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1.
C R Biol ; 342(5-6): 192-198, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31474522

RESUMO

Exposure to lead is a threat factor for neurodegenerative disorders progress as it could trigger dopaminergic deficiency. We aimed herein to assess the effect of acute lead exposure (25mg/kg B.W i.p.) during three continuous days on the dopaminergic and noradrenergic systems together with locomotor performance in Meriones shawi (M. shawi), then the neuroprotective potential of curcumin-III (30mg/kg B.W) by oral gavage. Pb-exposed M. shawi exhibited increased tyrosine hydroxylase (TH) immunoreactivity in substantia nigra compacta (SNc), ventral tegmental area (VTA), locus coeruleus (LC), and dorsal striatum (DS), unlike the controls. This was correlated with decreased locomotor performance. A noticeable protective effect by co-treatment with curcumin-III was observed; in consequence, TH-immunoreactivity and locomotor disturbance were restored in Pb-treated Meriones. Our data results proved, on the one hand, an evident neurotoxic effect of acute Pb exposure and, on the other hand, a potent therapeutic effect of curcumin-III. Thereby, this compound may be recommended as a neuroprotective molecule for neurodegenerative disorders involving catecholaminergic impairment initiated by metallic elements.


Assuntos
Corpo Estriado/patologia , Curcumina/análogos & derivados , Neurônios Dopaminérgicos/efeitos dos fármacos , Intoxicação do Sistema Nervoso por Chumbo/tratamento farmacológico , Intoxicação do Sistema Nervoso por Chumbo/patologia , Fármacos Neuroprotetores/uso terapêutico , Sistema Nervoso Parassimpático/patologia , Substância Negra/patologia , Administração Oral , Animais , Curcumina/uso terapêutico , Gerbillinae , Locus Cerúleo/patologia , Masculino , Transtornos dos Movimentos/psicologia , Área Tegmentar Ventral/patologia
2.
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
3.
Biomed Res Int ; 2019: 7654798, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31309116

RESUMO

This study aimed to screen the target miRNAs and to investigate the differential miR-3557/324-targeted signal mechanisms in the rats' model of Parkinson's disease (PD) with regular aerobic exercise. Rats were divided into sedentary control PD group (SED-PD, n = 18) and aerobic exercise PD group (EX-PD, n = 22). After 8 weeks of regular aerobic exercise, a 6-hydroxydopamine- (6-OHDA-) induced PD lesion model was constructed. Preregular aerobic exercises enhanced the injury resistance of rats with 6-OHDA-induced PD. The rotational behavior after injection of apomorphine hydrochloride was alleviated. Under the scanning electron microscopy, we found the neurons, axons, and villi of the striatum were clearly and tightly arranged, and neurons and axons significantly becoming larger. Tyrosine hydroxylase (TH) was increased significantly and α-synuclein protein expression was reduced in the EX-PD group compared to the SED-PD group. Screening from miRNA microarray chip, we further found upregulation of miR-3557 and downregulation of miR-324 were closely related to the calcium-modulating signaling pathway, remitting the progress of Parkinson's disease on aerobic exercise. Compared to the SED-PD group, Ca2+/calmodulin dependent protein kinase II (CaMK2α) was upregulated, but CaMKV and voltage-dependent anion-selective channel protein 1 (Vdac1) were significantly downregulated in the EX-PD group. Additionally, phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) expression were activated, and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) expression was upregulated in the EX-PD group. Conclusions: the adaptive mechanism of regular aerobic exercise delaying neurodegenerative diseases and lesions was that miR-3557/324 was activated to regulate one of its targets CaMKs signaling pathways. CaMKs, coordinated with mTOR pathway-related gene expression, improved UCH-L1 level to favor for delaying neurodegeneration or improving the pathogenesis of PD lesions.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/biossíntese , Proteínas de Ligação a Calmodulina/biossíntese , Corpo Estriado/metabolismo , Regulação da Expressão Gênica , MicroRNAs/biossíntese , Proteínas do Tecido Nervoso/biossíntese , Doença de Parkinson Secundária/metabolismo , Condicionamento Físico Animal , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Animais , Corpo Estriado/patologia , Corpo Estriado/fisiopatologia , Perfilação da Expressão Gênica , Masculino , Doença de Parkinson Secundária/patologia , Doença de Parkinson Secundária/fisiopatologia , Ratos , Ratos Sprague-Dawley
4.
Int J Mol Sci ; 20(14)2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31340557

