Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 115
Filtrar
1.
Int J Mol Sci ; 22(18)2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34576209

RESUMO

Ischemic stroke is the leading cause of mortality and long-term disability worldwide. Disruption of the blood-brain barrier (BBB) is a prominent pathophysiological mechanism, responsible for a series of subsequent inflammatory cascades that exacerbate the damage to brain tissue. However, the benefit of recanalization is limited in most patients because of the narrow therapeutic time window. Recently, mesenchymal stem cells (MSCs) have been assessed as excellent candidates for cell-based therapy in cerebral ischemia, including neuroinflammatory alleviation, angiogenesis and neurogenesis promotion through their paracrine actions. In addition, accumulating evidence on how MSC therapy preserves BBB integrity after stroke may open up novel therapeutic targets for treating cerebrovascular diseases. In this review, we focus on the molecular mechanisms of MSC-based therapy in the ischemia-induced prevention of BBB compromise. Currently, therapeutic effects of MSCs for stroke are primarily based on the fundamental pathogenesis of BBB breakdown, such as attenuating leukocyte infiltration, matrix metalloproteinase (MMP) regulation, antioxidant, anti-inflammation, stabilizing morphology and crosstalk between cellular components of the BBB. We also discuss prospective studies to improve the effectiveness of MSC therapy through enhanced migration into defined brain regions of stem cells. Targeted therapy is a promising new direction and is being prioritized for extensive research.

2.
Int J Mol Sci ; 22(15)2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34361041

RESUMO

Traumatic brain injury (TBI) is a leading cause of disability and mortality worldwide. It can instigate immediate cell death, followed by a time-dependent secondary injury that results from disproportionate microglial and astrocyte activation, excessive inflammation and oxidative stress in brain tissue, culminating in both short- and long-term cognitive dysfunction and behavioral deficits. Within the brain, the hippocampus is particularly vulnerable to a TBI. We studied a new pomalidomide (Pom) analog, namely, 3,6'-dithioPom (DP), and Pom as immunomodulatory imide drugs (IMiD) for mitigating TBI-induced hippocampal neurodegeneration, microgliosis, astrogliosis and behavioral impairments in a controlled cortical impact (CCI) model of TBI in rats. Both agents were administered as a single intravenous dose (0.5 mg/kg) at 5 h post injury so that the efficacies could be compared. Pom and DP significantly reduced the contusion volume evaluated at 24 h and 7 days post injury. Both agents ameliorated short-term memory deficits and anxiety behavior at 7 days after a TBI. The number of degenerating neurons in the CA1 and dentate gyrus (DG) regions of the hippocampus after a TBI was reduced by Pom and DP. DP, but not Pom, significantly attenuated the TBI-induced microgliosis and DP was more efficacious than Pom at attenuating the TBI-induced astrogliosis in CA1 and DG at 7D after a TBI. In summary, a single intravenous injection of Pom or DP, given 5 h post TBI, significantly reduced hippocampal neurodegeneration and prevented cognitive deficits with a concomitant attenuation of the neuroinflammation in the hippocampus.


Assuntos
Lesões Encefálicas Traumáticas/tratamento farmacológico , Gliose/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Fatores Imunológicos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Talidomida/análogos & derivados , Animais , Lesões Encefálicas Traumáticas/complicações , Cognição , Gliose/etiologia , Hipocampo/metabolismo , Fatores Imunológicos/farmacologia , Masculino , Memória , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley , Talidomida/farmacologia , Talidomida/uso terapêutico
3.
Redox Biol ; 46: 102067, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34315111

RESUMO

Traumatic brain injury (TBI) is a prevalent head injury worldwide which increases the risk of neurodegenerative diseases. Increased reactive oxygen species (ROS) and inflammatory chemokines after TBI induces secondary effects which damage neurons. Targeting NADPH oxidase or increasing redox systems are ways to reduce ROS and damage. Earlier studies show that C-C motif chemokine ligand 5 (CCL5) has neurotrophic functions such as promoting neurite outgrowth as well as reducing apoptosis. Although CCL5 levels in blood are associated with severity in TBI patients, the function of CCL5 after brain injury is unclear. In the current study, we induced mild brain injury in C57BL/6 (wildtype, WT) mice and CCL5 knockout (CCL5-KO) mice using a weight-drop model. Cognitive and memory functions in mice were analyzed by Novel-object-recognition and Barnes Maze tests. The memory performance of both WT and KO mice were impaired after mild injury. Cognition and memory function in WT mice quickly recovered after 7 days but recovery took more than 14 days in CCL5-KO mice. FJC, NeuN and Hypoxyprobe staining revealed large numbers of neurons damaged by oxidative stress in CCL5-KO mice after mTBI. NADPH oxidase activity show increased ROS generation together with reduced glutathione peroxidase-1 (GPX1) and glutathione (GSH) activity in CCL5-KO mice; this was opposite to that seen in WT mice. CCL5 increased GPX1 expression and reduced intracellular ROS levels which subsequently increased cell survival both in primary neuron cultures and in an overexpression model using SHSY5Y cell. Memory impairment in CCL5-KO mice induced by TBI could be rescued by i.p. injection of the GSH precursor - N-acetylcysteine (NAC) or intranasal delivery of recombinant CCL5 into mice after injury. We conclude that CCL5 is an important molecule for GPX1 antioxidant activation during post-injury day 1-3, and protects hippocampal neurons from ROS as well as improves memory function after trauma.

