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1.
Neurotox Res ; 2021 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-34599751

RESUMO

Oxidative stress is a key factor in the pathogenesis of several neurodegenerative disorders and is involved in the accumulation of amyloid beta plaques and Tau inclusions. Edaravone (EDR) is a free radical scavenger that is approved for motor neuron disease and acute ischemic stroke. EDR alleviates pathologies and cognitive impairment of AD via targeting multiple key pathways in transgenic mice. Herein, we aimed to study the effect of EDR on Tau pathology in P301L mice; an animal model of frontotemporal dementia (FTD), at two age time points representing the early and late stages of the disease. A novel EDR formulation was utilized in the study and the drug was delivered orally in drinking water for 3 months. Then, behavioral tests were conducted followed by animal sacrifice and brain dissection. Treatment with EDR improved the reference memory and accuracy in the probe trial as evaluated in Morris water maze, as well as novel object recognition and significantly alleviated motor deficits in these mice. EDR also reduced the levels of 4-hydroxy-2-nonenal and 3-nitrotyrosine adducts. In addition, immunohistochemistry showed that EDR reduced tau phosphorylation and neuroinflammation and partially rescued neurons against oxidative neurotoxicity. Moreover, EDR attenuated downstream pathologies involved in Tau hyperphosphorylation. These results suggest that EDR may be a potential therapeutic agent for the treatment of FTD.

2.
Biomed Pharmacother ; 144: 112273, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34700232

RESUMO

Neurogenesis in the adult brain is well recognized and plays a critical role in the maintenance of brain function and homeostasis. However, whether neurogenesis also occurs in the adult peripheral nervous system remains unknown. Here, using sensory ganglia (dorsal root ganglia, DRGs) as a model, we show that neurogenesis also occurs in the peripheral nervous system, but in a manner different from that in the central nervous system. Satellite glial cells (SGCs) express the neuronal precursor markers Nestin, POU domain, class 4, transcription factor 1, and p75 pan-neurotrophin receptor. Following sciatic nerve injury, the suppression of endogenous proBDNF by proBDNF antibodies resulted in the transformation of proliferating SGCs into doublecortin-positive cells in the DRGs. Using purified SGCs migrating out from the DRGs, the inhibition of endogenous proBDNF promoted the conversion of SGCs into neuronal phenotypes in vitro. Our findings suggest that SGCs are neuronal precursors, and that proBDNF maintains the SGC phenotype. Furthermore, the suppression of proBDNF signaling is necessary for neuronal phenotype acquisition by SGCs. Thus, we propose that peripheral neurogenesis may occur via the direct conversion of SGCs into neurons, and that this process is negatively regulated by proBDNF.

3.
Neurochem Int ; 151: 105196, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34601013

RESUMO

Alzheimer's disease (AD) is a highly prevalent neurodegenerative disorder characterized by the pathological hallmarks of ß-amyloid plaque deposits, tau pathology, inflammation, and cognitive decline. Hyperoside, a flavone glycoside isolated from Rhododendron brachycarpum G. Don (Ericaceae), has neuroprotective effects against Aß both in vitro and in vivo. However, whether hyperoside could delay AD pathogenesis remains unclear. In the present study, we observed if chronic treatment with hyperoside can reverse pathological progressions of AD in the APP/PS1 transgenic mouse model. Meanwhile, we attempted to elucidate the molecular mechanisms involved in regulating its effects. After 9 months of treatment, we found that hyperoside can improve spatial learning and memory in APP/PS1 transgenic mice, reduce amyloid plaque deposition and tau phosphorylation, decrease the number of activated microglia and astrocytes, and attenuate neuroinflammation and oxidative stress in the brain of APP/PS1 mice. These beneficial effects may be mediated in part by influencing reduction of BACE1 and GSK3ß levels. Hyperoside confers neuroprotection against the pathology of AD in APP/PS1 mouse model and is emerging as a promising therapeutic candidate drug for AD.

