to treat the signs and symptoms of HD.


Assuntos
Regulação Alostérica/efeitos dos fármacos , Agonistas de Receptores de Canabinoides/uso terapêutico , Corpo Estriado/efeitos dos fármacos , Doença de Huntington/tratamento farmacológico , Indóis/uso terapêutico , Receptor CB1 de Canabinoide/metabolismo , Animais , Agonistas de Receptores de Canabinoides/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Expressão Gênica/efeitos dos fármacos , Doença de Huntington/metabolismo , Doença de Huntington/fisiopatologia , Indóis/farmacologia , Masculino , Camundongos , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia
20.
J Ethnopharmacol ; 238: 111881, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31002838

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Everyday use of the herbal tea rooibos, produced from Aspalathus linearis (Brum.f) Dahlg. (Fabaceae) is customary in South Africa, a continuation of its historical use by indigenous people. Although evidence of its traditional indications is anecdotal, rooibos tea is regarded as a general health tea. AIMS OF THE STUDY: Available contemporary research indicates to broad cell protective activity of rooibos focusing on its antioxidative, anti-inflammatory, anti-hyperglycaemic and antithrombotic features affecting metabolic syndrome, cardiovascular risk and neuroprotection. Nevertheless little is known about its impact on brain functions. The present experiment aimed to evaluate the possible behavioural and neurochemical effects of long-term oral administration of "fermented"" rooibos herbal tea (FRHT) infusions to adult male Sprague-Dawley rats. MATERIALS AND METHODS: Infusions, prepared using 1, 2 and 4 g of "fermented"" (oxidised) A. linearis leaves for 100 ml of hot water, were characterised in terms of flavonoid content by ultra-high and high performance liquid chromatography (UHPLC-qTOF-MS, HPLC-DAD) and administered to rats as sole drinking fluid for 12 weeks. Spatial memory behaviour was assessed in a modified version of the Morris water maze. Dopamine, noradrenaline, serotonin and their metabolite levels (DOPAC, 3-MT, HVA, MHPG, 5-HIAA) were quantified in prefrontal cortex, hippocampus and striatum by HPLC-ECD. Body weight and blood glucose level were additionally estimated. RESULTS: All FRHT-treated rats showed improvement of long-term spatial memory defined as increased number of crossings over the previous platform position in SE quadrant of the water maze. It was not accompanied by excessive motor activity. Striatal dopamine and its metabolite 3-MT (3-methoxytyramine) levels were increased in treated rats. There were no differences in body weight gain between control and treated animals but blood glucose level was significantly lower in the latter ones. CONCLUSION: The improvement of long-term memory in FRHT-treated rats and stimulating impact of FRHT on their dopaminergic striatal transmission support the wellness enhancing effect of rooibos tea, contributing to a better understanding of the neurological background of traditional habitual consumption of this herbal tea.


Assuntos
Aspalathus/química , Corpo Estriado/efeitos dos fármacos , Dopamina/metabolismo , Extratos Vegetais/farmacologia , Animais , Corpo Estriado/metabolismo , Masculino , Extratos Vegetais/química , Folhas de Planta/química , Ratos , Ratos Sprague-Dawley , Chás de Ervas
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