RESUMO
Depression is one of the common non-motor symptoms of Parkinson's disease (PD). In the clinic, botulinum neurotoxin A (BoNT/A) has been used to treat depression. In this study, we investigated the mechanisms underlying the anti-depressive effect of BoNT/A in a PD mouse model. Mice were administered reserpine (3 µg/mL in the drinking water) for 10 weeks. From the 10th week, BoNT/A (10 U·kg-1·d-1) was injected into the cheek for 3 consecutive days. We showed that chronic administration of reserpine produced the behavioral phenotypes of depression and neurochemical changes in the substantia nigra pars compacta (SNpc) and striatum. BoNT/A treatment significantly ameliorated the depressive-like behaviors, but did not improve TH activity in SNpc of reserpine-treated mice. We demonstrated that BoNT/A treatment reversed reserpine-induced complement and microglia activation in the hippocampal CA1 region. Furthermore, BoNT/A treatment significantly attenuated the microglial engulfment of presynaptic synapses, thus ameliorating the apparent synapse and spine loss in the hippocampus in the reserpine-treated mice. Moreover, BoNT/A treatment suppressed microglia-mediated expression of pro-inflammatory cytokines TNF-α and IL-1ß in reserpine-treated mice. In addition, we showed that BoNT/A (0.1 U/mL) ameliorated reserpine-induced complement and microglia activation in mouse BV2 microglial cells in vitro. We conclude that BoNT/A ameliorates depressive-like behavior in a reserpine-induced PD mouse model through reversing the synapse loss mediated by classical complement induced-microglial engulfment as well as alleviating microglia-mediated proinflammatory responses. BoNT/A ameliorates depressive-like behavior, and reverses synapse loss mediated by classical complement pathway-initiated microglia engulfment as well as alleviates microglia-mediated proinflammatory response in the reserpine-induced Parkinson's disease mouse model.
Assuntos
Toxinas Botulínicas Tipo A , Doença de Parkinson , Camundongos , Animais , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Microglia/metabolismo , Toxinas Botulínicas Tipo A/metabolismo , Toxinas Botulínicas Tipo A/farmacologia , Reserpina/metabolismo , Reserpina/farmacologia , Doenças Neuroinflamatórias , Modelos Animais de Doenças , Hipocampo/metabolismo , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: Rigidity is one of the major manifestations of Parkinson's disease (PD), but no quantitative and objective imaging method has been developed to measure rigidity. Ultrasound shear wave elastography (SWE) can reflect the stiffness of tissue by providing a quantitative index. Thus, we conducted this study to evaluate the potential clinical value of SWE in assessing rigidity in PD. METHODS: A total of 63 subjects (44 patients with rigidity-dominant PD and 19 right-dominant-hand normal controls with matched age) were enrolled, and each underwent ultrasound SWE testing. The tests were conducted on the brachioradialis (BR) and biceps brachii (BB) on the more affected side in patients with PD and on the right side in normal controls. Differences in quantitative shear wave velocity (SWV) between patients with PD and normal controls were determined. The relationship of muscle SWV with joint rigidity, UPDRSIII, disease duration, sex, and age in patients with PD was analyzed. The intraclass correlation coefficient (ICC) was used to evaluate the reliability of SWE in assessing muscle stiffness in patients with PD. RESULTS: The mean SWVs of the BB and BR were higher in the PD group (3.65±0.46 and 4.62±0.89 m/s, respectively) than in normal controls (2.79±0.37 and 3.26±0.40 m/s, respectively). Stiffness in BR and BB was correlated with the upper-limb joint rigidity, UPDRSIII, and disease duration but not with sex or age in the PD group. The intraobserver correlation coefficients (ICCs) for interobserver and intraobserver variations in measuring SWV were 0.85 (95% confidence interval 0.56-0.95) and 0.85 (95% confidence interval 0.58-0.95), respectively, for BR and 0.90 (95% confidence interval 0.73-0.97) and 0.86 (95% confidence interval 0.61-0.95), respectively, for BB. CONCLUSIONS: SWV is associated with joint rigidity and disease duration, indicating that SWE can be potentially used as an objective and quantitative tool for evaluating rigidity.