4.
Curr Alzheimer Res ; 18(5): 428-442, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34488598

RESUMO

BACKGROUND: High cholesterol aggravates the risk development of Alzheimer's disease (AD). AD is closely related to the transport impairment of Amyloid-ß (Aß) in the blood-brain barrier. It is unclear whether high cholesterol affects the risk of cognitive impairment in AD by affecting Aß transport. The purpose of the study is to investigate whether high cholesterol regulates Aß transport through low-density Lipoprotein Receptor-Related Protein 1 (LRP1) and Receptor for Advanced Glycation End products (RAGE) in the risk development of AD. METHODS: We established high cholesterol AD mice model. The learning and memory functions were evaluated by Morris Water Maze (MWM). Cerebral microvascular endothelial cells were isolated, cultured, and observed. The expression levels of LRP1 and RAGE of endothelial cells and their effect on Aß transport in vivo were observed. The expression level of LRP1 and RAGE was detected in cultured microvessels after using Wnt inhibitor DKK-1 and ß-catenin inhibitor XAV-939. RESULTS: Hypercholesterolemia exacerbated spatial learning and memory impairment. Hypercholesterolemia increased serum Aß40 level, while serum Aß42 level did not change significantly. Hypercholesterolemia decreased LRP1 expression and increased RAGE expression in cerebral microvascular endothelial cells. Hypercholesterolemia increased brain apoptosis in AD mice. In in vitro experiment, high cholesterol decreased LRP1 expression and increased RAGE expression, increased Aß40 expression in cerebral microvascular endothelial cells. High cholesterol regulated the expressions of LRP1 and RAGE and transcriptional activity of LRP1 and RAGE promoters by the Wnt/ß-catenin signaling pathway. CONCLUSION: High cholesterol decreased LRP1 expression and increased RAGE expression in cerebral microvascular endothelial cells, which led to Aß transport disorder in the blood-brain barrier. Increased Aß deposition in the brain aggravated apoptosis in the brain, resulting to cognitive impairment of AD mice.

6.
Int J Mol Sci ; 22(14)2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34299000

RESUMO

Parkinson's disease (PD) is the most common movement disorder, characterized by progressive degeneration of the nigrostriatal pathway, which consists of dopaminergic cell bodies in substantia nigra and their neuronal projections to the striatum. Moreover, PD is associated with an array of non-motor symptoms such as olfactory dysfunction, gastrointestinal dysfunction, impaired regulation of the sleep-wake cycle, anxiety, depression, and cognitive impairment. Inflammation and concomitant oxidative stress are crucial in the pathogenesis of PD. Thus, this study aimed to model PD via intrastriatal injection of the inflammagen lipopolysaccharide (LPS)to investigate if the lesion causes olfactory and motor impairments, inflammation, oxidative stress, and alteration in synaptic proteins in the olfactory bulb, striatum, and colon. Ten µg of LPS was injected unilaterally into the striatum of 27 male C57BL/6 mice, and behavioural assessment was conducted at 4 and 8 weeks post-treatment, followed by tissue collection. Intrastriatal LPS induced motor impairment in C57BL/6 mice at 8 weeks post-treatment evidenced by reduced latency time in the rotarod test. LPS also induced inflammation in the striatum characterized by increased expression of microglial marker Iba-1 and astrocytic marker GFAP, with degeneration of dopaminergic neuronal fibres (reduced tyrosine hydroxylase immunoreactivity), and reduction of synaptic proteins and DJ-1 protein. Additionally, intrastriatal LPS induced inflammation, oxidative stress and alterations in synaptic proteins within the olfactory bulb, although this did not induce a significant impairment in olfactory function. Intrastriatal LPS induced mild inflammatory changes in the distal colon, accompanied by increased protein expression of 3-nitrotyrosine-modified proteins. This model recapitulated the major features of PD such as motor impairment and degeneration of dopaminergic neuronal fibres in the striatum, as well as some pathological changes in the olfactory bulb and colon; thus, this model could be suitable for understanding clinical PD and testing neuroprotective strategies.


