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1.
Int J Mol Sci ; 22(2)2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33430140

RESUMO

Neurodegenerative diseases are characterized by adverse cellular environments and pathological alterations causing neurodegeneration in distinct brain regions. This development is triggered or facilitated by conditions such as hypoxia, ischemia or inflammation and is associated with disruptions of fundamental cellular functions, including metabolic and ion homeostasis. Targeting intracellular downstream consequences to specifically reverse these pathological changes proved difficult to translate to clinical settings. Here, we discuss the potential of more holistic approaches with the purpose to re-establish a healthy cellular environment and to promote cellular resilience. We review the involvement of important molecular pathways (e.g., the sphingosine, δ-opioid receptor or N-Methyl-D-aspartate (NMDA) receptor pathways) in neuroprotective hypoxic conditioning effects and how these pathways can be targeted for chemical conditioning. Despite the present scarcity of knowledge on the efficacy of such approaches in neurodegeneration, the specific characteristics of Huntington's disease may make it particularly amenable for such conditioning techniques. Not only do classical features of neurodegenerative diseases like mitochondrial dysfunction, oxidative stress and inflammation support this assumption, but also specific Huntington's disease characteristics: a relatively young age of neurodegeneration, molecular overlap of related pathologies with hypoxic adaptations and sensitivity to brain hypoxia. The aim of this review is to discuss several molecular pathways in relation to hypoxic adaptations that have potential as drug targets in neurodegenerative diseases. We will extract the relevance for Huntington's disease from this knowledge base.


Assuntos
Hipóxia Celular/genética , Doença de Huntington/genética , Degeneração Neural/genética , Estresse Oxidativo/genética , Encéfalo/metabolismo , Encéfalo/patologia , Humanos , Doença de Huntington/metabolismo , Doença de Huntington/patologia , Mitocôndrias/genética , Mitocôndrias/metabolismo , N-Metilaspartato/metabolismo , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Fármacos Neuroprotetores/metabolismo , Transdução de Sinais/efeitos dos fármacos , Esfingosina/uso terapêutico
2.
Gene ; 767: 145148, 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32949698

RESUMO

Ischemic stroke is a common clinical cardiovascular disease and often accompanied by central nervous system injury. It often causes paralysis or loss of motor function after central nervous system injury and significantly reduces the patient's quality of life. At present, there is no effective treatment strategy for nerve damage caused by ischemic stroke. Therefore, it is urgently need to explore effective treatment targets. The protein expression of SOX5, VEGF and apoptosis related proteins were measured by western blot. The mRNA expression of SOX5 and VEGF were detected by RT-qPCR. The concentration of S100B and GFAP which are related to nerve damage were detected using ELISA assay. The transcriptional regulation of SOX5 on VEGF was detected using ChIP-PCR and dual luciferase reporter gene assays. The cell apoptosis was measured by TUNEL assay and cell viability was detected by CCK-8 assay. In our study, we found that the expression of SOX5 was significantly reduced when LPS induced apoptosis in PC-12 cells. Overexpression of SOX5 repaired LPS-induced apoptosis. SOX5 promotes VEGF expression as a transcription factor to activate the PI3K/AKT pathway. VEGF also repairs nerve injury and brain tissue injury caused by ischemic stroke. In conclusion, SOX5 transcription regulates the expression of VEGF to activate the PI3K/AKT pathway, which repaired nerve damage caused by ischemic stroke. Therefore, SOX5 could be a new targetto regulate VEGF which can repair nerve injury induced by ischemic stroke.


Assuntos
/tratamento farmacológico , Fatores de Transcrição SOXD/metabolismo , Animais , Apoptose/fisiologia , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Morte Celular , Proliferação de Células , Regulação da Expressão Gênica/genética , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Células PC12 , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Fatores de Transcrição SOXD/genética , Fatores de Transcrição SOXD/fisiologia , Transdução de Sinais/genética , Acidente Vascular Cerebral/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fatores de Crescimento do Endotélio Vascular/metabolismo
3.
J Stroke Cerebrovasc Dis ; 29(10): 105128, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32912509

RESUMO

BACKGROUND: The insulin-like growth factor 2 (IGF-2) is a growth factor and anti-inflammatory cytokine that plays a crucial role in memory consolidation. However, the precise role of this factor in acute brain damage is still unclear. The present study aimed to evaluate the variations in hippocampal IGF-2 distribution on different days and investigate the effect of recombinant IGF-2 on memory cell density, and IGF-2 distribution following acute hippocampal damage resulting from intracerebral hemorrhage (ICH). METHODS: ICH was induced by injection of 100 µL of autologous blood into the left hippocampus of 72 male Sprague-Dawley rats. Recombinant IGF-2 was injected into the damaged hippocampus 30 min post-induction of ICH in the ICH-IGF-2 group. Then, on postoperative days 1, 3, 7, and 14, samples of brain tissue were collected to perform histopathological and immunohistochemical examinations. RESULTS: The stereological study indicated that the volume of the hippocampus and the number of neurons had a significant reduction, and the infarct volume had a significant increase following ICH. Following the injection of IGF-2, a significant improvement was observed in stereological studies. Immunohistochemical data showed that IGF-2 distribution increased in the hippocampus on different days after ICH, and IGF-2 injection led to a dramatic reduction in this distribution. CONCLUSIONS: In summary, the gradual increase of endogenous IGF-2 as growth and anti-inflammatory factor following hemorrhagic stroke reveals a critical role of this factor in brain recovery after injury. Moreover, the injection of IGF-2 can prevent cell death and alleviate the damage caused by the hemorrhagic stroke.