Assuntos
Técnicas de Imagem por Elasticidade , Doença de Parkinson , Humanos , Músculo Esquelético/diagnóstico por imagem , Doença de Parkinson/diagnóstico por imagem , Reprodutibilidade dos Testes , Extremidade Superior/diagnóstico por imagemRESUMO
OBJECTIVES: In this study, we investigated the possible analgesic effects of Botulinum toxin type A (BoNT/A) on trigeminal neuralgia (TN). A modified TN mouse model was established by chronic constriction injury of the distal infraorbital nerve (dIoN-CCI) in mice, and the possible roles of microglia toll-like receptor 2 (TLR2) and neuroinflammation was investigated. METHODS: Male C57BL/6 mice were divided into 3 groups, including sham group, vehicle-treated TN group and BoNT/A-treated TN group. Bilateral mechanical pain hypersensitivity, anxiety-like and depressive-like behaviors were evaluated by using von Frey test, open field, elevated plus-maze testing, and forced swimming test in mice, respectively. The mRNA or protein expression levels of toll-like receptors (TLRs), glia activation markers and proinflammatory factors in the trigeminal nucleus caudalis (TNC) were tested by RT-qPCR, immunofluorescence and Western blotting. We also tested the pain behaviors of TN in Tlr2-/- mice. RESULTS: We found that unilateral subcutaneous injection of BoNT/A into the whisker pad on the ipsilateral side of dIoN-CCI mice significantly attenuated bilateral mechanical pain hypersensitivity and anxiety-like behaviors induced by dIoN-CCI surgery in mice. The dIoN-CCI surgery significantly up-regulated the expression of TLR2, MyD88, CD11b (a microglia marker), IL-1ß, TNF-α and IL-6 in the ipsilateral TNC in mice, and BoNT/A injection significantly inhibited the expression of these factors. Immunostaining results confirmed that BoNT/A injection significantly inhibited the microglia activation in the ipsilateral TNC in dIoN-CCI mice. TLR2 deficiency also alleviated bilateral mechanical pain hypersensitivity and the up-regulation of MyD88 expression in the TNC of dIoN-CCI mice. CONCLUSION: These results indicate that unilateral injection of BoNT/A attenuated bilateral mechanical pain hypersensitivity and anxiety-like behaviors in dIoN-CCI mice, and the analgesic effects of BoNT/A may be associated with the inhibition of TLR2-mediated neuroinflammation in the TNC.
Assuntos
Toxinas Botulínicas Tipo A , Neuralgia , Neuralgia do Trigêmeo , Animais , Ansiedade/tratamento farmacológico , Toxinas Botulínicas Tipo A/uso terapêutico , Hiperalgesia/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neuralgia/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Receptor 2 Toll-Like/genética , Neuralgia do Trigêmeo/tratamento farmacológicoRESUMO
Diabetic retinopathy (DR) is a leading cause of acquired blindness among adults. High glucose (HG) induces oxidative injury and apoptosis in retinal ganglion cells (RGCs), serving as a primary pathological mechanism of DR. MIND4-17 activates nuclear-factor-E2-related factor 2 (Nrf2) signaling via modifying one cysteine (C151) residue of Kelch-like ECH-associated protein 1 (Keap1). The current study tested its effect in HG-treated primary murine RGCs. We show that MIND4-17 disrupted Keap1-Nrf2 association, leading to Nrf2 protein stabilization and nuclear translocation, causing subsequent expression of key Nrf2 target genes, including heme oxygenase-1 and NAD(P)H quinone oxidoreductase 1. Functional studies showed that MIND4-17 pretreatment significantly inhibited HG-induced cytotoxicity and apoptosis in primary murine RGCs. Reactive oxygen species production and oxidative injury in HG-treated murine RGCs were attenuated by MIND4-17. Nrf2 silencing (by targeted small interfering RNA) or knockout (by CRISPR/Cas9 method) abolished MIND4-17-induced RGC cytoprotection against HG. Additionally, Keap1 knockout or silencing mimicked and abolished MIND4-17-induced activity in RGCs. In vivo, MIND4-17 intravitreal injection activated Nrf2 signaling and attenuated retinal dysfunction by light damage in mice. We conclude that MIND4-17 activates Nrf2 signaling to protect murine RGCs from HG-induced oxidative injury.
Assuntos
Glucose/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/metabolismo , Tiazóis/farmacologia , Animais , Sistemas CRISPR-Cas , Células Cultivadas , Retinopatia Diabética/genética , Retinopatia Diabética/metabolismo , Retinopatia Diabética/patologia , Técnicas de Inativação de Genes , Glucose/toxicidade , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/antagonistas & inibidores , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo/efeitos dos fármacos , Células Ganglionares da Retina/patologia , Transdução de Sinais/efeitos dos fármacosRESUMO
In pathogenesis of Parkinson's disease (PD), mitochondrial dysfunction causes substantial reactive oxygen species (ROS) production and oxidative stress, leading to dopaminergic (DA) neuronal cell death. Mitochondrial toxins, including MPP+ (1-methyl-4-phenylpyridinium ion) and rotenone, induce oxidative injury in cultured DA neuronal cells. The current study tested the potential effect of SC79, a first-in-class small-molecule Akt activator, against the process. In SH-SY5Y cells and primary murine DA neurons, SC79 significantly attenuated MPP+- and rotenone-induced viability reduction, cell death, and apoptosis. SC79 activated Akt signaling in DA neuronal cells. Akt inhibition (by LY294002 and MK-2206) or CRISPR-Cas9-mediated Akt1 knockout completely abolished SC79-induced DA neuroprotection against MPP+. Further studies demonstrated that SC79 attenuated MPP+- and rotenone-induced ROS production, mitochondrial depolarization, and lipid peroxidation in SH-SY5Y cells and primary DA neurons. Moreover, upregulation of Nrf2-dependent genes (HO1 and NQO1) and Nrf2 protein stabilization were detected in SC79-treated SH-SY5Y cells and primary DA neurons. Together we show that SC79 protects DA neuronal cells from mitochondrial toxins possibly via activation of Akt-Nrf2 signaling.