Assuntos
Astrócitos/metabolismo , Colo/metabolismo , Corpo Estriado/metabolismo , Neurônios Dopaminérgicos/metabolismo , Lipopolissacarídeos/metabolismo , Bulbo Olfatório/metabolismo , Doença de Parkinson/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Escala de Avaliação Comportamental , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Colo/patologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/patologia , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Proteína Glial Fibrilar Ácida/metabolismo , Imuno-Histoquímica , Inflamação/metabolismo , Inflamação/patologia , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas dos Microfilamentos/metabolismo , Microglia/metabolismo , Microglia/patologia , Bulbo Olfatório/efeitos dos fármacos , Bulbo Olfatório/patologia , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson/patologia , Doença de Parkinson/psicologia , Proteína Desglicase DJ-1/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Substância Negra/metabolismo , Substância Negra/patologia , Tirosina 3-Mono-Oxigenase/metabolismo , alfa-Sinucleína/metabolismo
7.
Neurotoxicology ; 85: 254-264, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34097939

RESUMO

Parkinson's disease (PD) is the second most common neurodegenerative disease, characterised by the loss of dopaminergic neurons in the substantia nigra. Mounting evidence indicates a crucial role of inflammation and concomitant oxidative stress in the disease progression. Therefore, the aim of this study was to investigate the ability of systemically administered lipopolysaccharide (LPS) to induce motor and non-motor symptoms of PD, inflammation, oxidative stress and major neuropathological hallmarks of the disease in regions postulated to be affected, including the olfactory bulb, hippocampus, midbrain and cerebellum. Twenty-one male C57BL/6 mice, approximately 20 weeks old, received a dose of 0.3 mg/kg/day of LPS systemically on 4 consecutive days and behavioural testing was conducted on days 14-18 post-treatment, followed by tissue collection. Systemically administered LPS increased latency time in the buried food seeking test (indicative of olfactory impairment), and decreased time spent in central zone of the open field (anxiety-like behaviour). However, there was no change in latency time in the rotarod test or the expression of tyrosine hydroxylase (TH) in the midbrain. Systemically administered LPS induced increased glial markers GFAP and Iba-1 and oxidative stress marker 3-nitrotyrosine (3-NT) in the olfactory bulb, hippocampus, midbrain and cerebellum, and there were region specific changes in the expression of NFκB, IL-1ß, α-synuclein, TH and BDNF proteins. The model could be useful to further elucidate early non-motor aspects of PD and the possible mechanisms contributing to the non-motor deficits.

8.
Mol Neurobiol ; 58(8): 3692-3711, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33797693

RESUMO

Alzheimer's disease (AD) is the most common cause of dementia among elderly people. Majority of AD cases are sporadic (SAD) with unknown cause. Transgenic animal models closely reflect the familial (genetic) aspect of the disease but not the sporadic type. However, most new drug candidates which are tested positive in transgenic animal models failed in clinical studies so far. Herein, we aim to develop an AD animal model that combines most of the neuropathological features seen in sporadic AD in humans with amyloid plaques observed in transgenic mice. Four-month-old wild-type and APP/PS1 AD mice were given a single intracerebroventricular (ICV) injection of 3 mg/kg streptozotocin (STZ), a diabetogenic agent. Three weeks later, their cognitive behavior was assessed, and their brain tissues were collected for biochemical and histological analysis. STZ produced cognitive deficits in both non-transgenic mice and AD mice. Biochemical analysis showed a severe decline in synaptic proteins, increase in tau phosphorylation, oxidative stress, disturbed brain insulin signaling with extensive neuroinflammation, and cell death. Significant increase was also observed in the level of the soluble beta amyloid precursor protein (APP) fragments and robust accumulation of amyloid plaques in AD mice compared to the control. These results suggest that STZ ICV treatment causes disturbance in multiple metabolic and cell signaling pathways in the brain that facilitated amyloid plaque accumulation and tau phosphorylation. Therefore, this animal model can be used to evaluate new AD therapeutic agents for clinical translation.