4.
Comput Math Methods Med ; 2021: 5571319, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34055038

RESUMO

Traumatic brain injury (TBI) causes major socioeconomic problems worldwide. In the United States, nearly three-quarters of patients with TBI have mild TBI (mTBI). 32% of these patients may develop dizziness. In this study, we analyzed the factor structure of the traditional Chinese version of the DHI and evaluate the differences in DHI factors between dizziness and nondizziness groups. In total, 315 patients with mTBI, comprising 158 with self-reported dizziness and 157 without dizziness, were recruited from three hospitals. The responses for Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Epworth Sleepiness Scale (ESS), and Pittsburgh Sleep Quality Index (PSQI) demonstrated between-group differences. The Chinese DHI had internal validity and had four factors that differed from the English version (3 aspects). The group effects for the physical subscale remained significantly different even after adjustments in the propensity score model. For the Chinese version, two of four factors remained significantly different in the effects between self-reported dizziness and nondizziness groups. The factors of our Chinese DHI differed from those of the original English version of DHI. After adjustments using the propensity score model, the physical subscale demonstrated significant differences between the self-reported dizziness and nondizziness groups. Only two factors from our Chinese DHI were significantly different; moreover, it contained only three physical, five functional, and three emotional items.


Assuntos
Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/fisiopatologia , Tontura/etiologia , Tontura/fisiopatologia , Modelos Neurológicos , Adulto , Biologia Computacional , Avaliação da Deficiência , Análise Fatorial , Feminino , Humanos , Idioma , Masculino , Pessoa de Meia-Idade , Pontuação de Propensão , Autorrelato , Inquéritos e Questionários , Taiwan
5.
Mol Psychiatry ; 2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33931731

RESUMO

Glucoregulatory efficiency and ATP production are key regulators for neuronal plasticity and memory formation. Besides its chemotactic and neuroinflammatory functions, the CC chemokine--CCL5 displays neurotrophic activity. We found impaired learning-memory and cognition in CCL5-knockout mice at 4 months of age correlated with reduced hippocampal long-term potentiation and impaired synapse structure. Re-expressing CCL5 in knockout mouse hippocampus restored synaptic protein expression, neuronal connectivity and cognitive function. Using metabolomics coupled with FDG-PET imaging and seahorse analysis, we found that CCL5 participates in hippocampal fructose and mannose degradation, glycolysis, gluconeogenesis as well as glutamate and purine metabolism. CCL5 additionally supports mitochondrial structural integrity, purine synthesis, ATP generation, and subsequent aerobic glucose metabolism. Overexpressing CCL5 in WT mice also enhanced memory-cognition performance as well as hippocampal neuronal activity and connectivity through promotion of de novo purine and glutamate metabolism. Thus, CCL5 actions on glucose aerobic metabolism are critical for mitochondrial function which contribute to hippocampal spine and synapse formation, improving learning and memory.

6.
Neuropsychol Rehabil ; 31(2): 211-230, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31696782

RESUMO

This study aims to evaluate the relationship between traumatic brain injury (TBI) and sleep disorders (SDs). We first initiated a questionnaire-based clinical survey to assess sleep problems in the early stage after a TBI, followed by a population-based cohort study to evaluate the long-term risk of SDs in TBI patients. For short-term clinical survey, mild (m)TBI patients and healthy controls were recruited to evaluate the sleep quality and daytime sleepiness using the Pittsburg Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS) within two weeks after a TBI. For long-term observation, a 5-year nationwide population-based cohort study that utilized a large administrative database was conducted. In the short-term survey, 236 mTBI patients and 223 controls were analyzed. Total scores of the PSQI and ESS were significantly higher in mTBI patients than in the controls. In the long-term cohort study, 6932 TBI cases and 34,660 matched controls were included. TBI cases had a 1.36-fold greater risk of SDs compared to the non-TBI controls during the 5-year follow-up period. Results showed that patients with TBI had a significantly higher risk of SDs than did controls both in the early stage and during a 5-year follow-up period.