Assuntos
1-Metil-4-fenilpiridínio/toxicidade , Acetatos/farmacologia , Benzopiranos/farmacologia , Neurônios Dopaminérgicos/patologia , Ativadores de Enzimas/farmacologia , Fármacos Neuroprotetores/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Rotenona/toxicidade , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Neurônios Dopaminérgicos/efeitos dos fármacos , Humanos , Camundongos Endogâmicos C57BL , Neuroproteção/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacosRESUMO
Recently, Parkinson's disease (PD) has been classified into three subtypes: postural instability gait difficulty (PIGD), tremor dominate (TD), and indeterminate PD. Transcranial sonography (TCS) is considered to be an important tool to diagnose PD. However, it is uncertain that whether there are differences in TCS image characteristics in different PD subtypes, so 373 idiopathic PD (188 PIGD, 108 TD, 77 indeterminate PD) were registered and received TCS in our investigation; also, the association between clinical characteristics and TCS results in different PD subtypes was analyzed. In accordance with several previous studies, we detected substantia nigra (SN) by TCS in 85.4% of patients with idiopathic PD; we concluded that PIGD patients had more serious disease than TD and indeterminate PD group (p < 0.05). They always had larger SN hyperechogenicity areas on TCS (p < 0.05), and we found that there was no correlation between SN hyperechogenicity and disease duration or severity (p > 0.05). Similarly, abnormal brainstem raphe signal was also more often in PIGD group than in TD and indeterminate PD group (p < 0.05), which might imply that PIGD group was vulnerable to suffer from depression in the future.
Assuntos
Encéfalo/diagnóstico por imagem , Ecoencefalografia , Doença de Parkinson/diagnóstico por imagem , Idoso , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/classificação , Índice de Gravidade de Doença , Fatores de TempoRESUMO
This study was conducted to investigate the role of different homocysteine metabolism-related vitamin (HMRV) levels in the correlation between hyperhomocysteinemia (HHCY) and ischemic stroke (IS) subtypes. Three hundred and forty-eight IS patients manifesting different vascular subtypes were subclassified on the basis of HMRV deficiencies. Correlation between HHCY and IS subtypes was investigated in all the subgroups. In this study, HHCY was significantly correlated with the IS subtypes in large artery atherosclerosis (OR 1.126, 95%CI: 1.051 ~ 1.206, P = 0.001) and small artery occlusion (OR 1.105, 95%CI: 1.023 ~ 1.193, P = 0.012). Subgroup analysis revealed a correlation between HHCY and IS subgroup (OR 1.201, 1.178, 95%CI: 1.081 ~ 1.334, 1.058 ~ 1.313, P = 0.001, P = 0.003, respectively) in HMRV deficiency, but not significantly with the IS subgroup in normal HMRV levels. Serum vitamin B12 concentrations are inversely correlated with both IS subtypes in HMRV deficiency subgroups (OR 0.992, 0.995, 95%CI: 0.987 ~ 0.996, 0.991 ~ 0.999, P < 0.001, P = 0.007, respectively), which may contribute to HHCY incidence in these populations. The correlation between HHCY and IS subtypes is affected by HMRV levels in this case-control study. Our findings are helpful to understand the inconsistency in prior homocysteine studies. Serum vitamin B12 levels may play a critical role in HHCY incidence in this Chinese population.Cerebrovascular disease has emerged as the leading cause of disability and mortality in both urban and rural areas of China (Neurology branch of Chinese Medical Association 2015). Ischemic stroke (IS) constitutes 60% to 80% of all cerebrovascular disease (Neurology branch of Chinese Medical Association 2014). Among a variety of risk factors, hyperhomocysteinemia (HHCY) has been closely correlated with IS due to intracranial small-vessel disease and extracranial large-artery disease (Selhub et al. 1995; Eikelboom et al. 2000; Alvarez et al. 2012; Jeon et al. 2014). However, the failure to lower homocysteine (HCY) via homocysteine metabolism-related vitamin (HMRV, including folic acid and vitamin B12 but not vitamin B6 in this study) supplementation to reduce stroke morbidity questions the role of HCY as a risk factor for stroke (Lonn et al. 2006; Hankey et al. 2010). Theoretically, HMRV supplementation merely lowers the incidence of stroke induced by HHCY resulting from HMRV deficiency, whereas HHCY-induced stroke concomitant with normal HMRV levels may be refractory to treatment. The correlation between HCY varying with HMRV levels and IS subtypes is still unclear. In this study, we investigated the impact of variation in HMRV levels on the correlation between HHCY and IS subtypes in 348 acute IS patients with large and small vessel diseases. We sought to determine the factors underlying the conflicting results associated with lowering HCY by HMRV supplementation to reduce stroke incidence.