RESUMO

Background: Several biophysical techniques have been successfully implemented to detect G protein-coupled receptors (GPCRs) heteromerization. Although these approaches have made it possible to ascertain the presence of GPCR heteromers in animal models of disease, no success has been accomplished in pathological human post-mortem brains. The AlphaScreen technology has been consistently used to quantify small analyte accumulation or depletion, bimolecular interactions, and post-translational modifications. The high signal-to-background, dynamic range and sensitivity exhibited by this technology support that it may be suitable to detect GPCR heteromers even under non-optimal conditions. Methods: Here, we describe the development of a new AlphaScreen assay to detect GPCR oligomers in human post-mortem brain. Results: Adenosine A2A-dopamine D2 receptor (A2AR/D2R) heteromer formation was monitored in caudate from healthy and Parkinson's disease (PD) subjects. The approach was first validated using striatal membranes from wild type and A2AR deficient mice. Secondly, we took advantage of the 6-hydroxydopamine hemiparkinsonian rat model to validate previous results. In addition, finally, A2AR/D2R heteromer formation was assessed in caudate membranes from human post-mortem brains. Importantly, our preliminary results revealed an increase in A2AR/D2R heteromer formation in PD brains. Conclusions: The new AlphaScreen assay allowed assessing GPCR heteromers in human post-mortem brains with high sensitivity.


Assuntos
Autopsia/métodos , Corpo Estriado/metabolismo , Ensaios de Triagem em Larga Escala/instrumentação , Doença de Parkinson Secundária/genética , Doença de Parkinson/genética , Receptor A2A de Adenosina/genética , Idoso , Idoso de 80 Anos ou mais , Animais , Autopsia/instrumentação , Estudos de Casos e Controles , Corpo Estriado/patologia , Modelos Animais de Doenças , Feminino , Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Knockout , Oxidopamina/administração & dosagem , Doença de Parkinson/diagnóstico , Doença de Parkinson/patologia , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/patologia , Multimerização Proteica , Ratos , Ratos Sprague-Dawley , Receptor A2A de Adenosina/química , Receptor A2A de Adenosina/metabolismo
5.
Horm Behav ; 114: 104543, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31220463

RESUMO

Long-standing studies established a role for the oxytocin system in social behavior, social reward, pair bonding and affiliation. Oxytocin receptors, implicated in pathological conditions affecting the social sphere such as autism spectrum disorders, can also modulate cognitive processes, an aspect generally overlooked. Here we examined the effect of acute (pharmacological) or genetic (Oxtr-/-) inactivation of oxytocin receptor-mediated signaling, in male mice, in several cognitive tests. In the novel object recognition test, both oxytocin receptor antagonist treated wild type animals and Oxtr-/- mice lacked the typical preference for novelty. Oxtr-/- mice even preferred the familiar object; moreover, their performance in the Morris water maze did not differ from wild types, suggesting that oxytocin receptor inactivation did not disrupt learning. Because the preference for novel objects could be rescued in Oxtr-/- mice with longer habituation periods, we propose that the loss of novelty preferences following Oxtr inactivation is due to altered processing of novel contextual information. Finally, we observed an increased expression of excitatory synaptic markers in the striatum of Oxtr-/- mice and a greater arborization and higher number of spines/neuron in the dorsolateral area of this structure, which drives habit formation. Our data also indicate a specific reshaping of dorsolateral striatal spines in Oxtr-/- mice after exposure to a novel environment, which might subtend their altered approach to novelty, and support previous work pointing at this structure as an important substrate for autistic behaviors.