Assuntos
Hemorragia Cerebral/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Fator de Crescimento Insulin-Like II/administração & dosagem , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Animais , Morte Celular/efeitos dos fármacos , Hemorragia Cerebral/metabolismo , Hemorragia Cerebral/patologia , Hipocampo/metabolismo , Hipocampo/patologia , Fator de Crescimento Insulin-Like II/metabolismo , Masculino , Neurônios/metabolismo , Neurônios/patologia , Fármacos Neuroprotetores/metabolismo , Ratos Sprague-Dawley , Proteínas Recombinantes/administração & dosagem , Fatores de Tempo , Distribuição Tecidual
4.
PLoS One ; 15(8): e0237025, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32797057

RESUMO

Troxerutin (TRX) is a water-soluble flavonoid which occurs commonly in the edible plants. Recent studies state that TRX improves the functionality of the nervous system and neutralizes Amyloid-ß induced neuronal toxicity. In this study, an in vitro assay based upon Neural stem cell (NSCs) isolated from the subventricular zone of the postnatal balb/c mice was established to explore the impact of TRX on individual neurogenesis processes in general and neuroprotective effect against ß-amyloid 1-42 (Aß42) induced inhibition in differentiation in particular. NSCs were identified exploiting immunostaining of the NSCs markers. Neurosphere clonogenic assay and BrdU/Ki67 immunostaining were employed to unravel the impact of TRX on proliferation. Differentiation experiments were carried out for a time span lasting from 48 h to 7 days utilizing ß-tubulin III and GFAP as neuronal and astrocyte marker respectively. Protective effects of TRX on Aß42 induced depression of NSCs differentiation were determined after 48 h of application. A neurosphere migration assay was carried out for 24 h in the presence and absence of TRX. Interestingly, TRX enhanced neuronal differentiation of NSCs in a dose-dependent manner after 48 h and 7 days of incubation and significantly enhanced neurite growth. A higher concentration of TRX also neutralized the inhibitory effects of Aß42 on neurite outgrowth and length after 48 h of incubation. TRX significantly stimulated cell migration. Overall, TRX not only promoted NSCs differentiation and migration but also neutralized the inhibitory effects of Aß42 on NSCs. TRX, therefore, offers an interesting lead structure from the perspective of drug design especially to promote neurogenesis in neurological disorders i.e. Alzheimer's disease.


Assuntos
Hidroxietilrutosídeo/análogos & derivados , Neuritos/efeitos dos fármacos , Crescimento Neuronal/fisiologia , Precursor de Proteína beta-Amiloide/farmacologia , Animais , Astrócitos/metabolismo , Diferenciação Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Flavonoides/farmacologia , Hidroxietilrutosídeo/metabolismo , Hidroxietilrutosídeo/farmacologia , Ventrículos Laterais/efeitos dos fármacos , Ventrículos Laterais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Neurogênese , Neurônios/metabolismo , Neuroproteção , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia
5.
EBioMedicine ; 59: 102980, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32862101

RESUMO

BACKGROUND: Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease as well as Lou Gehrig's disease, is a progressive neurological disorder selectively affecting motor neurons with no currently known cure. Around 20% of the familial ALS cases arise from dominant mutations in the sod1 gene encoding superoxide dismutase1 (SOD1) enzyme. Aggregation of mutant SOD1 in familial cases and of wild-type SOD1 in at least some sporadic ALS cases is one of the known causes of the disease. Riluzole, approved in 1995 and edaravone in 2017 remain the only drugs with limited therapeutic benefits. METHODS: We have utilised the ebselen template to develop novel compounds that redeem stability of mutant SOD1 dimer and prevent aggregation. Binding modes of compounds have been visualised by crystallography. In vitro neuroprotection and toxicity of lead compounds have been performed in mouse neuronal cells and disease onset delay of ebselen has been demonstrated in transgenic ALS mice model. FINDING: We have developed a number of ebselen-based compounds with improvements in A4V SOD1 stabilisation and in vitro therapeutic effects with significantly better potency than edaravone. Structure-activity relationship of hits has been guided by high resolution structures of ligand-bound A4V SOD1. We also show clear disease onset delay of ebselen in transgenic ALS mice model holding encouraging promise for potential therapeutic compounds. INTERPRETATION: Our finding established the new generation of organo-selenium compounds with better in vitro neuroprotective activity than edaravone. The potential of this class of compounds may offer an alternative therapeutic agent for ALS treatment. The ability of these compounds to target cysteine 111 in SOD may have wider therapeutic applications targeting cysteines of enzymes involved in pathogenic and viral diseases including main protease of SARS-Cov-2 (COVID-19). FUNDING: Project funding was supported by the ALS Association grant (WA1128) and Fostering Joint International Research (19KK0214) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan.