9.
Am J Chin Med ; 49(3): 677-703, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33704029

RESUMO

To investigate the therapeutic efficacy of Scutellarin (SCU) on neurite growth and neurological functional recovery in neonatal hypoxic-ischemic (HI) rats. Primary cortical neurons were cultured to detect the effect of SCU on cell viability of neurons under oxygen-glucose deprivation (OGD). Double immunofluorescence staining of Tuj1 and TUNEL then observed the neurite growth and cell apoptosis in vitro,and double immunofluorescence staining of NEUN and TUNEL was performed to examine the neuronal apoptosis and cell apoptosis in brain tissues after HI in vivo. Pharmacological efficacy of SCU was also evaluated in HI rats by neurobehavioral tests, triphenyl tetrazolium chloride staining, Hematoxylin and eosin staining and Nissl staining. Astrocytes and microglia expression in damaged brain tissues were detected by immunostaining of GFAP and Iba1. A quantitative real-time polymerase chain reaction and western blot were applied to investigate the genetic expression changes and the protein levels of autophagy-related proteins in the injured cortex and hippocampus after HI. We found that SCU administration preserved cell viability, promoted neurite outgrowth and suppressed apoptosis of neurons subjected to OGD both in vitroand in vivo. Meanwhile, 20 mg/kg SCU treatment improved neurological functions and decreased the expression of astrocytes and microglia in the cortex and hippocampus of HI rats. Additionally, SCU treatment depressed the elevated levels of autophagy-related proteins and the p75 neurotrophin receptor (p75NTR) in both cortex and hippocampus. This study demonstrated the potential therapeutic efficacy of SCU by enhancing neurogenesis and restoring long-term neurological dysfunctions, which might be associated with p75NTR depletion in HI rats.


Assuntos
Animais Recém-Nascidos , Apigenina/farmacologia , Apigenina/uso terapêutico , Encéfalo/fisiopatologia , Glucuronatos/farmacologia , Glucuronatos/uso terapêutico , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Hipóxia-Isquemia Encefálica/genética , Neurogênese/efeitos dos fármacos , Crescimento Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Autofagia/genética , Encéfalo/citologia , Encéfalo/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Hipóxia-Isquemia Encefálica/fisiopatologia , Proteínas do Tecido Nervoso/metabolismo , Neurônios/fisiologia , Ratos , Receptores de Fatores de Crescimento/metabolismo
11.
Stem Cells ; 39(6): 803-818, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33554422

RESUMO

The interplay between mesenchymal stem cells (MSCs) and immune cells has been studied for MSCs isolated from different tissues. However, the immunomodulatory capacity of urine stem cells (USCs) has not been adequately researched. The present study reports on the effect of USCs on peripheral blood lymphocytes. USCs were isolated and characterized before coculture with resting and with anti-CD3/CD28 bead stimulated lymphocytes. Similarly to bone marrow mesenchymal stem cells (BM-MSCs), USCs inhibited the proliferation of activated T lymphocytes and induced their apoptosis. However, they also induced strong activation, proliferation, and cytokine and antibody production by B lymphocytes. Molecular phenotype and supernatant analysis revealed that USCs secrete a range of cytokines and effector molecules, known to play a central role in B cell biology. These included B cell-activating factor (BAFF), interleukin 6 (IL-6) and CD40L. These findings raise the possibility of an unrecognized active role for kidney stem cells in modulating local immune cells.

12.
Neural Regen Res ; 16(8): 1453-1459, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33433458

RESUMO

Brain-derived neurotrophic factor (BDNF) regulates many neurological functions and plays a vital role during the recovery from central nervous system injuries. However, the changes in BDNF expression and associated factors following hypoxia-ischemia induced neonatal brain damage, and the significance of these changes are not fully understood. In the present study, a rat model of hypoxic-ischemic brain damage was established through the occlusion of the right common carotid artery, followed by 2 hours in a hypoxic-ischemic environment. Rats with hypoxic-ischemic brain damage presented deficits in both sensory and motor functions, and obvious pathological changes could be detected in brain tissues. The mRNA expression levels of BDNF and its processing enzymes and receptors (Furin, matrix metallopeptidase 9, tissue-type plasminogen activator, tyrosine Kinase receptor B, plasminogen activator inhibitor-1, and Sortilin) were upregulated in the ipsilateral hippocampus and cerebral cortex 6 hours after injury; however, the expression levels of these mRNAs were found to be downregulated in the contralateral hippocampus and cerebral cortex. These findings suggest that BDNF and its processing enzymes and receptors may play important roles in the pathogenesis and recovery from neonatal hypoxic-ischemic brain damage. This study was approved by the Animal Ethics Committee of the University of South Australia (approval No. U12-18) on July 30, 2018.