Assuntos
Transtorno Autístico/genética , Transtorno Autístico/patologia , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Comportamento Exploratório/fisiologia , Receptores de Ocitocina/genética , Animais , Comportamento Animal/fisiologia , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Knockout , Ocitocina/metabolismo , Ligação do Par , Comportamento Social
6.
Adv Pharmacol ; 84: 3-19, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31229176

RESUMO

Our working hypothesis is that a hypoadenosinergic state is a main pathogenetic factor that determines the sensory-motor symptoms and hyperarousal of restless legs syndrome (RLS). We have recently demonstrated that brain iron deficiency (BID) in rodents, a well-accepted animal model of RLS, is associated with a generalized downregulation of adenosine A1 receptors (A1R) in the brain and with hypersensitivity of corticostriatal glutamatergic terminals. Here, we first review the experimental evidence for a pivotal role of adenosine and A1R in the control of striatal glutamatergic transmission and the rationale for targeting putative downregulated striatal A1R in RLS patients, which is supported by recent clinical results obtained with dipyridamole, an inhibitor of the nucleoside transporters ENT1 and ENT2. Second, we perform optogenetic-microdialysis experiments in rats to demonstrate that A1R determine the sensitivity of corticostriatal glutamatergic terminals and the ability of dipyridamole to counteract optogenetically-induced corticostriatal glutamate release in both animals with BID and controls. Thus, a frequency of optogenetic stimulation that was ineffective at inducing cortico-striatal glutamate release in control rats became effective with the local perfusion of a selective A1R antagonist. Furthermore, in animals with and without BID, the striatal application of dipyridamole blocked the optogenetic-induced glutamate release and decreased basal levels of glutamate, which was counteracted by the A1R antagonist. The results support the clinical application of ENT1 inhibitors in RLS.


Assuntos
Adenosina/metabolismo , Corpo Estriado/patologia , Síndrome das Pernas Inquietas/tratamento farmacológico , Animais , Transporte Biológico , Ácido Glutâmico/metabolismo , Masculino , Optogenética , Ratos Sprague-Dawley , Receptor A1 de Adenosina/metabolismo
7.
PLoS One ; 14(6): e0218130, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31181111

RESUMO

BACKGROUND: Unresponsiveness to dopaminergic therapies is a key feature in the diagnosis of multiple system atrophy (MSA) and a major unmet need in the treatment of MSA patients caused by combined striatonigral degeneration (SND). Transgenic, alpha-synuclein animal models do not recapitulate this lack of levodopa responsiveness. In order to preclinically study interventions including striatal cell grafts, models that feature SND are required. Most of the previous studies focused on extensive nigral and striatal lesions corresponding to advanced MSA-P/SND. The aim of the current study was to replicate mild stage MSA-P/SND with L-dopa failure. METHODS AND RESULTS: Two different striatal quinolinic acid (QA) lesions following a striatal 6-OHDA lesion replicating mild and severe MSA-P/SND, respectively, were investigated and compared to 6-OHDA lesioned animals. After the initial 6-OHDA lesion there was a significant improvement of motor performance after dopaminergic stimulation in the cylinder and stepping test (p<0.001). Response to L-dopa treatment declined in both MSA-P/SND groups reflecting striatal damage of lateral motor areas in contrast to the 6-OHDA only lesioned animals (p<0.01). The remaining striatal volume correlated strongly with contralateral apomorphine induced rotation behaviour and contralateral paw use during L-dopa treatment in cylinder and stepping test (p<0.001). CONCLUSION: Our novel L-dopa response data suggest that L-dopa failure can be induced by restricted lateral striatal lesions combined with dopaminergic denervation. We propose that this sequential striatal double-lesion model replicates a mild stage of MSA-P/SND and is suitable to address neuro-regenerative therapies aimed at restoring dopaminergic responsiveness.


Assuntos
Levodopa/farmacologia , Atrofia de Múltiplos Sistemas/etiologia , Degeneração Estriatonigral/tratamento farmacológico , Animais , Comportamento Animal/efeitos dos fármacos , Corpo Estriado/patologia , Denervação , Modelos Animais de Doenças , Atividade Motora/efeitos dos fármacos , Ácido Quinolínico/efeitos adversos , Ratos
8.
Int J Mol Sci ; 20(11)2019 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-31146332