7.
J Neurotrauma ; 38(10): 1445-1449, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-25747875

RESUMO

Over 2 million people suffer from mild traumatic brain injury (mTBI) each year. Predicting symptoms of mTBI and the characterization of those symptoms has been challenging. Biomarkers that correlate clinical symptoms to disease outcome are desired to improve understanding of the disease and optimize patient care. Bone marrow kinase on chromosome X (BMX), a member of the TEC family of nonreceptor tyrosine kinases, is up-regulated after traumatic neural injury in a rat model of mTBI. The aim of this investigation was to determine whether BMX serum concentrations can effectively be used to predict outcomes after mTBI in a clinical setting. A total of 63 patients with mTBI (Glasgow Coma Score [GCS] between 13 and 15) were included. Blood samples taken at the time of hospital admission were analyzed for BMX. Data collected included demographic and clinical variables. Outcomes were assessed using the Dizziness Handicap Inventory (DHI) questionnaire at baseline and 6 weeks postinjury. The participant was asssigned to the case group if the subject's complaints of dizziness became worse at the sixth week assessment; otherwise, the participant was assigned to the control group. A receiver operating characteristic curve was constructed to explore BMX level. Significant associations were found between serum levels of BMX and dizziness. Areas under the curve for prediction of change in DHI postinjury were 0.76 for total score, 0.69 for physical score, 0.65 for emotional score, and 0.66 for functional score. Specificities were between 0.69 and 0.77 for total score and emotional score, respectively. Therefore, BMX demonstrates potential as a candidate serum biomarker of exacerbating dizziness post-mTBI.

8.
Int J Biol Sci ; 16(16): 3184-3199, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33162824

RESUMO

Background: Histone deacetylase (HDAC) inhibitors have emerged as a new class of anti-tumor agents for various types of tumors, including glioblastoma. Methods and results: We found that a novel HDAC inhibitor, MPT0B291, significantly reduced the cell viability and increased cell death of human and rat glioma cell lines, but not in normal astrocytes. We also demonstrated that MPT0B291 suppressed proliferation by inducing G1 phase cell cycle arrest and increased apoptosis in human and rat glioma cell lines by flow cytometry and immunocytochemistry. We further investigated the anti-tumor effects of MPT0B291 in xenograft (mouse) and allograft (rat) models. The IVIS200 images and histological analysis indicated MPT0B291 (25 mg/kg, p. o.) reduced tumor volume. Mechanistically, MPT0B291 increased phosphorylation and acetylation/activation of p53 and increased mRNA levels of the apoptosis related genes PUMA, Bax, and Apaf1 as well as increased protein level of PUMA, Apaf1 in C6 cell line. The expression of cell cycle related gene p21 was also increased and Cdk2, Cdk4 were decreased by MPT0B291. Conclusion: Our study highlights the anti-tumor efficacy of a novel compound MPT0B291 on glioma growth.

9.
Int J Mol Sci ; 21(11)2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32516998

RESUMO

Mesenchymal stem cells (MSCs) are emerging as an attractive approach for restorative medicine in central nervous system (CNS) diseases and injuries, such as traumatic brain injury (TBI), due to their relatively easy derivation and therapeutic effect following transplantation. However, the long-term survival of the grafted cells and therapeutic efficacy need improvement. Here, we review the recent application of MSCs in TBI treatment in preclinical models. We discuss the genetic modification approaches designed to enhance the therapeutic potency of MSCs for TBI treatment by improving their survival after transplantation, enhancing their homing abilities and overexpressing neuroprotective and neuroregenerative factors. We highlight the latest preclinical studies that have used genetically modified MSCs for TBI treatment. The recent developments in MSCs' biology and potential TBI therapeutic targets may sufficiently improve the genetic modification strategies for MSCs, potentially bringing effective MSC-based therapies for TBI treatment in humans.


Assuntos
Lesões Encefálicas Traumáticas/terapia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Animais , Lesões Encefálicas Traumáticas/etiologia , Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/patologia , Terapia Baseada em Transplante de Células e Tecidos , Gerenciamento Clínico , Suscetibilidade a Doenças , Técnicas de Transferência de Genes , Engenharia Genética/métodos , Terapia Genética , Humanos , Transplante de Células-Tronco Mesenquimais/métodos , Neurogênese
10.
Sci Rep ; 10(1): 6005, 2020 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-32265470