Assuntos
Esclerose Amiotrófica Lateral/tratamento farmacológico , Compostos Organosselênicos/uso terapêutico , Superóxido Dismutase-1/metabolismo , Esclerose Amiotrófica Lateral/mortalidade , Esclerose Amiotrófica Lateral/patologia , Animais , Azóis/química , Azóis/metabolismo , Azóis/uso terapêutico , Betacoronavirus/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Cristalografia por Raios X , Dimerização , Modelos Animais de Doenças , Estabilidade Enzimática , Camundongos , Camundongos Transgênicos , Simulação de Dinâmica Molecular , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Compostos Organosselênicos/química , Compostos Organosselênicos/metabolismo , Estrutura Terciária de Proteína , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/isolamento & purificação , Superóxido Dismutase-1/genética , Taxa de Sobrevida , Proteínas da Matriz Viral/química , Proteínas da Matriz Viral/metabolismo
6.
Life Sci ; 257: 118050, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32634425

RESUMO

BACKGROUND AND PURPOSE: Early brain injury is an essential pathological process after subarachnoid hemorrhage (SAH), with many cell death modalities. Ferroptosis is a newly discovered regulated cell death caused by the iron-dependent accumulation of lipid peroxidation, which can be prevented by glutathione peroxidase 4 (GPX4). Our study aimed to investigate the role of GPX4 in neuronal cell death after experimental SAH. METHODS: In vivo experimental SAH was induced by injecting autologous arterial blood into the prechiasmatic cistern in male Sprague-Dawley rats. Meanwhile, the in vitro SAH model was performed with primary rat cortical neurons cultured in medium containing hemoglobin (Hb). Adenovirus was used to overexpress GPX4 before experimental SAH. GPX4 expression was detected by western blot and immunofluorescence experiments. Malondialdehyde (MDA) was measured to evaluate the level of lipid peroxidation. Nissl staining was employed to assess cell death in vivo, whereas lactate dehydrogenase (LDH) release was used to evaluate cell damage in vitro. The brain water content and neurological deficits were evaluated to determine brain injury. RESULTS: Endogenous GPX4 was mainly expressed in neurons, and its expression decreased at 24 h after experimental SAH. Overexpression of GPX4 significantly reduced lipid peroxidation and cell death in the experimental SAH models both in vivo and in vitro. Moreover, overexpression of GPX4 ameliorated brain edema and neurological deficits at 24 h after SAH. CONCLUSIONS: The decrease of GPX4 expression potentially plays an important role in ferroptosis during early brain injury after SAH. Overexpression of GPX4 has a neuroprotective effect after SAH.


Assuntos
Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/uso terapêutico , Hemorragia Subaracnóidea/tratamento farmacológico , Animais , Antioxidantes/farmacologia , Encéfalo/metabolismo , Edema Encefálico/patologia , Lesões Encefálicas/etiologia , Morte Celular/efeitos dos fármacos , Modelos Animais de Doenças , Ferroptose/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley , Hemorragia Subaracnóidea/metabolismo
7.
Life Sci ; 253: 117671, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32335165

RESUMO

AIMS: We still do not have effective treatment for hippocampal demyelination and memory deficit, the two common comorbidities in multiple sclerosis (MS). This study aimed to assess the therapeutic effect of Piperine (the main alkaloid of black pepper) in an experimental model of demyelination. MAIN METHODS: Demyelination was induced in male Wistar rats by bilateral injection of lysolecithin (LPC) into the CA1 region of the hippocampus. Piperine (5, 10, 20 mg/kg) was daily injected intraperitoneally three days post LPC injection for ten days. The spatial memory was examined by the Morris water maze task. Demyelination and astrocyte activation were assessed by an immunohistological study. The gene expression analysis of TNF-α, IL1-ß, NF-κB, IL-10, Foxp3, iNOS, Nrf2, HO1, MBP, and BDNF was done using qPCR. The total antioxidant capacity of hippocampal tissue was measured using FRAP assay. KEY FINDINGS: Our results showed that piperine improved the memory performance and myelin repair in the hippocampal demyelination model. Piperine inhibited iNOS expression concomitant with enhanced expression levels of Nrf2, HO1 and the total antioxidant capacity in the hippocampal tissue. Piperine treatment significantly reduced the gene expression level of TNF-α, IL1-ß, NF-κB, and glial activation in the injured area; however, the mRNA level of IL-10, Foxp3, BDNF and MBP were significantly increased. SIGNIFICANCE: We found piperine to be an effective treatment for spatial memory impairment and myelin repair in the hippocampal demyelination model. However, further experimental evidence is needed to investigate the precise mechanisms underlying piperine as a promising therapeutic target in MS patients.