RESUMO

Neuroinflammation is implicated in dopaminergic neurodegeneration. We have previously demonstrated that (E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol (MMPP), a selective signal transducer and activator of transcription 3 (STAT3) inhibitor, has anti-inflammatory properties in several inflammatory disease models. We investigated whether MMPP could protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic cell loss and behavioral impairment. Imprinting control region (ICR) mice (8 weeks old, n = 10 per group) were administered MMPP (5 mg/kg) in drinking water for 1 month, and injected with MPTP (15 mg/kg, four times with 2 h intervals) during the last 7 days of treatment. MMPP decreased MPTP-induced behavioral impairments in rotarod, pole, and gait tests. We also showed that MMPP ameliorated dopamine depletion in the striatum and inflammatory marker elevation in primary cultured neurons by high-performance liquid chromatography and immunohistochemical analysis. Increased activation of STAT3, p38, and monoamine oxidase B (MAO-B) were observed in the substantia nigra and striatum after MPTP injection, effects that were attenuated by MMPP treatment. Furthermore, MMPP inhibited STAT3 activity and expression of neuroinflammatory proteins, including ionized calcium binding adaptor molecule 1 (Iba1), inducible nitric oxide synthase (iNOS), and glial fibrillary acidic protein (GFAP) in 1-methyl-4-phenylpyridinium (MPP+; 0.5 mM)-treated primary cultured cells. However, mitogen-activated protein kinase (MAPK) inhibitors augmented the activity of MMPP. Collectively, our results suggest that MMPP may be an anti-inflammatory agent that attenuates dopaminergic neurodegeneration and neuroinflammation through MAO-B and MAPK pathway-dependent inhibition of STAT3 activation.


Assuntos
Neurônios Dopaminérgicos/metabolismo , Intoxicação por MPTP/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Células Cultivadas , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Dopamina/metabolismo , Neurônios Dopaminérgicos/patologia , Proteína Glial Fibrilar Ácida/metabolismo , Inflamação , Intoxicação por MPTP/patologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Monoaminoxidase/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
9.
Toxicol Lett ; 313: 19-29, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31082522

RESUMO

Much efforts have been tried to clarify the molecular mechanism of alcohol-induced brain damage from the perspective of genome and protein; however, the effect of chronic alcohol exposure on global lipid profiling of brain is unclear. In the present study, by using Q-TOF/MS-based lipidomics approach, we investigated the comprehensive lipidome profiling of brain from the rats orally administrated with alcohol daily, continuously for one year. Through systematically analysis of all lipids in prefrontal cortex (PFC) and striatum region, we found that long-term alcohol exposure profoundly modified brain lipidome profiling. Notably, three kinds of lipid classes, glycerophospholipid (GP), glycerolipid (GL) and fatty acyls (FA), were significantly increased in these two brain regions. Interestingly, most of the modified lipids were involved in synthetic pathways of endoplasmic reticulum (ER), which may result in ER stress-related metabolic disruption. Moreover, alcohol-modified lipid species displayed long length of carbon chain with high degree of unsaturation. Taken together, our results firstly present that chronic alcohol exposure markedly modifies brain lipidomic profiling, which may activate ER stress and eventually result in neurotoxicity. These findings provide a new insight into the mechanism of alcohol-related brain damage.


Assuntos
Transtornos do Sistema Nervoso Induzidos por Álcool/metabolismo , Alcoolismo/metabolismo , Corpo Estriado/metabolismo , Metabolismo dos Lipídeos , Metabolômica/métodos , Córtex Pré-Frontal/metabolismo , Espectrometria de Massas por Ionização por Electrospray , Transtornos do Sistema Nervoso Induzidos por Álcool/patologia , Alcoolismo/patologia , Animais , Corpo Estriado/patologia , Modelos Animais de Doenças , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/patologia , Estresse do Retículo Endoplasmático , Ácidos Graxos/metabolismo , Glicerofosfolipídeos/metabolismo , Córtex Pré-Frontal/patologia , Ratos Wistar , Fatores de Tempo
10.
Mol Med Rep ; 19(6): 5169-5176, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059107