Assuntos
Ácido Fólico/sangue , Homocisteína/sangue , Hiper-Homocisteinemia/sangue , Arteriosclerose Intracraniana/sangue , Rim/fisiologia , Acidente Vascular Cerebral/sangue , Vitamina B 12/sangue , Idoso , Idoso de 80 Anos ou mais , Povo Asiático , Estudos de Casos e Controles , Transtornos Cerebrovasculares/sangue , Transtornos Cerebrovasculares/diagnóstico por imagem , Transtornos Cerebrovasculares/epidemiologia , China/epidemiologia , Feminino , Humanos , Hiper-Homocisteinemia/diagnóstico por imagem , Hiper-Homocisteinemia/epidemiologia , Arteriosclerose Intracraniana/diagnóstico por imagem , Arteriosclerose Intracraniana/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/epidemiologiaRESUMO
The purpose of our study was to assess the alteration of the brainstem raphe (BR) on transcranial sonography (TCS) in depression patients with or without Parkinson's disease (PD) and to explore whether the different changes of BR could reflect an increasing impairment of raphe structures. TCS was performed in patients with PD, depression with PD, depression only, and controls. Using the red nucleus as an internal standard, the BR was rated semi-quantitatively from grades 1-4 with grades 1-3 determined as abnormal. The rate of abnormal BR (≤grade 3) was found to be only 10 % in patients with PD (4/40) and 5 % in control patients (2/40). The rate of abnormal raphe was significantly higher (p < 0.05) in patients with both depression and PD (85 %, 34/40) or patients with depression only (87.5 %, 35/40). TCS of the raphe in most patients with mild depression scored grade 3, while those with moderate depression scored grade 2-3, and those with severe depression scored grade 1. The different BR echogenicity score reflected an increasing impairment of raphe structures in depression patients with or without PD (p < 0.05). TCS provides a good tool for assessing depression, more severe depressive symptoms were associated with different aspects in TCS studies.
Assuntos
Transtorno Depressivo/complicações , Transtorno Depressivo/diagnóstico por imagem , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico por imagem , Núcleos da Rafe/diagnóstico por imagem , Ecoencefalografia , Feminino , Humanos , Pacientes Internados , Masculino , Pessoa de Meia-Idade , Pacientes Ambulatoriais , Escalas de Graduação Psiquiátrica , Núcleo Rubro/diagnóstico por imagem , Índice de Gravidade de DoençaRESUMO
OBJECTIVE: We investigated the relationship between serum cystatin C (CysC) levels and cognitive dysfunction and disease progression in patients with Parkinson disease. BACKGROUND: Previous studies have reported altered CysC levels in neurodegenerative disorders, but only a few studies have explored the role of CysC and its relationship to cognitive dysfunction in Parkinson disease. METHODS: We measured serum levels of CysC, creatinine, urea, and uric acid in 142 patients with Parkinson disease and 146 healthy controls. We assessed disease progression using the Hoehn and Yahr scale, and cognitive function using the Montreal Cognitive Assessment (Beijing version). RESULTS: The patients with Parkinson disease had significantly higher CysC levels than the controls (P<0.001). CysC level correlated significantly with age (r=0.494, P<0.001), sex (r=0.150, P=0.011), and serum creatinine level (r=0.377, P<0.001), but not with levels of urea or uric acid (P>0.05). CysC level was a significant independent predictor of Parkinson disease (odds ratio=23.143, 95% confidence interval: 5.485-97.648, P<0.001) in multivariate logistic regression analysis. In the Parkinson disease group, a higher CysC level was associated with a more advanced Hoehn and Yahr stage (r=0.098, P<0.05) and a lower Montreal Cognitive Assessment score (r=-0.381, P=0.003). CONCLUSIONS: Serum CysC levels can predict disease severity and cognitive dysfunction in patients with Parkinson disease. The exact role of CysC remains to be determined.
Assuntos
Disfunção Cognitiva/sangue , Cistatina C/sangue , Progressão da Doença , Doença de Parkinson/sangue , Índice de Gravidade de Doença , Idoso , Disfunção Cognitiva/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/complicaçõesRESUMO
In the present study, we investigated whether restoring descending noradrenergic inhibitory tone can attenuate pain in a PD rat model, which was established by stereotaxic infusion of 6-hydroxydopamine (6-OHDA) into the bilateral striatum (CPu). PD rats developed thermal and mechanical hypersensitivity at the 4th week after surgery. HPLC analysis showed that NE content, but not dopamine or 5-HT, significantly decreased in lumbar spinal cord in PD rats. Additional noradrenergic depletion by injection of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) aggravated pain hypersensitivity in PD rats. At the 5th week after injection of 6-OHDA, systemic treatment with pharmacological norepinephrine (NE) precursor droxidopa (L-DOPS) or α2 adrenoceptor agonist clonidine significantly attenuated thermal and mechanical pain hypersensitivity in PD rats. Furthermore, application of norepinephrine (NE) and 5-hydroxytryptamine (5-HT) reuptake inhibitors duloxetine, but not 5-HT selective reuptake inhibitors sertraline, significantly inhibited thermal and mechanical pain hypersensitivity in PD rats. Systemic administration of Madopar (L-DOPA) or the D2/D3 agonist pramipexole slightly inhibited the thermal, but not mechanical, hypersensitivity in PD rats. Thus, our study revealed that impairment of descending noradrenergic system may play a key role in PD-associated pain and restoring spinal noradrenergic inhibitory tone may serve as a novel strategy to manage PD-associated pain.