13.
Eur J Drug Metab Pharmacokinet ; 46(2): 235-248, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33507523

RESUMO

BACKGROUND AND OBJECTIVE: p75ECD-Fc is a novel antagonist of toxic amyloid beta protein and other neurodegenerative factors with potential for the treatment of Alzheimer's disease (AD). Preclinical studies showed that it can alleviate the AD pathologies in animal models of dementia. In a previous paper, we used non-compartmental pharmacokinetic analysis to obtain preliminary pharmacokinetic data for p75ECD-Fc in Sprague Dawley (SD) rats. We also studied the tissue distribution in terms of drug metabolism that helped us to understand possible mechanisms of action. Here, we aim to develop population pharmacokinetic models that can describe the pharmacokinetics of p75ECD-Fc in serum and tissues. METHODS: p75ECD-Fc was delivered to SD rats via two routes (intravenous and subcutaneous) at a single dose of 3 mg/kg (n = 15). Blood (n = 12) and tissue samples (n = 10-15) were then separated at different time points for a total duration of 42 days post dosage. The concentration of p75ECD-Fc in serum and tissues was measured using an enzyme-linked immunosorbent assay. RESULTS: Data were best fitted to a 2-compartment model with linear elimination kinetics. The population parameter estimates for clearance, and volume of central and peripheral compartments were 0.000176 L/h, 0.0145 L and 0.0263 L, respectively. The presence of anti-drug antibodies was added to the final model as a covariate on clearance. The subcutaneous bioavailability was estimated to be 53.5% with a first-order absorption rate constant of 0.00745 1/h. By modeling of individual tissue concentrations, p75ECD-Fc was found to exhibit modest tissue distribution with estimated tissue/plasma partition coefficients (R) ranging from 0.004 to 0.2. CONCLUSION: This is the first report of a pharmacokinetic model for p75ECD-Fc and these results may facilitate the ongoing development of p75ECD-Fc and translation to clinical studies.


Assuntos
Modelos Biológicos , Proteínas Recombinantes/farmacocinética , Animais , Anticorpos/imunologia , Disponibilidade Biológica , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Injeções Intravenosas , Injeções Subcutâneas , Masculino , Ratos , Ratos Sprague-Dawley , Fatores de Tempo , Distribuição Tecidual
14.
Int J Mol Sci ; 22(1)2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33466423

RESUMO

Elucidation of the biological functions of extracellular vesicles (EVs) and their potential roles in physiological and pathological processes is an expanding field of research. In this study, we characterized USC-derived EVs and studied their capacity to modulate the human immune response in vitro. We found that the USC-derived EVs are a heterogeneous population, ranging in size from that of micro-vesicles (150 nm-1 µm) down to that of exosomes (60-150 nm). Regarding their immunomodulatory functions, we found that upon isolation, the EVs (60-150 nm) induced B cell proliferation and IgM antibody secretion. Analysis of the EV contents unexpectedly revealed the presence of BAFF, APRIL, IL-6, and CD40L, all known to play a central role in B cell stimulation, differentiation, and humoral immunity. In regard to their effect on T cell functions, they resembled the function of mesenchymal stem cell (MSC)-derived EVs previously described, suppressing T cell response to activation. The finding that USC-derived EVs transport a potent bioactive cargo opens the door to a novel therapeutic avenue for boosting B cell responses in immunodeficiency or cancer.


Assuntos
Linfócitos B/imunologia , Vesículas Extracelulares/imunologia , Ativação Linfocitária/imunologia , Adulto , Diferenciação Celular/imunologia , Proliferação de Células/fisiologia , Exossomos/imunologia , Humanos , Imunidade Humoral/imunologia , Imunoglobulina M/imunologia , Imunomodulação/imunologia , Masculino , Células-Tronco Mesenquimais/imunologia , Pessoa de Meia-Idade , Linfócitos T/imunologia , Adulto Jovem
15.
Theranostics ; 11(2): 715-730, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33391501