RESUMO

The aim of the present study was to probe the mechanism of apoptosis induced by endoplasmic reticulum stress (ERS) in manganese­induced rats. A total of 60 Sprague­Dawley rats were randomly divided into a Vehicle group, LoMag group, HiMag group, and HiMag + 4­phenylbutyrate (PBA) group. Manganese content was measured by Inductively Coupled Plasma­Atomic Emission Spectrometry. Pathogenic morphology, the cellular structure of the striatum and ER were observed by hematoxylin and eosin staining and electron microscopy. The TUNEL method was used to examine neuronal apoptosis in the rat striatum. The expression levels of glucose­regulated protein 78KD (GRP78), C/EBP homologous protein (CHOP), c­Jun N­terminal kinase (JNK) and caspase­12 were analyzed by western blot analysis. The results revealed that striatal manganese concentrations in the LoMag and HiMag groups were higher than that in the Vehicle group (P<0.01). Rat striatal neuronal structure and apoptotic rates in the LoMag and HiMag groups were higher than those in the Vehicle group (P<0.05). 4­PBA treatment effectively reduced the apoptotic cell number (P<0.05). In addition, ER swelling and vacuolization in the HiMag + PBA group was reduced compared with that in the HiMag group. In addition, the protein expression levels of GRP78, CHOP, JNK and caspase­12 in the LoMag and HiMag groups were higher than those in the Vehicle group (P<0.05). However, the expression of these four proteins was reduced by 4­PBA treatment (P<0.05). In conclusion, 4­PBA significantly reduced the damage and apoptosis induced by manganese exposure in rats.


Assuntos
Estresse do Retículo Endoplasmático/efeitos dos fármacos , Manganês/toxicidade , Animais , Apoptose/efeitos dos fármacos , Caspase 12/metabolismo , Corpo Estriado/química , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Retículo Endoplasmático/química , Retículo Endoplasmático/metabolismo , Proteínas de Choque Térmico/metabolismo , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/ultraestrutura , Fenilbutiratos/farmacologia , Ratos , Ratos Sprague-Dawley , Espectrofotometria Atômica , Fator de Transcrição CHOP/metabolismo
11.
Cell Stress Chaperones ; 24(3): 581-594, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31025239

RESUMO

Cognitive issues in stroke arise as a result of reperfusion of a clogged artery, which is reported to exacerbate the injury in the brain leading to oxidative stress. Through the present work, we try to understand the regional variations across brain regions mainly cortex and striatum associated with the progression of ischemia-reperfusion injury (IRI). In a rat model of IRI, the influence of varying ischemia and reperfusion times on the biochemical phases across the brain regions were monitored. IRI resulted in the blood-brain barrier disruption and developed mild areas of risk. The brain's tolerance towards IRI indicated a progressive trend in the injury and apoptosis from ischemia to reperfusion that was supported by the activities of plasma lactate dehydrogenase and tissue caspase-3. Cognitive impairment in these rats was an implication of cellular oxidative stress (higher lipid peroxidation and lower antioxidant enzyme activity) that persisted by 24-h reperfusion. The oxidative stress was prominent in the cortex than the striatum and was supported by the lower ATP level. Upregulated Mn-SOD expression leading to a preserved mitochondria in the striatum could be attributed to the regional protection. Overall, a progression of IRI was observed from striatum to cortex leading to 5-day cognitive decline.


Assuntos
Trifosfato de Adenosina/metabolismo , Barreira Hematoencefálica/metabolismo , Cognição , Corpo Estriado/metabolismo , Estresse Oxidativo , Traumatismo por Reperfusão/metabolismo , Adenosina Trifosfatases/metabolismo , Animais , Barreira Hematoencefálica/patologia , Corpo Estriado/patologia , Masculino , Mitocôndrias/metabolismo , Ratos , Ratos Wistar
12.
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
13.
Nat Commun ; 10(1): 1917, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015467

RESUMO

STXBP1 and SCN2A gene mutations are observed in patients with epilepsies, although the circuit basis remains elusive. Here, we show that mice with haplodeficiency for these genes exhibit absence seizures with spike-and-wave discharges (SWDs) initiated by reduced cortical excitatory transmission into the striatum. Mice deficient for Stxbp1 or Scn2a in cortico-striatal but not cortico-thalamic neurons reproduce SWDs. In Stxbp1 haplodeficient mice, there is a reduction in excitatory transmission from the neocortex to striatal fast-spiking interneurons (FSIs). FSI activity transiently decreases at SWD onset, and pharmacological potentiation of AMPA receptors in the striatum but not in the thalamus suppresses SWDs. Furthermore, in wild-type mice, pharmacological inhibition of cortico-striatal FSI excitatory transmission triggers absence and convulsive seizures in a dose-dependent manner. These findings suggest that impaired cortico-striatal excitatory transmission is a plausible mechanism that triggers epilepsy in Stxbp1 and Scn2a haplodeficient mice.