Assuntos
Norepinefrina/antagonistas & inibidores , Dor/tratamento farmacológico , Doença de Parkinson/tratamento farmacológico , Medula Espinal/efeitos dos fármacos , Animais , Benzilaminas/administração & dosagem , Benzilaminas/uso terapêutico , Corpo Estriado/efeitos dos fármacos , Modelos Animais de Doenças , Levodopa/administração & dosagem , Levodopa/uso terapêutico , Masculino , Norepinefrina/metabolismo , Oxidopamina/uso terapêutico , Ratos Sprague-DawleyRESUMO
OBJECTIVES: The low triiodothyronine (T3) syndrome indicates poor prognosis for patients with cerebral infarction. It is unknown, however, whether basic conditions or severities in the patients with the low T3 syndrome are different compared to those without the low T3 syndrome. METHODS: We compared the risk factors and the severity of the disease using the National Institutes of Health stroke scale (NIHSS) score at the worst condition for cerebral infarction in patients with or without the low T3 syndrome in order to better understand the characteristics underlying the worse prognosis in patients with the low T3 syndrome. RESULTS: We found that cerebral infarction patients with the low T3 syndrome were significantly older (p<0.001) and significantly more likely to be female (p=0.002) and had hypertension (p=0.04) or homocystinemia (p=0.001), but less likely to smoke (p=0.008), compared to patients without the low T3 syndrome. The proportion of NIHSS score ≥8 in the patients with LAA-ICA-associated cerebral infarction accompanied by the low T3 syndrome was significantly higher than in those without the low T3 syndrome (p=0.001). CONCLUSION: We concluded that increased numbers of risk factors for cerebral infarction and more severe neurological deficits may be important causes for worse prognosis in the patients with the low T3 syndrome which may more likely occur in patients with LAA-ICA cerebral infarction. Intense secondary prevention in cerebral infarction especially in older women are needed.
Assuntos
Doenças das Artérias Carótidas/complicações , Doenças das Artérias Carótidas/diagnóstico , Infarto Cerebral/complicações , Infarto Cerebral/diagnóstico , Síndromes do Eutireóideo Doente/complicações , Síndromes do Eutireóideo Doente/diagnóstico , Doenças do Sistema Nervoso/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Doenças das Artérias Carótidas/epidemiologia , Artéria Carótida Interna/patologia , Infarto Cerebral/epidemiologia , Síndromes do Eutireóideo Doente/epidemiologia , Feminino , Humanos , Pacientes Internados/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/epidemiologia , Doenças do Sistema Nervoso/etiologia , Prognóstico , Índice de Gravidade de DoençaRESUMO
OBJECTIVE: Botulinum toxin A has been shown to be effective in managing depression. This study aimed to evaluate the antidepressant and antianxiety effects of two different doses of botulinum toxin A in patients with mild to moderate depression. METHODS: A total of 140 patients diagnosed with mild to moderate depression at the Department of Neurology of the Second Affiliated Hospital of Soochow University from September 2020 to September 2021 were enrolled for the study. The patients were allocated into two groups and treated with two different doses of botulinum toxin A (50 units or 100 units). Depression scores (HAMD, HAMA, SDS, and SAS) were evaluated at baseline and 1, 2, 4, 8, and 12 weeks after treatment. RESULTS: There was a significant improvement in the depressive and anxiety symptoms following treatment with the botulinum toxin A after 12 weeks compared to the baseline. However, there were no significant differences between the two groups. Further, the factor scores of anxiety/somatization, blocking, sleep disorder, and cognitive disorder were significantly decreased after 12 weeks of treatment with 50 units of botulinum toxin A compared to the baseline (P < 0.05). Further, the factor scores of somatic and mental anxiety were significantly decreased at different time points after treatment with 50 units of botulinum toxin A compared to the baseline (P < 0.05). CONCLUSION: Local injections of 50 units and 100 units of botulinum toxin A shows equal efficacy. Therefore, 50 units of botulinum toxin A could be used clinically to manage mild to moderate depression.