RESUMO

Rationale: Brain-derived neurotrophic factor precursor (proBDNF) is expressed in the central nervous system (CNS) and the immune system. However, the role of proBDNF in the pathogenesis of multiple sclerosis (MS) is unknown. Methods: Peripheral blood and post-mortem brain and spinal cord specimens were obtained from multiple sclerosis patients to analyze proBDNF expression in peripheral lymphocytes and infiltrating immune cells in the lesion site. The proBDNF expression profile was also examined in the experimental autoimmune encephalomyelitis (EAE) mouse model, and polyclonal and monoclonal anti-proBDNF antibodies were used to explore their therapeutic effect in EAE. Finally, the role of proBDNF in the inflammatory immune activity of peripheral blood mononuclear cells (PBMCs) was verified in vitro experiments. Results: High proBDNF expression was detected in the circulating lymphocytes and infiltrated inflammatory cells at the lesion sites of the brain and spinal cord in MS patients. In the EAE mouse model, proBDNF was upregulated in CNS and in circulating and splenic lymphocytes. Systemic but not intracranial administration of anti-proBDNF blocking antibodies attenuated clinical scores, limited demyelination, and inhibited proinflammatory cytokines in EAE mice. Immuno-stimulants treatment increased the proBDNF release and upregulated the expression of p75 neurotrophic receptors (p75NTR) in lymphocytes. The monoclonal antibody against proBDNF inhibited the inflammatory response of PBMCs upon stimulations. Conclusion: The findings suggest that proBDNF from immune cells promotes the immunopathogenesis of MS. Monoclonal Ab-proB may be a promising therapeutic agent for treating MS.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Encéfalo/metabolismo , Encefalomielite Autoimune Experimental/patologia , Leucócitos Mononucleares/metabolismo , Leucócitos/metabolismo , Esclerose Múltipla/patologia , Precursores de Proteínas/metabolismo , Medula Espinal/metabolismo , Animais , Encéfalo/imunologia , Estudos de Casos e Controles , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Humanos , Leucócitos/imunologia , Leucócitos Mononucleares/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/imunologia , Esclerose Múltipla/metabolismo , Medula Espinal/imunologia
16.
Behav Brain Res ; 396: 112905, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-32926907

RESUMO

The precursor of brain derived neurotrophic factor (proBDNF) and its receptor p75NTR are upregulated in depressive patients and chronic stress-induced depressive animals, suggesting that activation of p75NTR signalling may underlie pathogenesis of depression. In the present study we hypothesize that the blockade of p75NTR may have therapeutic effect on depressive mice under chronic stress. The treatment of mice with the recombinant fusion protein of p75NTR extracellular domain and fragment C of immunoglobulin (p75ECD-Fc) significantly reduced the immobility time in the forced swim test and tail suspension test, and increased the time spent in the central zone in the open field test in mice exposed to chronic unpredictable mild stress (CUMS). p75ECD-Fc treatment also significantly increased the length and density of neuronal dendritic spines in the dentate gyrus and amygdala. Our data indicate that blocking p75NTR signalling can alleviate depressive and anxiety-like behaviours of chronically stressed mice and improve the dendritic spinogenesis of neurons under stress.


Assuntos
Depressão/tratamento farmacológico , Depressão/fisiopatologia , Receptores de Fator de Crescimento Neural/antagonistas & inibidores , Proteínas Recombinantes de Fusão/administração & dosagem , Estresse Psicológico/fisiopatologia , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Espinhas Dendríticas/efeitos dos fármacos , Giro Denteado/efeitos dos fármacos , Depressão/etiologia , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Projetos Piloto , Distribuição Aleatória , Método Simples-Cego , Estresse Psicológico/complicações
17.
J Psychiatr Res ; 133: 166-173, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33341455