Assuntos
Corpo Estriado/metabolismo , Proteínas Munc18/genética , Canal de Sódio Disparado por Voltagem NAV1.2/genética , Neocórtex/metabolismo , Convulsões/genética , Transmissão Sináptica , Potenciais de Ação/efeitos dos fármacos , Animais , Anticonvulsivantes/farmacologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/patologia , Dioxóis/farmacologia , Eletroencefalografia , Epilepsia Tipo Ausência/tratamento farmacológico , Epilepsia Tipo Ausência/genética , Epilepsia Tipo Ausência/metabolismo , Epilepsia Tipo Ausência/fisiopatologia , Etossuximida/farmacologia , Regulação da Expressão Gênica , Haploinsuficiência , Interneurônios/efeitos dos fármacos , Interneurônios/metabolismo , Interneurônios/patologia , Camundongos , Camundongos Knockout , Proteínas Munc18/deficiência , Canal de Sódio Disparado por Voltagem NAV1.2/deficiência , Neocórtex/efeitos dos fármacos , Neocórtex/patologia , Vias Neurais/efeitos dos fármacos , Vias Neurais/metabolismo , Piperidinas/farmacologia , Receptores de AMPA/genética , Receptores de AMPA/metabolismo , Convulsões/metabolismo , Convulsões/fisiopatologia , Convulsões/prevenção & controle , Transdução de Sinais , Tálamo/efeitos dos fármacos , Tálamo/metabolismo
14.
Elife ; 82019 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-31017573

RESUMO

Huntington's disease (HD) is initially characterized by an inability to suppress unwanted movements, a deficit attributable to impaired synaptic activation of striatal indirect pathway spiny projection neurons (iSPNs). To better understand the mechanisms underlying this deficit, striatal neurons in ex vivo brain slices from mouse genetic models of HD were studied using electrophysiological, optical and biochemical approaches. Distal dendrites of iSPNs from symptomatic HD mice were hypoexcitable, a change that was attributable to increased association of dendritic Kv4 potassium channels with auxiliary KChIP subunits. This association was negatively modulated by TrkB receptor signaling. Dendritic excitability of HD iSPNs was rescued by knocking-down expression of Kv4 channels, by disrupting KChIP binding, by restoring TrkB receptor signaling or by lowering mutant-Htt (mHtt) levels with a zinc finger protein. Collectively, these studies demonstrate that mHtt induces reversible alterations in the dendritic excitability of iSPNs that could contribute to the motor symptoms of HD.


Assuntos
Corpo Estriado/patologia , Proteína Huntingtina/metabolismo , Doença de Huntington/patologia , Doença de Huntington/fisiopatologia , Proteínas Mutantes/metabolismo , Neurônios/metabolismo , Canais de Potássio Shal/metabolismo , Animais , Modelos Animais de Doenças , Proteína Huntingtina/genética , Camundongos , Proteínas Mutantes/genética
15.
J Neuroinflammation ; 16(1): 91, 2019 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-30995916

RESUMO

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.


Assuntos
Corpo Estriado/enzimologia , Corpo Estriado/patologia , Inflamação/enzimologia , Inflamação/patologia , NADPH Oxidase 2/metabolismo , Animais , Corpo Estriado/imunologia , Progressão da Doença , Ácido Glutâmico/toxicidade , Inflamação/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
16.
Biosens Bioelectron ; 135: 111-119, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-31004921