Assuntos
Toxinas Botulínicas Tipo A , Fármacos Neuromusculares , Humanos , Toxinas Botulínicas Tipo A/uso terapêutico , Fármacos Neuromusculares/uso terapêutico , Depressão/tratamento farmacológico , Resultado do Tratamento , InjeçõesRESUMO
BACKGROUND: Foot dystonia occurs in patients with Parkinson's disease (PD) and leads to pain, malformation, and difficulty with walking. Botulinum toxin injections may be effective for foot dystonia, but the extent of improvement and effects on motor function are unclear. METHODS: In this study, we performed botulinum toxin injections for foot dystonia in 25 patients with PD. At 3 weeks and 3 months post-infection, we assessed changes in plantar pressure distribution utilizing the Pressure Plate system; dystonia using the Modified Ashworth Spasm score; pain using the visual analog scale (VAS) score; and lower extremity function using the Calf-raise Senior (CRS) test, Timed Up and Go (TUG) test, and gait parameters (eg, stride length, step length). RESULTS: We found improved Modified Ashworth Spasm score (p < 0.01) and VAS score (p < 0.01) post-injection. CRS test score (3 weeks, p = 0.006; 3 months, p = 0.068), stride length (3 weeks, p = 0.012; 3 months, p = 0.715), and step length (3 weeks, p = 0.011; 3 months, p = 0.803) also improved. Plantar pressure distribution improved after botulinum toxin injection (metatarsal 1, 3 weeks, p = 0.031; 3 months, p = 0.144; metatarsal 2, 3 weeks, p = 0.049; 3 months, p = 0.065; metatarsal 3, 3 weeks, p = 0.002; 3 months, p = 0.017; metatarsal 4, 3 weeks, p = 0.017; 3 months, p = 0.144; medial heel, 3 weeks, p = 0.01; 3 months, p = 0.395; lateral heel, 3 weeks, p = 0.035; 3 months, p = 0.109). CONCLUSION: Botulinum toxin injection for foot dystonia in patients with PD can reduce spasms and pain and normalize plantar pressure distribution, which improves balance and lower extremity function.
Assuntos
Toxinas Botulínicas Tipo A , Distonia , Fármacos Neuromusculares , Doença de Parkinson , Humanos , Toxinas Botulínicas Tipo A/uso terapêutico , Distonia/tratamento farmacológico , Distonia/etiologia , Doença de Parkinson/complicações , Doença de Parkinson/tratamento farmacológico , Fármacos Neuromusculares/uso terapêutico , Dor/tratamento farmacológico , Espasmo , Resultado do TratamentoRESUMO
Background: Post-stroke depression (PSD) is a frequent complication following a stroke, characterized by prolonged feelings of sadness and loss of interest, which can significantly impede stroke rehabilitation, increase disability, and raise mortality rates. Traditional antidepressants often have significant side effects and poor patient adherence, necessitating the exploration of more suitable treatments for PSD. Previous researchers and our research team have discovered that Botulinum Toxin A (BoNT-A) exhibits antidepressant effects. Therefore, our objective was to assess the efficacy and side effects of BoNT-A treatment in patients with PSD. Methods: A total of 71 stroke patients meeting the inclusion criteria were allocated to the two group. 2 cases were excluded due to severe neurological dysfunction that prevented cooperation and 4 cases were lost follow-up. Ultimately, number of participants in the BoNT-A group (n = 32) and Sertraline group (n = 33). Treatment efficacy was evaluated 1, 2, 4, 8 and 12 weeks post-treatment. Results: There were no significant differences in baseline characteristics between the two groups (p > 0.05). Both groups exhibited comparable treatment efficacy, with fewer side effects observed in the BoNT-A group compared to the Sertraline group. BoNT-A therapy demonstrated significant effects as early as the first week (p < 0.05), and by the 12th week, there was a notable decrease in neuropsychological scores, significantly lower than the baseline level. The analysis revealed significant differences in measurements of the Hamilton Depression Scale (HAMD) (F(770) = 12.547, p = 0.000), Hamilton Anxiety Scale (HAMA) (F(951) = 10.422, p = 0.000), Self-Rating Depression Scale (SDS) (F(1385) = 10.607, p = 0.000), and Self-Rating Anxiety Scale (SAS) (F(1482) = 11.491, p = 0.000). Conclusion: BoNT-A treatment effectively reduces depression symptoms in patients with PSD on a continuous basis.
RESUMO
Signaling mediated by brain-derived neurotrophic factor (BDNF), which is supported by the postsynaptic scaffolding protein PSD-95, has antidepressant effects. Conversely, clinical depression is associated with reduced BDNF signaling. We found that peptidomimetic compounds that bind to PSD-95 promoted signaling by the BDNF receptor TrkB in the hippocampus and reduced depression-like behaviors in mice. The compounds CN2097 and Syn3 both bind to the PDZ3 domain of PSD-95, and Syn3 also binds to an α-helical region of the protein. Syn3 reduced depression-like behaviors in two mouse models of stress-induced depression; CN2097 had similar but less potent effects. In hippocampal neurons, application of Syn3 enhanced the formation of TrkB-Gαi1/3-PSD-95 complexes and potentiated downstream PI3K-Akt-mTOR signaling. In mice subjected to chronic mild stress (CMS), systemic administration of Syn3 reversed the CMS-induced, depression-associated changes in PI3K-Akt-mTOR signaling, dendrite complexity, spine density, and autophagy in the hippocampus and reduced depression-like behaviors. Knocking out Gαi1/3 in hippocampal neurons prevented the therapeutic effects of Syn3, indicating dependence of these effects on the TrkB pathway. The findings suggest that compounds that induce the formation of PSD-95-TrkB complexes have therapeutic potential to alleviate depression.