RESUMO

Refracture of cemented vertebrae occurs commonly after vertebroplasty (VP) for osteoporotic vertebral compression fracture (OVCF). It can result in severe pain or neurological deficit, but no preventive medication is available. Owing to the bone anabolic benefits of teriparatide (TP), this study was aimed to compare the outcomes of cemented vertebrae with TP to those without TP. Patients who received VP for OVCF with at least 1 year follow-up were included. The anterior body height (ABH) and middle body height (MBH) and kyphotic angle (KA) were measured before VP and 1 week and at least 1 year after VP. Refracture was defined as a 15% decrease in ABH or MBH and 8° decrease in KA compared with those at postoperative 1 week. The clinical outcomes were evaluated. 35 VP procedures in 21 patients treated with TP (TP group), and, matched to that, 29 out of 133 patients treated with VP alone (VP group) were included. One year after VP, ABH and MBH were significantly greater, except KA, in the TP group (VP group vs. TP group: KA - 4.97° ± 12.1 vs. -2.85° ± 12.21°, p = 0.462, ABH 1.56 ± 0.48 cm vs. 1.84 ± 0.56 cm, p = 0.027, MBH 1.49 ± 0.39 cm vs. 1.73 ± 0.41 cm, p = 0.017). The refracture rates of KA, ABH, and MBH were significantly lower in the TP group (VP group vs. TP group: KA 42.11% vs.8.57%, p < 0.001; ABH 76.32% vs. 28.57%, p < 0.0001; MBH 76.32% vs. 28.57%, p < 0.0001). In single-level subgroup comparison, TP was associated with better improvement of pain VAS and better radiological outcomes. TP was associated with higher BHs and fewer refractures than VP alone, with comparable clinical outcomes 1 year after VP. TP may be associated with better improvement of pain VAS in those with single-level VP procedure. Higher BH was due to the better maintenance effect of TP.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Fraturas por Compressão/cirurgia , Fraturas da Coluna Vertebral/cirurgia , Teriparatida/uso terapêutico , Vertebroplastia , Idoso , Idoso de 80 Anos ou mais , Estatura , Estudos de Coortes , Feminino , Fraturas por Compressão/tratamento farmacológico , Humanos , Masculino , Fraturas da Coluna Vertebral/tratamento farmacológico , Resultado do Tratamento
11.
Int J Mol Sci ; 21(8)2020 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-32326191

RESUMO

BACKGROUND: Stroke is one of the leading causes of death and disability worldwide and places a heavy burden on the economy in our society. Current treatments, such as the use of thrombolytic agents, are often limited by a narrow therapeutic time window. However, the regeneration of the brain after damage is still active days, even weeks, after stroke occurs, which might provide a second window for treatment. Emodin, a traditional Chinese medicinal herb widely used to treat acute hepatitis, has been reported to possess antioxidative capabilities and protective effects against myocardial ischemia/reperfusion injury. However, the underlying mechanisms and neuroprotective functions of Emodin in a rat middle cerebral artery occlusion (MCAO) model of ischemic stroke remain unknown. This study investigates neuroprotective effects of Emodin in ischemia both in vitro and in vivo. METHODS: PC12 cells were exposed to oxygen-glucose deprivation to simulate hypoxic injury, and the involved signaling pathways and results of Emodin treatment were evaluated. The therapeutic effects of Emodin in ischemia animals were further investigated. RESULTS: Emodin reduced infarct volume and cell death following focal cerebral ischemia injury. Emodin treatment restored PC12 cell viability and reduced reactive oxygen species (ROS) production and glutamate release under conditions of ischemia/hypoxia. Emodin increased Bcl-2 and glutamate transporter-1 (GLT-l) expression but suppressed activated-caspase 3 levels through activating the extracellular signal-regulated kinase (ERK)-1/2 signaling pathway. CONCLUSION: Emodin induced Bcl-2 and GLT-1 expression to inhibit neuronal apoptosis and ROS generation while reducing glutamate toxicity via the ERK-1/2 signaling pathway. Furthermore, Emodin alleviated nerve cell injury following ischemia/reperfusion in a rat MCAO model. Emodin has neuroprotective effects against ischemia/reperfusion injury both in vitro and in vivo, which may be through activating the ERK-1/2 signaling pathway.


Assuntos
Emodina/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismo , Animais , Biomarcadores , Sobrevivência Celular , Suscetibilidade a Doenças , Hipóxia/metabolismo , Imuno-Histoquímica , Células PC12 , Ratos , Traumatismo por Reperfusão/tratamento farmacológico
12.
Brain Stimul ; 13(3): 655-663, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32289694