RESUMO

The detection of Cu2+ ion, one of the metal ions substantial in cerebral physiology, is critical in studying brain activities and understanding brain functions. However, repetitive measurements of Cu2+ in the progress of physiological and pathological events is still challenging, because lack of the platform for repetitive on-line detection-regeneration cycle. Herein we report the design of a regenerated electrochemical biosensor combined with the in vivo microdialysis system. In this biosensor, hyperbranched polyethyleneimine (hPEI) acts as a regenerated recognition unit for Cu2+. Just by a simple rinse of ethylenediaminetetraacetic acid (EDTA) disodium salt, the Cu2+ and Cu+ ions on the biosensor interface were chelated with EDTA disodium salt, thus achieving the regeneration of the biosensor. In addition, 6-(ferrocenyl)hexanethiol (FcHT) serves as the inner reference moiety to elevate the sensing accuracy over regeneration cycles. As a result, this ratiometric electrochemical biosensor not only revealed high sensitivity and selectivity, but also exhibited excellent stability during multiple regeneration processing. This biosensor was capable of determining Cu2+ with a linear range between 0.05 and 12 µM and low detection limit (LOD) of 13 nM. Then, the platform has been successfully applied in repetitive Cu2+ analysis in rat brain under global cerebral ischemia/reperfusion events. The combination of results from 7 rats indicates global cerebral ischemia caused an obvious increase of the Cu2+ level, while reperfusion brought this level back to normal.


Assuntos
Isquemia Encefálica/patologia , Cobre/análise , Corpo Estriado/patologia , Animais , Técnicas Biossensoriais/métodos , Cátions Bivalentes/análise , Corpo Estriado/química , Técnicas Eletroquímicas/métodos , Masculino , Ratos Sprague-Dawley , Traumatismo por Reperfusão/patologia
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.
Mol Neurobiol ; 56(10): 7003-7021, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30968343

RESUMO

Multiple systems atrophy (MSA) is a rare neurodegenerative disorder characterized by the accumulation of α-synuclein in glial cells and neurodegeneration in the striatum, substantia nigra, and cerebellum. Aberrant miRNA regulation has been associated with neurodegeneration, including alterations of specific miRNAs in brain tissue, serum, and cerebrospinal fluid from MSA patients. Still, a causal link between deregulation of miRNA networks and pathological changes in the transcriptome remains elusive. We profiled ~ 800 miRNAs in the striatum of MSA patients in comparison to healthy individuals to identify specific miRNAs altered in MSA. In addition, we performed a parallel screening of 700 transcripts associated with neurodegeneration to determine the impact of miRNA deregulation on the transcriptome. We identified 60 miRNAs with abnormal levels in MSA brains that are involved in extracellular matrix receptor interactions, prion disease, inflammation, ubiquitin-mediated proteolysis, and addiction pathways. Using the correlation between miRNA expression and the abundance of their known targets, miR-124-3p, miR-19a-3p, miR-27b-3p, and miR-29c-3p were identified as key regulators altered in MSA, mainly contributing to neuroinflammation. Finally, our study also uncovered a potential link between Alzheimer's disease (AD) and MSA pathologies that involves miRNAs and deregulation of BACE1. Our results provide a comprehensive appraisal of miRNA alterations in MSA and their effect on the striatal transcriptome, supporting that aberrant miRNA expression is highly correlated with changes in gene transcription associated with MSA neuropathology, in particular those driving inflammation, disrupting myelination, and potentially impacting α-synuclein accumulation via deregulation of autophagy and prion mechanisms.


Assuntos
Corpo Estriado/patologia , Redes Reguladoras de Genes , Inflamação/genética , MicroRNAs/genética , Atrofia de Múltiplos Sistemas/genética , RNA Mensageiro/genética , Autofagia/genética , Transporte Biológico , Regulação da Expressão Gênica , Humanos , Inflamação/patologia , MicroRNAs/metabolismo , Modelos Biológicos , Bainha de Mielina/genética , Degeneração Neural/genética , RNA Mensageiro/metabolismo , Transcriptoma/genética
19.
PLoS One ; 14(3): e0212738, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30849082

RESUMO

We aim to identify physiologic regulators of dopamine (DA) signaling in obesity but previously did not find a compelling relationship with insulin sensitivity measured by oral-minimal model (OMM) and DA subtype 2 and 3 receptor (D2/3R) binding potential (BPND). Reduced disposition index (DI), a ß-cell function metric that can also be calculated by OMM, was shown to predict a negative reward behavior that occurs in states of lower endogenous DA. We hypothesized that reduced DI would occur with higher D2/3R BPND, reflecting lower endogenous DA. Participants completed PET scanning, with a displaceable radioligand to measure D2/3R BPND, and a 5-hour oral glucose tolerance test to measure DI by OMM. We studied 26 age-similar females without (n = 8) and with obesity (n = 18) (22 vs 39 kg/m2). Reduced DI predicted increased striatal D2/3R BPND independent of BMI. By accounting for ß-cell function, we were able to determine that the state of insulin and glucose metabolism is pertinent to striatal D2/3R BPND in obesity. Clinical Trial Registration Number: NCT00802204.