Assuntos
Alcaloides/farmacologia , Benzodioxóis/farmacologia , Doenças Desmielinizantes/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Lisofosfatidilcolinas/metabolismo , Transtornos da Memória/tratamento farmacológico , Bainha de Mielina/efeitos dos fármacos , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Alcaloides/metabolismo , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Benzodioxóis/metabolismo , Citocinas/genética , Citocinas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Modelos Animais , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia , Piperidinas/metabolismo , Alcamidas Poli-Insaturadas/metabolismo , Ratos , Ratos Wistar , Memória Espacial/efeitos dos fármacos
8.
Sci Rep ; 10(1): 6654, 2020 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-32313035

RESUMO

Microglia act as the protective immune cell of the brain. By surveying the tissue to identify and rectify problems, they function to maintain the health of brain cells. The prion protein N-terminal cleavage fragment, N1, has demonstrated neuroprotective activities in vitro and in vivo. This study aimed to elucidate whether N1 could modulate microglial function and, if so, determine the consequences for the surrounding tissue. Using a mixed neuronal lineage and microglia co-culture system, we showed that N1 stimulation changed overall morphology and metabolism, suggesting enhanced cellular viability. Furthermore, N1 induced an increase in Cxcl10 secretion in the co-cultures. Recombinant Cxcl10, administered exogenously, mediated the changes in the mixed neuronal lineage culture morphology and metabolism in the absence of microglia, but no effect of Cxcl10 was observed on microglia cultured on their own. Direct cell-to-cell contact was required for N1 to influence microglia in the co-cultures, and this was linked with restructuring of microglial membrane composition to include a higher GM1 content at interaction sites with surrounding cells. Our findings show that N1 can play a regulatory role in microglial function in the context of an inter-connected network of cells by changing both cellular interaction sites and cytokine secretion.


Assuntos
Microglia/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/farmacologia , Proteínas Priônicas/farmacologia , Animais , Encéfalo/citologia , Encéfalo/metabolismo , Comunicação Celular/efeitos dos fármacos , Diferenciação Celular , Quimiocina CXCL10/genética , Quimiocina CXCL10/metabolismo , Técnicas de Cocultura , Gangliosídeo G(M1)/metabolismo , Expressão Gênica/efeitos dos fármacos , Genes Reporter , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Camundongos , Camundongos Knockout , Microglia/citologia , Microglia/metabolismo , Células-Tronco Neurais/citologia , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/metabolismo , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/metabolismo , Cultura Primária de Células , Proteínas Priônicas/química , Proteínas Priônicas/metabolismo , Príons/química , Príons/metabolismo , Receptores CXCR3/genética , Receptores CXCR3/metabolismo , Análise de Célula Única
9.
Arch Biochem Biophys ; 686: 108364, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32315653

RESUMO

Fucoxanthin (Fx), a major carotenoid found in brown seaweed, is known to show a unique and wide variety of biological activities. Upon absorption, Fx is metabolized to fucoxanthinol and amarouciaxanthin, and these metabolites mainly accumulate in visceral white adipose tissue (WAT). As seen in other carotenoids, Fx can quench singlet oxygen and scavenge a wide range of free radicals. The antioxidant activity is related to the neuroprotective, photoprotective, and hepatoprotective effects of Fx. Fx is also reported to show anti-cancer activity through the regulation of several biomolecules and signaling pathways that are involved in either cell cycle arrest, apoptosis, or metastasis suppression. Among the biological activities of Fx, anti-obesity is the most well-studied and most promising effect. This effect is primarily based on the upregulation of thermogenesis by uncoupling protein 1 expression and the increase in the metabolic rate induced by mitochondrial activation. In addition, Fx shows anti-diabetic effects by improving insulin resistance and promoting glucose utilization in skeletal muscle.


Assuntos
Suplementos Nutricionais/análise , Alga Marinha/química , Xantofilas/química , Xantofilas/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Animais , Fármacos Antiobesidade/química , Fármacos Antiobesidade/metabolismo , Antioxidantes/química , Antioxidantes/metabolismo , Descoberta de Drogas , Radicais Livres/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/metabolismo , Resistência à Insulina , Fígado/metabolismo , Estrutura Molecular , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores Depuradores/metabolismo , Oxigênio Singlete/metabolismo , Proteína Desacopladora 1/química , Proteína Desacopladora 1/metabolismo , Xantofilas/efeitos adversos , beta Caroteno/análogos & derivados , beta Caroteno/química
10.
PLoS One ; 15(4): e0229520, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32236105

RESUMO

Therapeutic hypothermia (TH) is an attractive target for mild traumatic brain injury (mTBI) treatment, yet significant gaps in our mechanistic understanding of TH, especially at the cellular level, remain and need to be addressed for significant forward progress to be made. Using a recently-established 3D in-vitro neural hydrogel model for mTBI we investigated the efficacy of TH after compressive impact injury and established critical treatment parameters including target cooling temperature, and time windows for application and maintenance of TH. Across four temperatures evaluated (31.5, 33, 35, and 37°C), 33°C was found to be most neuroprotective after 24 and 48 hours post-injury. Assessment of TH administration onset time and duration showed that TH should be administered within 4 hours post-injury and be maintained for at least 6 hours for achieving maximum viability. Cellular imaging showed TH reduced the percentage of cells positive for caspases 3/7 and increased the expression of calpastatin, an endogenous neuroprotectant. These findings provide significant new insight into the biological parameter space that renders TH effective in mitigating the deleterious effects of cellular mTBI and provides a quantitative foundation for the future development of animal and preclinical treatment protocols.


