RESUMO
Neurons in the subthalamic nucleus (STN) become hyperactive following nerve injury and promote pain-related responses in mice. Considering that the anterior cingulate cortex (ACC) is involved in pain and emotion processing and projects to the STN, we hypothesize that ACC neurons may contribute to hyperactivity in STN neurons in chronic pain. In the present study, we showed that ACC neurons enhanced activity in response to noxious stimuli and to alterations in emotional states and became hyperactive in chronic pain state established by spared nerve injury of the sciatic nerve (SNI) in mice. In naïve mice, STN neurons were activated by noxious stimuli, but not by alterations in emotional states. Pain responses in STN neurons were attenuated in both naïve and SNI mice when ACC neurons were inhibited. Furthermore, optogenetic activation of the ACC-STN pathway induced bilateral hyperalgesia and depression-like behaviors in naive mice; conversely, inhibition of this pathway is sufficient to attenuate hyperalgesia and depression-like behaviors in SNI mice and naïve mice subjected to stimulation of STN neurons. Finally, mitigation of pain-like and depression-like behaviors in SNI mice by inhibition of the ACC-STN projection was eliminated by activation of STN neurons. Our results demonstrate that hyperactivity in the ACC-STN pathway may be an important pathophysiology in comorbid chronic pain and depression. Thus, the ACC-STN pathway may be an intervention target for the treatment of the comorbid chronic pain and depression.
Assuntos
Dor Crônica , Camundongos , Masculino , Animais , Giro do Cíngulo/fisiologia , Hiperalgesia , Depressão , Neurônios/fisiologiaRESUMO
The comorbidity of chronic pain and depression poses tremendous challenges for the treatment of either one because they exacerbate each other with unknown mechanisms. As the posterior insular cortex (PIC) integrates multiple somatosensory and emotional information and is implicated in either chronic pain or depression, we hypothesize that the PIC and its projections may contribute to the pathophysiology of comorbid chronic pain and depression. We show that PIC neurons were readily activated by mechanical, thermal, aversive, and stressful and appetitive stimulation in naive and neuropathic pain male mice subjected to spared nerve injury (SNI). Optogenetic activation of PIC neurons induced hyperalgesia and conditioned place aversion in naive mice, whereas inhibition of these neurons led to analgesia, conditioned place preference (CPP), and antidepressant effect in both naive and SNI mice. Combining neuronal tracing, optogenetics, and electrophysiological techniques, we found that the monosynaptic glutamatergic projections from the PIC to the basolateral amygdala (BLA) and the ventromedial nucleus (VM) of the thalamus mimicked PIC neurons in pain modulation in naive mice; in SNI mice, both projections were enhanced accompanied by hyperactivity of PIC, BLA, and VM neurons and inhibition of these projections led to analgesia, CPP, and antidepressant-like effect. The present study suggests that potentiation of the PICâBLA and PICâVM projections may be important pathophysiological bases for hyperalgesia and depression-like behavior in neuropathic pain and reversing the potentiation may be a promising therapeutic strategy for comorbid chronic pain and depression.
Assuntos
Dor Crônica , Neuralgia , Camundongos , Masculino , Animais , Hiperalgesia , Dor Crônica/complicações , Depressão , Córtex Insular , Tonsila do Cerebelo/metabolismo , Neuralgia/metabolismo , Comorbidade , Tálamo , Antidepressivos/uso terapêuticoRESUMO
BACKGROUND: Central pontine myelinolysis (CPM) is a rare demyelinating disorder caused by the loss of myelin in the center of the basis pontis. CPM typically occurs with rapid correction of severe chronic hyponatremia and subsequent disturbances in serum osmolality. Although hyperglycaemia is recognized as a pathogenetic factor in serum osmolality fluctuations, CPM is rarely seen in the context of diabetes. CASE PRESENTATION: A 66-year-old Chinese male presented with a history of gait imbalance, mild slurred speech and dysphagia for two weeks. MRI showed the mass lesions in the brainstem, and laboratory examinations showed high blood glucose and HbA1c, as well as increased serum osmolality. The patient was diagnosed with CPM secondary to hyperosmolar hyperglyceamia and received insulin treatment as well as supportive therapy. After six weeks of followup, the patient had fully recovered to a normal state. CONCLUSION: CPM is a potentially fatal neurological condition and can occur in uncontrolled diabetes mellitus. Early diagnosis and timely treatment are crucial for improving the prognosis.