RESUMO

Previous studies showed that blood BDNF levels in mood disorders were reduced. However, little is known about the changes of BDNF and its precursor proBDNF in lymphocytes. In addition, earlier studies using commercial ELISA kits cannot distinguish mature BDNF from proBDNF. We aimed to investigate the change of mBDNF and proBDNF levels in the peripheral blood and their diagnostic value in the mood disorders using a specific Enzyme-Linked Immunosorbent Assay (ELISA). Serum mBDNF levels were significantly decreased in major depressive disorder (MDD) (n = 90) and bipolar disorder (BD) (n = 15) groups (P < 0.0001), whereas there was no significant change in suicidal group (n = 14) compared to the control group (n = 96). In the subgroups of MDD, the serum mBDNF level in MDD patients with severe symptoms was significantly lower than that with moderate symptoms (P < 0.05). The serum mBDNF levels in antidepressant-free patients were significantly lower than in antidepressant-treated patients (P < 0.01). Serum mBDNF yielded good diagnostic effectiveness for MDD and BD with sensitivity and specificity around 80-83%. The levels of mBDNF, proBDNF and its receptor sortilin were upregulated in lymphocytes of MDD patients relative to control subjects. Specific ELISA assays for mature BDNF confirmed the reduction of serum mBDNF level in MDD and BD. The measurement of mBDNF level could be a potential diagnostic marker with a cut-off point at 12.4 ng/ml. Upregulations of proBDNF and mBDNF in lymphocytes of MDD patients might be considered as novel pathological biomarkers for MDD.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Transtorno Depressivo Maior , Antidepressivos , Transtorno Depressivo Maior/tratamento farmacológico , Ensaio de Imunoadsorção Enzimática , Humanos , Transtornos do Humor/tratamento farmacológico
18.
Front Cell Dev Biol ; 8: 529544, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33262982

RESUMO

Neonatal hypoxic ischemic encephalopathy (HIE) due to birth asphyxia is common and causes severe neurological deficits, without any effective therapies currently available. Neuronal death is an important driving factors of neurological disorders after HIE, but the regulatory mechanisms are still uncertain. Long non-coding RNA (lncRNA) or ceRNA network act as a significant regulator in neuroregeneration and neuronal apoptosis, thus owning a great potential as therapeutic targets in HIE. Here, we found a new lncRNA, is the most functional in targeting the Igfbp3 gene in HIE, which enriched in the cell growth and cell apoptosis processes. In addition, luciferase reporter assay showed competitive regulatory binding sites to the target gene Igfbp3 between TCONS00044054 (Vi4) and miR-185-5p. The change in blood miR-185-5p and Igfbp3 expression is further confirmed in patients with brain ischemia. Moreover, Vi4 overexpression and miR-185-5p knock-out promote the neuron survival and neurite growth, and suppress the cell apoptosis, then further improve the motor and cognitive deficits in rats with HIE, while Igfbp3 interfering got the opposite results. Together, Vi4-miR-185-5p-Igfbp3 regulatory network plays an important role in neuron survival and cell apoptosis and further promote the neuro-functional recovery from HIE, therefore is a likely a drug target for HIE therapy.

19.
Neurotox Res ; 38(4): 1063, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32948991

RESUMO

Dr. Chang-Qi Li should be added as co-author because Fig. 1 originated from him.

20.
Neuroscience ; 446: 261-270, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32798590

RESUMO

Up-regulation of proBDNF in ischemic brain and the detrimental role of proBDNF on cellular survival has already been established. We propose that the up-regulated proBDNF may trigger the harmful events and evoke a secondary ischemic damage after ischemia. This study aimed to establish the neuroprotective effects of anti-proBDNF antibody in a rat photothrombotic ischemic model. Photothrombotic ischemic model was performed on Sprague Dawley rats and anti-proBDNF antibodies were administered intraperitoneally to the ischemic rats at a dose of 5 mg/kg after 6 hours (6 h) and on 3 days (3d) after ischemia. Behavioural tests were performed for sensorimotor functional analyses. Animals were euthanized at 7d for histochemical and biochemical studies. We observed higher proBDNF expression around the ischemic infarct. Higher level of apoptosis and inflammation was evident at 7d after ischemia on brain sections. Interestingly, the anti-proBDNF treatment instigated significant reduction of the infarction size as detected by Haematoxylin and Eosin (H&E) staining. Similar reduction of apoptotic signaling proteins in western blot and immunostaining after anti-proBDNF treatment was found. Up-regulation of synaptic protein expression was also observed after this treatment. Significant sensorimotor functional improvements were also noticed at 7d after anti-proBDNF treatment. We conclude that anti-proBDNF treatment is anti-apoptotic and anti-inflammatory, and plays advantageous role in promoting cellular growth and improving sensorimotor function after ischemic insult. Taken together, our study suggests that this anti-proBDNF treatment can be considered as a therapeutic approach for ischemic recovery.


Assuntos
Isquemia Encefálica , Fármacos Neuroprotetores , Animais , Isquemia Encefálica/tratamento farmacológico , Fator Neurotrófico Derivado do Encéfalo , Isquemia , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley
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