RESUMO

BACKGROUND: Transcranial direct current stimulation (tDCS) has been proven to be able to modulate motor cortical plasticity might have potential as an alternative, adjunctive therapy for Parkinson's disease (PD). However, the efficacy of tDCS in PD is still uncertain. A disease animal model may be useful to clarify the existence of a treatment effect and to explore an effective therapeutic strategy using tDCS protocols. OBJECTIVE: The current study was designed to identify the comprehensive therapeutic effects of tDCS in 6-hydroxydopamine (6-OHDA)-lesioned PD rats. METHODS: Following early and long-term tDCS application (starting 24 h after PD lesion, 300 µA anodal tDCS, 20 min/day, 5 days/week) in awake PD animals for a total of 4 weeks, the effects of tDCS on motor and non-motor behaviors as well as dopaminergic neuron degeneration levels, were identified. RESULTS: We found that the 4-week tDCS intervention significantly alleviated 6-OHDA-induced motor deficits in locomotor activity, akinesia, gait pattern and anxiety-like behavior, but not in apomorphine-induced rotations, recognition memory and depression-like behavior. Immunohistochemically, tyrosine hydroxylase (TH)-positive neurons in the substantia nigra were significantly preserved in the tDCS intervention group. CONCLUSIONS: These results suggest that early and long-term tDCS could exert neuroprotective effects and reduce the aggravation of motor dysfunctions in a 6-OHDA-induced PD rat model. Furthermore, this preclinical model may enhance the promising possibility of the potential use of tDCS and serve as a translational platform to further identify the therapeutic mechanism of tDCS for PD or other neurological disorders.


Assuntos
Oxidopamina/toxicidade , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/prevenção & controle , Estimulação Transcraniana por Corrente Contínua/métodos , Animais , Eletrodos Implantados , Marcha/efeitos dos fármacos , Marcha/fisiologia , Masculino , Córtex Motor/efeitos dos fármacos , Córtex Motor/patologia , Transtornos Parkinsonianos/patologia , Ratos , Ratos Wistar , Fatores de Tempo , Resultado do Tratamento
13.
World Neurosurg ; 138: e634-e641, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32173550

RESUMO

OBJECTIVE: The interlaminar fusion combination involving C1-C2 screwing fixation is one of the most effective techniques for atlantoaxial dislocation or subluxation, and the bone graft is usually stabilized by wiring constructs. However, some adverse events were reported during the insertion of sublaminar wiring, such as accidentally damaging the spinal cord or dura. Thus we used the miniplate to stabilize the harvest bone graft on the C1-C2 laminar, which led to a shorter operation time and prevented spinal canal violation. This study investigated the safety and efficacy of the novel surgical technique, namely miniplate-augmented interlaminar fusion. METHODS: We retrospectively reviewed 43 patients who underwent posterior atlantoaxial fusion with the miniplate-augmented iliac crest autograft at our institute. Complications related to surgery were recorded and calculated. After operation, patients were followed up through routine radiography to examine whether the fusion of the atlantoaxial segment was achieved. Success of fusion was defined as follows: 1) the presence of bone bridging between the bone graft and both the atlas and axis; and 2) the absence of movement of the atlantoaxial spinous process on flexion-extension radiography, which meant that the variation of length measured in 2 views, respectively, was <1 mm. The first time when radiography showed successful fusion after surgery was termed as fusion time and was recorded individually. In addition, overall fusion rates and mean fusion times were analyzed. RESULTS: Of 43 patients, long-term follow-up data were available for 31 patients, whereas the remaining 12 patients had dropped out (mean follow-up duration, 24.91 months; range, 6-72 months). Among 31 patients, 22 (70.96%) were women and 9 (29.03%) were men. The mean age was 63.33 years. Regarding the etiology, atlantoaxial dislocations or subluxations were caused due to degeneration, rheumatoid arthritis, odontoid fracture, trauma, and os odontoideum in 14 (45%), 3 (10%), 5 (16%), 8 (26%), and 1 (3%) patient(s), respectively. Successful fusion was achieved in 30 (96.77%) patients, with a mean fusion time of 6.23 months, whereas only 1 (3.23%) patient did not meet the fusion criteria. No complications related to the miniplate occurred. We noted vertebral artery rupture not requiring blood transfusion in 1 patient, aspiration pneumonia in 1 patient, urinary tract infection in 1 patient, anemia requiring transfusion in 1 patient, and leg dysesthesia in 1 patient. No neurologic deficit was found. CONCLUSIONS: Miniplate-augmented interlaminar fusion with C1-C2 screwing resulted in excellent fusion rates with a considerably low probability of complications. Hence this novel technique for bone graft fixation with atlantoaxial screwing has a good efficacy and safety and can serve as an alternative for bone graft fixation during C1-C2 fusion.