Assuntos
Hiperglicemia , Hiponatremia , Mielinólise Central da Ponte , Masculino , Humanos , Idoso , Mielinólise Central da Ponte/diagnóstico por imagem , Mielinólise Central da Ponte/etiologia , Hiperglicemia/complicações , Imageamento por Ressonância MagnéticaRESUMO
Excessive self-grooming is an important behavioral phenotype of the stress response in rodents. Elucidating the neural circuit that regulates stress-induced self-grooming may suggest potential treatment to prevent maladaptation to stress that is implicated in emotional disorders. Stimulation of the subthalamic nucleus (STN) has been found to induce strong self-grooming. In this study we investigated the role of the STN and a related neural circuit in mouse stress-related self-grooming. Body-restraint and foot-shock stress-induced self-grooming models were established in mice. We showed that both body restraint and foot shock markedly increased the expression of c-Fos in neurons in the STN and lateral parabrachial nucleus (LPB). Consistent with this, the activity of STN neurons and LPB glutamatergic (Glu) neurons, as assessed with fiber photometry recording, was dramatically elevated during self-grooming in the stressed mice. Using whole-cell patch-clamp recordings in parasagittal brain slices, we identified a monosynaptic projection from STN neurons to LPB Glu neurons that regulates stress-induced self-grooming in mice. Enhanced self-grooming induced by optogenetic activation of the STN-LPB Glu pathway was attenuated by treatment with fluoxetine (18 mg·kg-1·d-1, p.o., for 2 weeks) or in the presence of a cage mate. Furthermore, optogenetic inhibition of the STN-LPB pathway attenuated stress-related but not natural self-grooming. Taken together, these results suggest that the STN-LPB pathway regulates the acute stress response and is a potential target for intervention in stress-related emotional disorders.
Assuntos
Núcleo Subtalâmico , Camundongos , Animais , Asseio Animal , Núcleo Subtalâmico/fisiologia , Neurônios/fisiologiaRESUMO
Purpose: To study the underlying molecular mechanisms of p53 in the mitochondrial dysfunction and the pathogenesis of Parkinson's disease (PD), and provide a potential therapeutic target for PD treatment.Methods: We review the contributions of p53 to mitochondrial changes leading to apoptosis and the subsequent degeneration of dopaminergic neurons in PD.Results: P53 is a multifunctional protein implicated in the regulation of diverse cellular processes via transcription-dependent and transcription-independent mechanisms. Mitochondria are vital subcellular organelles for that maintain cellular function, and mitochondrial defect and impairment are primary causes of dopaminergic neuron degeneration in PD. Increasing evidence has revealed that mitochondrial dysfunction-associated dopaminergic neuron degeneration is tightly regulated by p53 in PD pathogenesis. Neurodegenerative stress triggers p53 activation, which induces mitochondrial changes, including transmembrane permeability, reactive oxygen species production, Ca2+ overload, electron transport chain defects and other dynamic alterations, and these changes contribute to neurodegeneration and are linked closely with PD occurrence and development. P53 inhibition has been shown to attenuate mitochondrial dysfunction and protect dopaminergic neurons from degeneration under conditions of neurodegenerative stress.Conclusions: p53 appears to be a potential target for neuroprotective therapy of PD.