Assuntos
Astrócitos/metabolismo , Lesões Encefálicas Traumáticas/terapia , Encéfalo , Hipotermia Induzida/métodos , Neurônios/metabolismo , Células-Tronco/metabolismo , Animais , Astrócitos/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Caspase 3/metabolismo , Caspase 7/metabolismo , Células Cultivadas , Neurônios/patologia , Fármacos Neuroprotetores/metabolismo , Ratos Sprague-Dawley , Células-Tronco/patologia
11.
PLoS Biol ; 18(3): e3000638, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32208418

RESUMO

Caenorhabditis elegans and its cognate bacterial diet comprise a reliable, widespread model to study diet and microbiota effects on host physiology. Nonetheless, how diet influences the rate at which neurons die remains largely unknown. A number of models have been used in C. elegans as surrogates for neurodegeneration. One of these is a C. elegans strain expressing a neurotoxic allele of the mechanosensory abnormality protein 4 (MEC-4d) degenerin/epithelial Na+ (DEG/ENaC) channel, which causes the progressive degeneration of the touch receptor neurons (TRNs). Using this model, our study evaluated the effect of various dietary bacteria on neurodegeneration dynamics. Although degeneration of TRNs was steady and completed at adulthood in the strain routinely used for C. elegans maintenance (Escherichia coli OP50), it was significantly reduced in environmental and other laboratory bacterial strains. Strikingly, neuroprotection reached more than 40% in the E. coli HT115 strain. HT115 protection was long lasting well into old age of animals and was not restricted to the TRNs. Small amounts of HT115 on OP50 bacteria as well as UV-killed HT115 were still sufficient to produce neuroprotection. Early growth of worms in HT115 protected neurons from degeneration during later growth in OP50. HT115 diet promoted the nuclear translocation of DAF-16 (ortholog of the FOXO family of transcription factors), a phenomenon previously reported to underlie neuroprotection caused by down-regulation of the insulin receptor in this system. Moreover, a daf-16 loss-of-function mutation abolishes HT115-driven neuroprotection. Comparative genomics, transcriptomics, and metabolomics approaches pinpointed the neurotransmitter γ-aminobutyric acid (GABA) and lactate as metabolites differentially produced between E. coli HT115 and OP50. HT115 mutant lacking glutamate decarboxylase enzyme genes (gad), which catalyze the conversion of GABA from glutamate, lost the ability to produce GABA and also to stop neurodegeneration. Moreover, in situ GABA supplementation or heterologous expression of glutamate decarboxylase in E. coli OP50 conferred neuroprotective activity to this strain. Specific C. elegans GABA transporters and receptors were required for full HT115-mediated neuroprotection. Additionally, lactate supplementation also increased anterior ventral microtubule (AVM) neuron survival in OP50. Together, these results demonstrate that bacterially produced GABA and other metabolites exert an effect of neuroprotection in the host, highlighting the role of neuroactive compounds of the diet in nervous system homeostasis.


Assuntos
Caenorhabditis elegans/fisiologia , Escherichia coli/fisiologia , Neurônios/patologia , Ácido gama-Aminobutírico/metabolismo , Fatores Etários , Animais , Bactérias/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Colágeno/genética , Dieta , Escherichia coli/genética , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Regulação Bacteriana da Expressão Gênica , Glutamato Descarboxilase/genética , Glutamato Descarboxilase/metabolismo , Interneurônios/patologia , Interneurônios/fisiologia , Lactatos/metabolismo , Lactatos/farmacologia , Mecanorreceptores/patologia , Mecanorreceptores/fisiologia , Mutação , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia , Ácido gama-Aminobutírico/farmacologia
12.
Sci Rep ; 10(1): 5507, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32218474

RESUMO

Cerebral metabolism, which can be monitored by magnetic resonance spectroscopy (MRS), changes rapidly after brain ischaemic injury. Hyperpolarisation techniques boost 13C MRS sensitivity by several orders of magnitude, thereby enabling in vivo monitoring of biochemical transformations of hyperpolarised (HP) 13C-labelled precursors with a time resolution of seconds. The exogenous administration of the metabolite L-lactate was shown to decrease lesion size and ameliorate neurological outcome in preclinical studies in rodent stroke models, as well as influencing brain metabolism in clinical pilot studies of acute brain injury patients. The aim of this study was to demonstrate the feasibility of measuring HP [1-13C] L-lactate metabolism in real-time in the mouse brain after ischaemic stroke when administered after reperfusion at a therapeutic dose. We showed a rapid, time-after-reperfusion-dependent conversion of [1-13C] L-lactate to [1-13C] pyruvate and [13C] bicarbonate that brings new insights into the neuroprotection mechanism of L-lactate. Moreover, this study paves the way for the use of HP [1-13C] L-lactate as a sensitive molecular-imaging biosensor in ischaemic stroke patients after endovascular clot removal.