Assuntos
Vértebras Cervicais/cirurgia , Fusão Vertebral/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Articulação Atlantoaxial/anormalidades , Articulação Atlantoaxial/diagnóstico por imagem , Articulação Atlantoaxial/cirurgia , Parafusos Ósseos , Transplante Ósseo , Vértebras Cervicais/diagnóstico por imagem , Anormalidades Congênitas , Feminino , Seguimentos , Humanos , Ílio/transplante , Fixadores Internos , Luxações Articulares/cirurgia , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos , Resultado do Tratamento
14.
J Neurotrauma ; 37(1): 14-26, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31298621

RESUMO

Traumatic brain injury (TBI) is a progressive and complex pathological condition that results in multiple adverse consequences, including impaired learning and memory. Transplantation of mesenchymal stem cells (MSCs) has produced limited benefits in experimental TBI models. Fibroblast growth factor 21 (FGF21) is a novel metabolic regulator that has neuroprotective effects, promotes remyelination, enhances angiogenesis, and elongates astrocytic processes. In this study, MSCs were genetically engineered to overexpress FGF21 in order to improve their efficacy in TBI. MSCs overexpressing FGF21 (MSC-FGF21) were transplanted to mouse brain by intracerebroventricular injection 24 h after TBI was induced by controlled cortical impact (CCI). Hippocampus-dependent spatial learning and memory, assessed by the Morris water maze test, was markedly decreased 3-4 weeks after TBI, a deficit that was robustly recovered by treatment with MSC-FGF21, but not MSC-mCherry control. Hippocampus-independent learning and memory, assessed by the novel object recognition test, was also impaired; these effects were blocked by treatment with both MSC-FGF21 and MSC-mCherry control. FGF21 protein levels in the ipsilateral hippocampus were drastically reduced 4 weeks post-TBI, a loss that was restored by treatment with MSC-FGF21, but not MSC-mCherry. MSC-FGF21 treatment also partially restored TBI-induced deficits in neurogenesis and maturation of immature hippocampal neurons, whereas MSC-mCherry was less effective. Finally, MSC-FGF21 treatment also normalized TBI-induced impairments in dendritic arborization of hippocampal neurons. Taken together, the results indicate that MSC-FGF21 treatment significantly improved TBI-induced spatial memory deficits, impaired hippocampal neurogenesis, and abnormal dendritic morphology. Future clinical investigations using MSC-FGF21 to improve post-TBI outcomes are warranted.


Assuntos
Lesões Encefálicas Traumáticas/patologia , Fatores de Crescimento de Fibroblastos/metabolismo , Transplante de Células-Tronco Mesenquimais/métodos , Neurogênese , Recuperação de Função Fisiológica , Animais , Modelos Animais de Doenças , Hipocampo/patologia , Aprendizagem em Labirinto , Memória , Camundongos , Camundongos Endogâmicos C57BL , Neurogênese/fisiologia
15.
Exp Neurol ; 324: 113135, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31778663

RESUMO

Traumatic brain injury (TBI) is one of the most common causes of death and disability worldwide. We investigated whether inhibition of p53 using pifithrin (PFT)-α or PFT-µ provides neuroprotective effects via p53 transcriptional dependent or -independent mechanisms, respectively. Sprague Dawley rats were subjected to controlled cortical impact TBI followed by the administration of PFTα or PFT-µ (2 mg/kg, i.v.) at 5 h after TBI. Brain contusion volume, as well as sensory and motor functions were evaluated at 24 h after TBI. TBI-induced impairments were mitigated by both PFT-α and PFT-µ. Fluoro-Jade C staining was used to label degenerating neurons within the TBI-induced cortical contusion region that, together with Annexin V positive neurons, were reduced by PFT-µ. Double immunofluorescence staining similarly demonstrated that PFT-µ significantly increased HO-1 positive neurons and mRNA expression in the cortical contusion region as well as decreased numbers of 4-hydroxynonenal (4HNE)-positive cells. Levels of mRNA encoding for p53, autophagy, mitophagy, anti-oxidant, anti-inflammatory related genes and proteins were measured by RT-qPCR and immunohistochemical staining, respectively. PFT-α, but not PFT-µ, significantly lowered p53 mRNA expression. Both PFT-α and PFT-µ lowered TBI-induced pro-inflammatory cytokines (IL-1ß and IL-6) mRNA levels as well as TBI-induced autophagic marker localization (LC3 and p62). Finally, treatment with PFT-µ mitigated TBI-induced declines in mRNA levels of PINK-1 and SOD2. Our data suggest that both PFT-µ and PFT-α provide neuroprotective actions through regulation of oxidative stress, neuroinflammation, autophagy, and mitophagy mechanisms, and that PFT-µ, in particular, holds promise as a TBI treatment strategy.