Assuntos
Corpo Estriado , Células Secretoras de Insulina/metabolismo , Obesidade , Tomografia por Emissão de Pósitrons , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Adulto , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Dopamina/metabolismo , Feminino , Humanos , Células Secretoras de Insulina/patologia , Pessoa de Meia-Idade , Obesidade/diagnóstico por imagem , Obesidade/metabolismo , Obesidade/patologia
20.
Biomed Res Int ; 2019: 4379639, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30834264

RESUMO

Objective: To study the protective effect of Echinacoside for 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced dopaminergic (DA) neurons injury in the subacute mouse model of Parkinson's disease (PD) and to explore its mechanism of action. Methods: We chose 10 weeks of healthy wild type C57BL/6 male mice, hypodermic MPTP 30 mg/kg/day, five days, to prepare PD subacute mouse model. Behavior indexes of open field test and pole test were applied to examine the function of ECH to PD subacute mice model of PD sample action. The effects of ECH on dopaminergic neurons and astrocyte were examined using Immunohistochemistry including tyrosine hydroxylase (TH) and glial fibrillary acidic protein (GFAP) expression. The total numbers of TH-positive neurons and GFAP-positive cells in the substantia nigra pars compacts (SNpc) and ventral tegmental area (VTA) were obtained stereologically using the optical fractionator method. Enzyme-linked immunosorbent assay (ELISA) method was used to detect the inflammatory cytokines in the serum, including TNF-α (Ttumor necrosis factor alpha) and IFN-γ (interferon gamma). Protein expressions of ionized calcium binding adaptor molecule 1 (IBA-1), TNF-α, Cleaved caspase-3, glial derived neurotrophic factor (GDNF), and phosphorylated and total extracellular signal-regulated kinase (p-ERK and ERK) in the anatomical region of substantia nigra (SN) were tested by protein immunoblot method (i.e., Western blotting). Results: ECH reversed the reduction of total distance in open field test in MPTP-induced PD model mice (P < 0.01), shortened the return time and total time of PD subacute model mice in pole test (P < 0.01, P < 0.05), significantly reversed the reduction of TH positive neurons induced by MPTP (P < 0.05), and reduced the activation of astrocytes (P < 0.05). Meanwhile, ECH significantly inhibited the expression of IBA-1, Cleaved caspase-3, and TNF-α in midbrain of MPTP model mice (P < 0.05, P < 0.05, and P < 0.05) and upregulated the expression of GDNF (P < 0.05). And ECH lowered the level of TNF-α and IFN-γ in serum (P < 0.05, P < 0.05). Conclusion: ECH has protective effects on the MPTP subacute model mice, its mechanism may be through inhibiting activation of microglia and astrocytes, reducing inflammatory reaction and promoting the secretion of neurotrophic factors, and eventually resulting in the reduction of the DA neurons apoptosis.


Assuntos
Glicosídeos/administração & dosagem , Intoxicação por MPTP/tratamento farmacológico , Fármacos Neuroprotetores/administração & dosagem , Doença de Parkinson/tratamento farmacológico , Animais , Proteínas de Ligação ao Cálcio/genética , Caspase 3/genética , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/patologia , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/genética , Humanos , Imuno-Histoquímica , Intoxicação por MPTP/genética , Intoxicação por MPTP/patologia , Camundongos , Proteínas dos Microfilamentos/genética , Microglia/efeitos dos fármacos , Microglia/patologia , Doença de Parkinson/genética , Doença de Parkinson/patologia , Substância Negra/efeitos dos fármacos , Substância Negra/patologia , Fator de Necrose Tumoral alfa/genética , Tirosina 3-Mono-Oxigenase/genética
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