Assuntos
Isquemia Encefálica/metabolismo , Ácido Láctico/metabolismo , Fármacos Neuroprotetores/metabolismo , Acidente Vascular Cerebral/metabolismo , Animais , Bicarbonatos/metabolismo , Técnicas Biossensoriais/métodos , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/terapia , Isótopos de Carbono , Sistemas Computacionais , Modelos Animais de Doenças , Estudos de Viabilidade , Humanos , Imuno-Histoquímica , Infarto da Artéria Cerebral Média/diagnóstico por imagem , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/terapia , Ácido Láctico/administração & dosagem , Espectroscopia de Ressonância Magnética/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Imagem Molecular/métodos , Transportadores de Ácidos Monocarboxílicos/metabolismo , Fármacos Neuroprotetores/administração & dosagem , Ácido Pirúvico/metabolismo , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/terapia
13.
Chem Biol Interact ; 325: 109020, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32092300

RESUMO

Overactivation of N-methyl-D-aspartate (NMDA) receptors has been associated with neurodegenerative disorders such as Alzheimer's disease (AD), cerebral vascular disorders and amyotrophic lateral sclerosis (ALS). We have previously designed and synthesized a series of memantine nitrate and some of them have shown vessel dilatory effects and neuroprotective effects; however, the detailed mechanisms have not been elucidated. In this study, we further demonstrated that memantine nitrate-06 (MN-06), one of the novel compounds derived from memantine, possessed significant neuroprotective effects against glutamate-induced excitotoxicity in rat primary cerebellar granule neurons (CGNs). Pretreatment of MN-06 reversed the activation of GSK3b and the suppression of phosphorylated Akt induced by glutamate. In addition, the neuroprotective effects of MN-06 could be abolished by LY294002, the specific phosphatidylinositol 3-kinase (PI3-K) inhibitor. Ca2+ imaging shown that pretreatment of MN-06 prevented Ca2+ influx induced by glutamate. Moreover, MN-06 might inhibit the NMDA-mediated current by antagonizing NDMA receptors, which was further confirmed by molecular docking simulation. Taken together, MN-06 protected against glutamate-induced excitotoxicity by blocking calcium influx and attenuating PI3-K/Akt/GSK-3b pathway, indicating that MN-06 might be a potential drug for treating neurodegenerative disorders.


Assuntos
Cálcio/metabolismo , Ácido Glutâmico/toxicidade , Glicogênio Sintase Quinase 3 beta/metabolismo , Memantina/farmacologia , Neurônios/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Apoptose/efeitos dos fármacos , Transporte Biológico/efeitos dos fármacos , Contagem de Células , Cerebelo/citologia , Hipocampo/citologia , Memantina/metabolismo , Simulação de Acoplamento Molecular , Neurônios/citologia , Neurônios/metabolismo , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia , Conformação Proteica , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/química , Receptores de N-Metil-D-Aspartato/metabolismo , Transdução de Sinais/efeitos dos fármacos
14.
Int J Mol Sci ; 21(4)2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32070035

RESUMO

Cadherin epidermal growth factor (EGF) laminin G (LAG) seven-pass G-type receptor 1 (CELSR1) is a member of a special subgroup of adhesion G protein-coupled receptors. Although Celsr1 has been reported to be a sensitive gene for stroke, the effect of CELSR1 in ischemic stroke is still not known. Here, we investigated the effect of CELSR1 on neuroprotection, neurogenesis and angiogenesis in middle cerebral artery occlusion (MCAO) rats. The mRNA expression of Celsr1 was upregulated in the subventricular zone (SVZ), hippocampus and ischemic penumbra after cerebral ischemic injury. Knocking down the expression of Celsr1 in the SVZ with a lentivirus significantly reduced the proliferation of neuroblasts, the number of CD31-positive cells, motor function and rat survival and increased cell apoptosis and the infarct volume in MCAO rats. In addition, the expression of p-PKC in the SVZ and peri-infarct tissue was downregulated after ischemia/ reperfusion. Meanwhile, in the dentate gyrus of the hippocampus, knocking down the expression of Celsr1 significantly reduced the proliferation of neuroblasts; however, it had no influence on motor function, cell apoptosis or angiogenesis. These data indicate that CELSR1 has a neuroprotective effect on cerebral ischemia injury by reducing cell apoptosis in the peri-infarct cerebral cortex and promoting neurogenesis and angiogenesis, mainly through the Wnt/PKC pathway.


Assuntos
Isquemia Encefálica/genética , Caderinas/genética , Neurogênese/genética , Acidente Vascular Cerebral/genética , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Isquemia Encefálica/patologia , Proliferação de Células/genética , Modelos Animais de Doenças , Regulação da Expressão Gênica/genética , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Infarto da Artéria Cerebral Média/genética , Infarto da Artéria Cerebral Média/patologia , Ventrículos Laterais/metabolismo , Ventrículos Laterais/patologia , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/patologia , Fármacos Neuroprotetores/metabolismo , RNA Mensageiro/genética , Ratos , Acidente Vascular Cerebral/patologia , Via de Sinalização Wnt/genética
15.
Clin Interv Aging ; 15: 185-193, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32103921

RESUMO

Background: Alzheimer's disease is a devastating neurodegenerative disorder. Its worldwide prevalence is over 24 million and is expected to double by 2040. Finding ways to prevent its cognitive decline is urgent. Methods: A two-sample Mendelian randomization study was performed instrumenting glutamine, which is abundant in blood, capable of crossing the blood-brain barrier, and involved in a metabolic cycle with glutamate in the brain. Results: The results reveal a protective effect of circulating glutamine against Alzheimer's disease (inverse-variance weighted method, odds ratio per 1-standard deviation increase in circulating glutamine = 0.83; 95% CI 0.71, 0.97; P = 0.02). Conclusion: These findings lend credence to the emerging story supporting the modifiability of glutamine/glutamate metabolism for the prevention of cognitive decline. More circulating glutamine might mean that more substrate is available during times of stress, acting as a neuroprotectant. Modifications to exogenous glutamine may be worth exploring in future efforts to prevent and/or treat Alzheimer's disease.