Assuntos
Autofagia/efeitos dos fármacos , Benzotiazóis/uso terapêutico , Lesões Encefálicas Traumáticas/tratamento farmacológico , Lesões Encefálicas Traumáticas/patologia , Encefalite/tratamento farmacológico , Mitofagia/efeitos dos fármacos , Neurônios/patologia , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Sulfonamidas/uso terapêutico , Tolueno/análogos & derivados , Proteína Supressora de Tumor p53/antagonistas & inibidores , Animais , Antioxidantes/metabolismo , Comportamento Animal , Contusão Encefálica/tratamento farmacológico , Contusão Encefálica/patologia , Contusão Encefálica/psicologia , Lesões Encefálicas Traumáticas/psicologia , Citocinas/metabolismo , Encefalite/patologia , Heme Oxigenase (Desciclizante)/biossíntese , Masculino , Ratos , Ratos Sprague-Dawley , Tolueno/uso terapêutico
16.
CNS Neurosci Ther ; 26(6): 636-649, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31828969

RESUMO

AIM: Traumatic brain injury (TBI) is one of the most common causes of morbidity and mortality of both young adults and the elderly, and is a key contributing factor in about 30% of all injury-associated deaths occurring within the United States of America. Albeit substantial impact has been made to improve our comprehension of the mechanisms that underpin the primary and secondary injury stages initiated by a TBI incident, this knowledge has yet to successfully translate into the development of an effective TBI pharmacological treatment. Developing consent suggests that a TBI can concomitantly trigger multiple TBI-linked cascades that then progress in parallel and, if correct, the multifactorial nature of TBI would make the discovery of a single effective mechanism-targeted drug unlikely. DISCUSSION: We review recent data indicating that the small molecular weight drug (-)-phenserine tartrate (PhenT), originally developed for Alzheimer's disease (AD), effectively inhibits a broad range of mechanisms pertinent to mild (m) and moderate (mod)TBI, which in combination underpin the ensuing cognitive and motor impairments. In cellular and animal models at clinically translatable doses, PhenT mitigated mTBI- and modTBI-induced programmed neuronal cell death (PNCD), oxidative stress, glutamate excitotoxicity, neuroinflammation, and effectively reversed injury-induced gene pathways leading to chronic neurodegeneration. In addition to proving efficacious in well-characterized animal TBI models, significantly mitigating cognitive and motor impairments, the drug also has demonstrated neuroprotective actions against ischemic stroke and the organophosphorus nerve agent and chemical weapon, soman. CONCLUSION: In the light of its tolerability in AD clinical trials, PhenT is an agent that can be fast-tracked for evaluation in not only civilian TBI, but also as a potentially protective agent in battlefield conditions where TBI and chemical weapon exposure are increasingly jointly occurring.

17.
J Vis Exp ; (153)2019 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-31814625

RESUMO

Stem cell-based therapies for brain injuries, such as traumatic brain injury (TBI), are a promising approach for clinical trials. However, technical hurdles such as invasive cell delivery and tracking with low transplantation efficiency remain challenges in translational stem-based therapy. This article describes an emerging technique for stem cell labeling and tracking based on the labeling of the mesenchymal stem cells (MSCs) with superparamagnetic iron oxide (SPIO) nanoparticles, as well as intranasal delivery of the labeled MSCs. These nanoparticles are fluorescein isothiocyanate (FITC)-embedded and safe to label the MSCs, which are subsequently delivered to the brains of TBI-induced mice by the intranasal route. They are then tracked non-invasively in vivo by real-time magnetic resonance imaging (MRI). Important advantages of this technique that combines SPIO for cell labeling and intranasal delivery include (1) non-invasive, in vivo MSC tracking after delivery for long tracking periods, (2) the possibility of multiple dosing regimens due to the non-invasive route of MSC delivery, and (3) possible applications to humans, owing to the safety of SPIO, non-invasive nature of the cell-tracking method by MRI, and route of administration.


Assuntos
Lesões Encefálicas Traumáticas/patologia , Rastreamento de Células/métodos , Nanopartículas de Magnetita , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Animais , Lesões Encefálicas Traumáticas/terapia , Modelos Animais de Doenças , Compostos Férricos , Imageamento por Ressonância Magnética/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL
18.
J Biomed Sci ; 26(1): 94, 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31787098

RESUMO

BACKGROUND: Insulin-like growth factor 1 (IGF-1) is an important pleiotropic hormone that exerts neuroprotective and neuroreparative effects after a brain injury. However, the roles of IGF-1 variants in mild traumatic brain injury (mTBI) are not yet fully understood. This study attempted to elucidate the effects of IGF-1 variants on the risk and neuropsychiatric outcomes of mTBI. METHODS: Based on 176 recruited mTBI patients and 1517 control subjects from the Taiwan Biobank project, we first compared the genotypic distributions of IGF-1 variants between the two groups. Then, we analyzed associations of IGF-1 variants with neuropsychiatric symptoms after mTBI, including anxiety, depression, dizziness, and sleep disturbances. Functional annotation of IGF-1 variants was also performed through bioinformatics databases. RESULTS: The minor allele of rs7136446 was over-represented in mTBI patients compared to community-based control subjects. Patients carrying minor alleles of rs7136446 and rs972936 showed more dizziness and multiple neuropsychiatric symptoms after brain injury. CONCLUSIONS: IGF-1 variants were associated with the risk and neuropsychiatric symptoms of mTBI. The findings highlight the important role of IGF-1 in the susceptibility and clinical outcomes of mTBI.