RESUMO
The basal ganglia including the subthalamic nucleus (STN) and substantia nigra pars reticulata (SNr) are involved in pain-related responses, but how they regulate pain processing remains unknown. Here, we identify a pathway, consisting of GABAergic neurons in the SNr (SNrGABA) and glutamatergic neurons in the STN (STNGlu) and the lateral parabrachial nucleus (LPBGlu), that modulates acute and persistent pain states in both male and female mice. The activity of STN neurons was enhanced in acute and persistent pain states. This enhancement was accompanied by hypoactivity in SNrGABA neurons and strengthening of the STN-LPB glutamatergic projection. Reversing the dysfunction in the SNrGABA-STNGlu-LPBGlu pathway attenuated activity of LPBGlu neurons and mitigated pain-like behaviors. Therefore, the SNrGABA-STNGlu-LPBGlu pathway regulates pathological pain and is a potential target for pain management.
Assuntos
Neurônios GABAérgicos , Substância Negra , Masculino , Feminino , Camundongos , Animais , Substância Negra/metabolismo , Estimulação Elétrica , Neurônios GABAérgicos/metabolismo , Ácido gama-Aminobutírico/metabolismo , Dor/metabolismoRESUMO
OBJECTIVE: To understand the satisfaction level and it's related factors of urban residents towards community-based preventive and health care service in Beijing. METHODS: The community-based preventive and health care services were sorted as child immunization program, infectious disease prevention and control, and pregnant and maternal care. Based on the proportion of three categories service recipients accounted for the total number. A total of 431 service recipients were randomly and proportionally sampled from registered names. Then the service satisfaction household survey was carried out with standard questionnaire, and non-conditional logistic regression was conducted on the analysis of satisfaction and its related factors. RESULTS: General satisfaction score was 3.93, with the satisfaction ratio of 71.9% (310/431). The satisfaction level of child immunization program and pregnant and maternal care was high, but that of infectious disease prevention and control was lower among three categories service recipients, with the satisfaction score of 3.99, 3.96 and 3.79, and the satisfaction ratio of 75.7% (165/218), 76.2% (77/101) and 60.7% (68/112) respectively. Initial impression (OR = 7.9, P = 0.008), service convenience (OR = 11.0, P<0.01), environment (OR = 23.4, P<0.01), skill (OR = 29.5, P<0.01), attitude (OR = 6.6, P = 0.020), privacy respect (OR = 88.1, P<0.01), equipment (OR = 25.7, P<0.01) and price (OR = 4.4, P = 0.013 ) were influencing factors. CONCLUSION: The general satisfaction should be considered high. While the apparatus and equipment should be renewed, the service environment should be improved. The service skill and attitude should improve more, and the residents' privacy should be respected. The preventive and health care services of infectious disease prevention and control should be strengthened.
Assuntos
Serviços de Saúde Comunitária , Comportamento do Consumidor , Garantia da Qualidade dos Cuidados de Saúde , China , Humanos , Inquéritos e Questionários , População UrbanaRESUMO
Mitochondria are important organelles in virtually all eukaryotic cells, and are involved in a wide range of physiological and pathophysiological processes. Besides the generation of cellular energy in the form of adenosine triphosphate, mitochondria are also involved in calcium homeostasis, reactive oxygen species production and the activation of the intrinsic cell death pathway, thus determining cell survival and death. Mitochondrial abnormalities have been implicated in a wide range of disorders, including neurodegenerative disease such as Parkinson's disease (PD), and considered as a primary cause and central event responsible for the progressive loss of dopaminergic neurons in PD. Thus, reversion or attenuation of mitochondrial dysfunction should alleviate the severity or progression of the disease. The present review systematically summarizes the possible mechanisms associated with mitochondriamediated dopaminergic neuron damage in PD, in an attempt to elucidate the requirement for further studies for the development of effective PD treatments.