Assuntos
Doença de Alzheimer , Barreira Hematoencefálica/fisiologia , Encéfalo/metabolismo , Disfunção Cognitiva/prevenção & controle , Glutamina , Idoso , Doença de Alzheimer/sangue , Doença de Alzheimer/metabolismo , Cognição/fisiologia , Feminino , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Glutamina/sangue , Glutamina/genética , Glutamina/metabolismo , Humanos , Masculino , Análise da Randomização Mendeliana/métodos , Fármacos Neuroprotetores/metabolismo , Receptores de Glutamato/metabolismo
16.
Curr Neuropharmacol ; 18(5): 431-445, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31903883

RESUMO

BACKGROUND: Balance in neurotransmission is essential for the proper functioning of the nervous system and even a small, but prolonged disturbance, can induce the negative feedback mechanisms leading to various neuropathologies. Neurodegenerative and mood disorders such as Alzheimer's, Parkinson's or affective disorders are increasing medical and social problems. Among the wide spectrum of potentially destructive events, oxidative stress and disrupted metabolism of some neurotransmitters such as acetylcholine, GABA, glutamate, serotonin or dopamine appear to play a decisive role. Biologically active plant polyphenols have been shown to exert a positive impact on the function of the central nervous system by modulation of metabolism and the action of some neurotransmitters. METHODS: Based on published research, the pharmacological activities of some naturally occurring polyphenols have been reviewed, with a focus on their potential therapeutic importance in the regulation of neurotransmitter systems. RESULTS: Phytochemicals can be classified into several groups and most of them possess anticancer, antioxidative, anti-inflammatory and neuroprotective properties. They can also modulate the metabolism or action of some neurotransmitters and/or their receptors. Based on these properties, phytochemicals have been used in traditional medicine for ages, although it was focused mainly on treating symptoms. However, growing evidence indicates that polyphenols may also prevent or slow neurological diseases. CONCLUSION: Phytochemicals seem to be less toxic than synthetic drugs and they can be a safer alternative for currently used preparations, which exert adverse side effects. The neuroprotective actions of some plant polyphenols in the regulation of neurotransmitters metabolism, functioning of neurotransmitters receptors and antioxidative defense have potential therapeutic applications in various neurodegenerative disorders.


Assuntos
Encéfalo/efeitos dos fármacos , Doenças do Sistema Nervoso/prevenção & controle , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Polifenóis/administração & dosagem , Animais , Encéfalo/metabolismo , Humanos , Neurônios/metabolismo , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia , Polifenóis/metabolismo , Polifenóis/farmacologia , Transmissão Sináptica/efeitos dos fármacos
17.
Cell Mol Life Sci ; 77(12): 2315-2330, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31960113

RESUMO

Amyloid precursor protein (APP) is a transmembrane protein expressed largely within the central nervous system. Upon cleavage, it does not produce the toxic amyloid peptide (Aß) only, which is involved in neurodegenerative progressions but via a non-amyloidogenic pathway it is metabolized to produce a soluble fragment (sAPPα) through α-secretase. While a lot of studies are focusing on the role played by APP in the pathogenesis of Alzheimer's disease, sAPPα is reported to have numerous neuroprotective effects and it is being suggested as a candidate with possible therapeutic potential against Alzheimer's disease. However, the mechanisms through which sAPPα precisely works remain elusive. We have presented a comprehensive review of how sAPPα is regulating the neuroprotective effects in different biological models. Moreover, we have focused on the role of sAPPα during different developmental stages of the brain, neurogenic microenvironment in the brain and how this metabolite of APP is regulating the neurogenesis which is regarded as a compelling approach to ameliorate the impaired learning and memory deficits in dementia and diseases like Alzheimer's disease. sAPPα exerts beneficial physiological, biochemical and behavioral effects mitigating the detrimental effects of neurotoxic compounds. It has shown to increase the proliferation rate of numerous cell types and promised the synaptogenesis, neurite outgrowth, cell survival and cell adhesion. Taken together, we believe that further studies are warranted to investigate the exact mechanism of action so that sAPPα could be developed as a novel therapeutic target against neuronal deficits.


Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Neuroproteção/fisiologia , Fármacos Neuroprotetores/metabolismo , Doença de Alzheimer/metabolismo , Animais , Encéfalo/metabolismo , Humanos , Neurônios/metabolismo
18.
J Agric Food Chem ; 68(6): 1609-1620, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-31957426

RESUMO

Oxidative stress is known to be a key factor in many neurodegenerative diseases. Inflammation also plays a relevant role in a myriad of pathologies such as diabetes and atherosclerosis. Polyphenols coming from dietary sources, such as pterostilbene, may be beneficial in this type of diseases. However, most of them are rapidly metabolized and excreted, yielding very low phenolic bioavailability what makes it difficult to find out which are the mechanisms responsible for the observed bioactivity. Herein, we evaluate the effects of pterostilbene and its metabolites against H2O2-induced cell damage in human neuroblastoma SH-SY5Y cells and against lipopolysaccharide (LPS)-challenged RAW 264.7 macrophages. Among the metabolites tested, 3-methyl-4'-glucuronate-resveratrol (also called 4'-glucuronate pinostilbene, PIN-GlcAc, 11) prevented neuronal death via attenuation of reactive oxygen species (ROS) levels and increased REDOX activity in neurons. This compound is also able to ameliorate LPS-mediated inflammation on macrophages via inhibition of IL-6 and NO production. Thus, polyphenol from dietary sources could be part of potential functional foods designed to ameliorate the onset and progression of certain neurodegenerative diseases via oxidative stress reduction.


Assuntos
Anti-Inflamatórios/farmacologia , Neuroblastoma/metabolismo , Fármacos Neuroprotetores/farmacologia , Estilbenos/farmacologia , Animais , Anti-Inflamatórios/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Peróxido de Hidrogênio/toxicidade , Interleucina-6/genética , Interleucina-6/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Neuroblastoma/fisiopatologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo , Estilbenos/metabolismo
19.
Eur J Pharmacol ; 871: 172926, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31958456

RESUMO

Neurodegenerative diseases affect millions of people around the world. Several studies point out caspase-3 as a key player in the development and progression of neurological disorders including amyotrophic lateral sclerosis, Alzheimer's, Parkinson's and Huntington's diseases. Furthermore, oxidative stress and mitochondrial dysfunction plays an important role in neurodegenerative pathologies leading to neuronal damage and cell death. Pharmacological properties of nitrones such as free radical trapping and neuroprotection has been previously described. In the present work, we have assessed ten non-cytotoxic nitrones for their ability to inhibit apoptosis plus their potential to reduce active caspase-3 and oxidative stress in the hippocampal neuronal cell line HT22. Our results highlight the faculty of nitrones to inhibit apoptosis by a mechanism that involves active caspase-3 reduction and decrease of reactive oxygen species. Moreover, docking and molecular dynamics approaches lead to a detailed analysis at the atomic level of the nitrones binding mode to caspase-3 suggesting that compounds bind in a region close to the catalytic site. All these data place these molecules as excellent hits for further efforts to redesign novel compounds in the search of a new therapy against neurodegenerative disorders.


Assuntos
Antioxidantes/farmacologia , Simulação por Computador , Fármacos Neuroprotetores/farmacologia , Óxidos de Nitrogênio/farmacologia , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Caspase 3/química , Caspase 3/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Hipocampo/citologia , Camundongos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Fármacos Neuroprotetores/antagonistas & inibidores , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/metabolismo , Óxidos de Nitrogênio/metabolismo , Conformação Proteica
20.
J Med Chem ; 63(1): 216-230, 2020 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-31838846

RESUMO

Gain-of-function of BK channels or knockout of their ß4 subunit is associated with spontaneous epilepsy. Currently, efficacy of BK (α + ß4) channel modulators in preventing epilepsy was never reported. Here, we show that martentoxin selectively inhibits BK (α + ß4) channels by interaction with the extracellular loop of the BK ß4 subunit (hß4-loop) at a molar ratio 4:1 (hß4-loop vs martentoxin). Residues Glu104, Glu122, Gln124, Lys125, and Glu128 of the hß4-loop form hydrogen bonds with residues Asp5, Glu13, Lys20, Ser24, Gln26, Lys28, and Arg35 of martentoxin, by which martentoxin reduces the neuronal spiking frequency and increases interspike intervals. Intrahippocampal infusion of martentoxin significantly increases the latency time of seizure, reduces seizure duration and seizure numbers on pentylenetetrazole-induced presensitized rats, inhibits hippocampal hyperexcitability and c-Fos expression, and displays neuroprotective effects on hippocampal neurons. These results suggest that the BK (α + ß4) channel is a novel therapeutic target of intractable epilepsy and martentoxin contributes to the rational drug design for epilepsy treatment.


Assuntos
Anticonvulsivantes/uso terapêutico , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/metabolismo , Subunidades beta do Canal de Potássio Ativado por Cálcio de Condutância Alta/metabolismo , Bloqueadores dos Canais de Potássio/uso terapêutico , Venenos de Escorpião/uso terapêutico , Convulsões/prevenção & controle , Animais , Anticonvulsivantes/metabolismo , Antagonistas de Receptores de GABA-A/farmacologia , Humanos , Masculino , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Pentilenotetrazol/farmacologia , Bloqueadores dos Canais de Potássio/metabolismo , Ligação Proteica , Ratos Sprague-Dawley , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/uso terapêutico , Venenos de Escorpião/metabolismo
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