Assuntos
Fator Neurotrófico Derivado do Encéfalo , Depressão , Proteína 4 Homóloga a Disks-Large , Hipocampo , Transdução de Sinais , Animais , Proteína 4 Homóloga a Disks-Large/metabolismo , Proteína 4 Homóloga a Disks-Large/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Depressão/metabolismo , Depressão/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Camundongos , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Masculino , Camundongos Knockout , Estresse Psicológico/metabolismo , Estresse Psicológico/tratamento farmacológico , Receptor trkB/metabolismo , Receptor trkB/genética , Camundongos Endogâmicos C57BL , Comportamento Animal/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/efeitos dos fármacosRESUMO
Objective: Individual differences were observed in the clinical efficacy of Botulinum toxin A (BoNT-A) in the treatment of the primary Meige syndrome. Our study aimed to explore the potential associations between the clinical efficacy of BoNT-A in the treatment of the primary Meige syndrome and variants of SNAP25, SV2C and ST3GAL2, which are involving in the translocation of the BoNT-A in vivo. Methods: Patients with the primary Meige syndrome treated with BoNT-A were enrolled. Clinical efficacy was evaluated by the maximum improvement rate of motor symptoms and the duration of efficacy. Variants of SNAP25, SV2C and ST3GAL2 were obtained by Sanger sequencing. Another cohort diagnosed with primary cervical dystonia was also enrolled in the replication stage. Results: Among the 104 primary Meige syndrome patients, 80 patients (76.9%) had a good efficacy (the maximum improvement rate of motor symptoms ≥30%) and 24 (23. 1%) had a poor (the maximum improvement rate of motor symptoms <30%). As to the duration of efficacy, 52 patients (50.0%) had a long duration of efficacy (≥4 months), and 52 (50.0%) had a short (<4 months). In terms of primary Meige syndrome, SNAP25 rs6104571 was found associating with the maximum improvement rate of motor symptoms (Genotype: P = 0.02, OR = 0.26; Allele: P = 0.013, OR = 0.29), and SV2C rs31244 was found associating with the duration of efficacy (Genotype: P = 0.024, OR = 0.13; Allele: P = 0.012, OR = 0.13). Besides, we also conducted the association analyses between the variants and BoNT-A-related adverse reactions. Although, there was no statistical difference between the allele of SV2C rs31244 and BoNT-A-related adverse reactions, there was a trend (P = 0.077, OR = 2.56). In the replication stage, we included 39 patients with primary cervical dystonia to further expanding the samples' size. Among the 39 primary cervical dystonia patients, 25 patients (64.1%) had a good efficacy (the maximum improvement rate of motor symptoms ≥50%) and 14 (35.9%) had a poor (the maximum improvement rate of motor symptoms <50%). As to the duration of efficacy, 32 patients (82.1%) had a long duration of efficacy (≥6 months), and 7 (17.9%) had a short (<6 months). Integrating primary Meige syndrome and primary cervical dystonia, SV2C rs31244 was still found associating with the duration of efficacy (Genotype: P = 0.002, OR = 0. 23; Allele: P = 0.001, OR = 0. 25). Conclusion: In our study, SNAP25 rs6104571 was associated with the maximum improvement rate of motor symptoms in patients with primary Meige syndrome treated with BoNT-A, and patients carrying this variant had a lower improvement rate of motor symptoms. SV2C rs31244 was associated with duration of treatment in patients with primary Meige syndrome treated with BoNT-A and patients carrying this variant had a shorter duration of treatment. Patients with primary Meige syndrome carrying SV2C rs31244 G allele have an increase likelihood of BoNT-A-related adverse reactions. Involving 39 patients with primary cervical dystonia, the results further verify that SV2C rs31244 was associated with duration of treatment and patients carrying this variant had a shorter duration of treatment.