Assuntos
Neurônios Dopaminérgicos/metabolismo , Mitocôndrias/genética , Doença de Parkinson/genética , Cálcio/metabolismo , Morte Celular/genética , Neurônios Dopaminérgicos/patologia , Humanos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/genéticaRESUMO
Oxidative stress appears to be a central event responsible for the degeneration of dopaminergic neurons in Parkinson's disease (PD). 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine or its toxic metabolite 1methyl4phenylpyridinium (MPP+) are classical widelyused pharmacological and toxic agents to model PD; they cause the production of reactive oxygen species by inhibiting mitochondrial complex I, leading to DNA oxidative damage and subsequent neuronal death. Previous findings have suggested that proliferating cell nuclear antigen (PCNA), a critical regulatory protein for DNA repair, is involved in dopaminergic neuron damage in the MPP+induced PD model. The naturally occurring dithiol compound, αlipoic acid (ALA) has been reported to provide neuroprotection in in vitro models of PD. The molecular mechanism by which ALA reduces neuronal death in PD remains to be fully elucidated. The present study aimed to analyze the ability of ALA to protect neuronal PC12 cells from the toxicity induced by MPP+, and the molecular mechanism underlying these actions using MTT and lactate dehydrogenase cytotoxicity assays, Hoechst 33258 staining and western blot analysis. The results demonstrated that ALA efficiently increased the production of PCNA in MPP+treated PC12 cells. Accordingly, ALA treatment attenuated MPP+induced toxicity in the PC12 cells, and reduced cell apoptosis. The increase in the expression levels of PCNA by ALA in the MPP+treated PC12 cells appeared to be mediated by repression of the p53 protein, as the expression of p53 was increased by MPP+treatment and reduced by ALA. Taken together, these results indicated that ALA protected dopaminergic neurons against MPP+induced neurotoxicity through its ability to upregulate the DNA repair protein, PCNA, via the P53 pathway.
Assuntos
Fármacos Neuroprotetores/administração & dosagem , Doença de Parkinson Secundária/tratamento farmacológico , Antígeno Nuclear de Célula em Proliferação/genética , Ácido Tióctico/administração & dosagem , Proteína Supressora de Tumor p53/genética , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/efeitos adversos , Animais , Modelos Animais de Doenças , Complexo I de Transporte de Elétrons/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Intoxicação por MPTP , Neurônios/efeitos dos fármacos , Neurônios/patologia , Estresse Oxidativo/efeitos dos fármacos , Células PC12 , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/genética , Antígeno Nuclear de Célula em Proliferação/biossíntese , Ratos , Espécies Reativas de Oxigênio/metabolismo , Proteína Supressora de Tumor p53/biossínteseRESUMO
Endothelial dysfunction and injury are central events in the pathogenesis of ischemic vascular disorders. Endothelial progenitor cells (EPCs) are mobilized from the bone marrow into the peripheral circulation, where they locate to sites of injured endothelium and are involved in endothelial repair and vascular regeneration. During these processes, EPCs are exposed to oxidative stress, a crucial pathological condition, which occurs during vascular injury and limits the efficacy of EPCs in the repair of injured endothelium. Statins are effective inhibitors of 3hydroxy3methylglutaryl coenzyme A reductase, and are commonly used to manage and prevent ischemic vascular disease by reducing plasma cholesterol levels. In addition to lowering cholesterol, statins have also been reported to exert pleiotropic actions, including antiinflammatory and antioxidative activities. The present study aimed to investigate the ability of atorvastatin to protect endothelial colonyforming cells (ECFCs), a homogeneous subtype of EPCs, from hydrogen peroxide (H2O2)induced oxidative damage, and to determine the mechanism underlying this protective action. MTT assay, acridine orange/ethidium bromide staining, reactive oxygen species assay, western blot analysis and tube formation assay were employed. The results demonstrated that H2O2 induced cell death and decreased the tubeforming ability of the ECFCs, in a concentrationdependent manner; however, these effects were partially attenuated following administration of atorvastatin. The reversion of the quantitative and qualitative impairment of the H2O2treated ECFCs appeared to be mediated by the regulation of annexin A2, as the expression levels of annexin A2 were decreased following treatment with H2O2 and increased following treatment with atorvastatin. These results indicated that annexin A2 may be involved in the H2O2induced damage of ECFCs, and in the protective activities of atorvastatin in response to oxidative stress.