Assuntos
Ansiedade/genética , Concussão Encefálica/genética , Depressão/genética , Tontura/genética , Fator de Crescimento Insulin-Like I/genética , Polimorfismo Genético , Transtornos do Sono-Vigília/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Ansiedade/etiologia , Concussão Encefálica/complicações , Depressão/etiologia , Tontura/etiologia , Feminino , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Transtornos do Sono-Vigília/etiologia , Taiwan , Adulto Jovem
19.
Cell Transplant ; 28(9-10): 1183-1196, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31177840

RESUMO

Traumatic brain injury (TBI), a major cause of mortality and morbidity, affects 10 million people worldwide, with limited treatment options. We have previously shown that (-)-phenserine (Phen), an acetylcholinesterase inhibitor originally designed and tested in clinical phase III trials for Alzheimer's disease, can reduce neurodegeneration after TBI and reduce cognitive impairments induced by mild TBI. In this study, we used a mouse model of moderate to severe TBI by controlled cortical impact to assess the effects of Phen on post-trauma histochemical and behavioral changes. Animals were treated with Phen (2.5 mg/kg, IP, BID) for 5 days started on the day of injury and the effects were evaluated by behavioral and histological examinations at 1 and 2 weeks after injury. Phen significantly attenuated TBI-induced contusion volume, enlargement of the lateral ventricle, and behavioral impairments in motor asymmetry, sensorimotor functions, motor coordination, and balance functions. The morphology of microglia was shifted to an active from a resting form after TBI, and Phen dramatically reduced the ratio of activated to resting microglia, suggesting that Phen also mitigates neuroinflammation after TBI. While Phen has potent anti-acetylcholinesterase activity, its (+) isomer Posiphen shares many neuroprotective properties but is almost completely devoid of anti-acetylcholinesterase activity. We evaluated Posiphen at a similar dose to Phen and found similar mitigation in lateral ventricular size increase, motor asymmetry, motor coordination, and balance function, suggesting the improvement of these histological and behavioral tests by Phen treatment occur via pathways other than anti-acetylcholinesterase inhibition. However, the reduction of lesion size and improvement of sensorimotor function by Posiphen were much smaller than with equivalent doses of Phen. Taken together, these results show that post-injury treatment with Phen over 5 days significantly ameliorates severity of TBI. These data suggest a potential development of this compound for clinical use in TBI therapy.


Assuntos
Comportamento Animal/efeitos dos fármacos , Contusão Encefálica , Fármacos Neuroprotetores/farmacologia , Fisostigmina/análogos & derivados , Animais , Contusão Encefálica/tratamento farmacológico , Contusão Encefálica/metabolismo , Contusão Encefálica/patologia , Contusão Encefálica/fisiopatologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Inflamação/fisiopatologia , Masculino , Camundongos , Microglia/metabolismo , Microglia/patologia , Fisostigmina/farmacologia , Fatores de Tempo
20.
Brain Res ; 1720: 146301, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31226324

RESUMO

Although a good deal is known about the genetics and pathophysiology of Parkinson's disease (PD), and information is emerging about its cause, there are no pharmacological treatments shown to have a significant, sustained capacity to prevent or attenuate the ongoing neurodegenerative processes. However, there is accumulating clinical results to suggest that physical exercise is such a treatment, and studies of animal models of the dopamine (DA) deficiency associated with the motor symptoms of PD further support this hypothesis. Exercise is a non-pharmacological, economically practical, and sustainable intervention with little or no risk and with significant additional health benefits. In this study, we investigated the long-term effects of voluntary exercise on motor behavior and brain biochemistry in the transgenic MitoPark mouse PD model with progressive degeneration of the DA systems caused by DAT-driven deletion of the mitochondrial transcription factor TFAM in DA neurons. We found that voluntary exercise markedly improved behavioral function, including overall motor activity, narrow beam walking, and rotarod performance. There was also improvement of biochemical markers of nigrostriatal DA input. This was manifested by increased levels of DA measured by HPLC, and of the DA membrane transporter measured by PET. Moreover, exercise increased oxygen consumption and, by inference, ATP production via oxidative phosphorylation. Thus, exercise augmented aerobic mitochondrial oxidative metabolism vs glycolysis in the nigrostriatal system. We conclude that there are clear-cut physiological mechanisms for beneficial effects of exercise in PD.


Assuntos
Doença de Parkinson/metabolismo , Esforço Físico/fisiologia , Animais , Biomarcadores/metabolismo , Corpo Estriado/efeitos dos fármacos , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mitocôndrias/metabolismo , Atividade Motora/fisiologia , Doença de Parkinson/terapia , Substância Negra/efeitos dos fármacos , Fatores de Transcrição/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...