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AIM: To observe the changes in the thickness of peripapillary retinal nerve fiber layer (pRNFL) and peripapillary vessel density (pVD) in patients with different stages of Parkinson's disease (PD). METHODS: Totally 47 patients (47 eyes) with primary PD were divided into the mild group and the moderate-to-severe group according to Hoehn & Yahr (H&Y) stage. Among them, there were 27 cases (27 eyes) in mild group and 20 cases (20 eyes) in moderate-to-severe group. And 20 cases (20 eyes) who were included in the control group were healthy people who came to our hospital for health screening at the same time. All participants underwent optical coherence tomography angiography (OCTA) examinations. The pRNFL thickness, total vessel density (tVD) and capillary vessel density (cVD) of the optic disc in average, superior half, inferior half, superior nasal (SN), nasal superior (NS), nasal inferior (NI), inferior nasal (IN), inferior temporal (IT), temporal inferior (TI), temporal superior (TS), and superior temporal (ST) were measured. One-way ANOVA was used to compare the differences of optic disc parameters among the three groups, and Pearson and Spearman correlations were used to analyze the correlation between pRNFL, pVD and the disease duration, H&Y stage and UPDRS-III score in patients with PD, respectively. RESULTS: There were significant differences in pRNFL thickness in average, superior half, inferior half, SN, NS, IN, IT and ST quadrants among the three groups (P<0.05). In PD group, the pRNFL thickness in average, superior half, inferior half, NS and IT quadrants were negatively correlated with H&Y stage and UPDRS-III score, respectively (P<0.05). There were statistically significant differences in the cVD of whole image, inferior half, NI and TS quadrants, the tVD of the whole image, inferior half, and peripapillary among the three groups (P<0.05). In PD group, the tVD of whole image and the cVD of NI and TS quadrants were negatively correlated with the H&Y stage, respectively (P<0.05); the cVD of TS quadrant was negatively correlated with UPDRS-III score (P<0.05). CONCLUSION: The thickness of pRNFL in PD patients is significantly decreased, and it is negatively correlated with H&Y stage and UPDRS-III score. With the increase of the severity of the disease, the pVD parameters in PD patients increase at first in the mild group, and then decrease in the moderate-to-severe group, and negatively correlate with H&Y stage and UPDRS-III score.
RESUMO
The stem cell factor (SCF) binds to c-Kit in endothelial cells, thus activating downstream signaling and angiogenesis. Herein, we examined the role of G protein subunit alpha inhibitory (Gαi) proteins in this process. In MEFs and HUVECs, Gαi1/3 was associated with SCF-activated c-Kit, promoting c-Kit endocytosis, and binding of key adaptor proteins, subsequently transducing downstream signaling. SCF-induced Akt-mTOR and Erk activation was robustly attenuated by Gαi1/3 silencing or knockout (KO), or due to dominant negative mutations but was strengthened substantially following ectopic overexpression of Gαi1/3. SCF-induced HUVEC proliferation, migration, and capillary tube formation were suppressed after Gαi1/3 silencing or KO, or due to dominant negative mutations. In vivo, endothelial knockdown of Gαi1/3 by intravitreous injection of endothelial-specific shRNA adeno-associated virus (AAV) potently reduced SCF-induced signaling and retinal angiogenesis in mice. Moreover, mRNA and protein expressions of SCF increased significantly in the retinal tissues of streptozotocin-induced diabetic retinopathy (DR) mice. SCF silencing, through intravitreous injection of SCF shRNA AAV, inhibited pathological retinal angiogenesis and degeneration of retinal ganglion cells in DR mice. Finally, the expression of SCF and c-Kit increased in proliferative retinal tissues of human patients with proliferative DR. Taken together, Gαi1/3 mediate SCF/c-Kit-activated signaling and angiogenesis.
Assuntos
Células Endoteliais , Transdução de Sinais , Animais , Humanos , Camundongos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Células Endoteliais/metabolismo , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , RNA Interferente Pequeno/metabolismo , Transdução de Sinais/genética , Fator de Células-Tronco/genética , Fator de Células-Tronco/metabolismo , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismoRESUMO
Higher plasma urate level is reported to be associated with a reduced risk and slower progression of Parkinson's disease (PD). In this study, we explored the effects of urate on dopaminergic neurons in nigrostriatal pathway in the 6-hydroxydopamine (6-OHDA) unilaterally lesioned rats. Uric acid (UA), when given twice daily at 200 mg/kg intraperitoneally for 10 consecutive days, elevated urate (the anionic form of UA) in plasma and striatum by 55% and 36.8%, respectively, as compared with vehicle group. This regimen of UA was found to ameliorate the behavioral deficits, dopaminergic neuron loss as well as dopamine depletion in the nigrostriatal system. Moreover, UA administration was capable of increasing glutathione level and superoxide dismutase activity while decreasing malondialdehyde accumulation in striatum. In addition, the phosphorylation of both protein kinase B (Akt) and glycogen synthase kinase 3 beta (GSK3ß) in the lesioned striata of 6-OHDA-lesioned rats was dramatically reduced as compared with sham-operated rats. This reduction was attenuated in the Parkinsonian rats receiving UA treatment. Similarly, in vitro findings showed that UA alleviated the decrease in Akt activation and the increase in GSK3ß activity caused by 6-OHDA. Furthermore, neuroprotection by urate and its regulation on GSK3ß phosphorylation at Ser9 was found to be abolished in the presence of PI3K inhibitor. Therefore, our findings demonstrated that urate was able to protect dopaminergic neurons in rat nigrostriatal pathway against the neurotoxicity of 6-OHDA, and showed that its beneficial effects may be related to its regulation on Akt/GSK3ß signaling.