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1.
Sci Rep ; 11(1): 10749, 2021 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-34031437

RESUMO

Ethoxyquin (EQ), a quinolone-based antioxidant, has demonstrated neuroprotective properties against several neurotoxic drugs in a phenotypic screening and is shown to protect axons in animal models of chemotherapy-induced peripheral neuropathy. We assessed the effects of EQ on peripheral nerve function in the db/db mouse model of type II diabetes. After a 7 week treatment period, 12-week-old db/db-vehicle, db/+ -vehicle and db/db-EQ treated animals were evaluated by nerve conduction, paw withdrawal against a hotplate, and fiber density in hindlimb footpads. We found that the EQ group had shorter paw withdrawal latency compared to vehicle db/db group. The EQ group scored higher in nerve conduction studies, compared to vehicle-treated db/db group. Morphology studies yielded similar results. To investigate the potential role of mitochondrial DNA (mtDNA) deletions in the observed effects of EQ, we measured total mtDNA deletion burden in the distal sciatic nerve. We observed an increase in total mtDNA deletion burden in vehicle-treated db/db mice compared to db/+ mice that was partially prevented in db/db-EQ treated animals. These results suggest that EQ treatment may exert a neuroprotective effect in diabetic neuropathy. The prevention of diabetes-induced mtDNA deletions may be a potential mechanism of the neuroprotective effects of EQ in diabetic neuropathy.


Assuntos
Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 2/complicações , Neuropatias Diabéticas/prevenção & controle , Etoxiquina/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Animais , DNA Mitocondrial/efeitos dos fármacos , DNA Mitocondrial/genética , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Tipo 2/genética , Neuropatias Diabéticas/etiologia , Neuropatias Diabéticas/genética , Modelos Animais de Doenças , Etoxiquina/farmacologia , Camundongos , Mutação , Condução Nervosa/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Nervo Isquiático/química , Nervo Isquiático/efeitos dos fármacos
2.
Nat Med ; 25(12): 1873-1884, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31806906

RESUMO

Herpes simplex virus-1 (HSV-1) encephalitis (HSE) is typically sporadic. Inborn errors of TLR3- and DBR1-mediated central nervous system cell-intrinsic immunity can account for forebrain and brainstem HSE, respectively. We report five unrelated patients with forebrain HSE, each heterozygous for one of four rare variants of SNORA31, encoding a small nucleolar RNA of the H/ACA class that are predicted to direct the isomerization of uridine residues to pseudouridine in small nuclear RNA and ribosomal RNA. We show that CRISPR/Cas9-introduced bi- and monoallelic SNORA31 deletions render human pluripotent stem cell (hPSC)-derived cortical neurons susceptible to HSV-1. Accordingly, SNORA31-mutated patient hPSC-derived cortical neurons are susceptible to HSV-1, like those from TLR3- or STAT1-deficient patients. Exogenous interferon (IFN)-ß renders SNORA31- and TLR3- but not STAT1-mutated neurons resistant to HSV-1. Finally, transcriptome analysis of SNORA31-mutated neurons revealed normal responses to TLR3 and IFN-α/ß stimulation but abnormal responses to HSV-1. Human SNORA31 thus controls central nervous system neuron-intrinsic immunity to HSV-1 by a distinctive mechanism.


Assuntos
Encefalite por Herpes Simples/genética , Herpesvirus Humano 1/genética , Neurônios/imunologia , RNA Nucleolar Pequeno/genética , Adulto , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/virologia , Pré-Escolar , Encefalite por Herpes Simples/imunologia , Encefalite por Herpes Simples/patologia , Encefalite por Herpes Simples/virologia , Feminino , Predisposição Genética para Doença , Herpesvirus Humano 1/imunologia , Herpesvirus Humano 1/patogenicidade , Humanos , Imunidade/genética , Lactente , Masculino , Metagenoma/genética , Metagenoma/imunologia , Pessoa de Meia-Idade , Neurônios/virologia , RNA Nucleolar Pequeno/imunologia
3.
Proc Natl Acad Sci U S A ; 115(37): E8775-E8782, 2018 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-30154162

RESUMO

Herpes simplex virus type 1 (HSV-1) encephalitis (HSE) is the most common sporadic viral encephalitis in Western countries. Some HSE children carry inborn errors of the Toll-like receptor 3 (TLR3)-dependent IFN-α/ß- and -λ-inducing pathway. Induced pluripotent stem cell (iPSC)-derived cortical neurons with TLR3 pathway mutations are highly susceptible to HSV-1, due to impairment of cell-intrinsic TLR3-IFN immunity. In contrast, the contribution of cell-intrinsic immunity of human trigeminal ganglion (TG) neurons remains unclear. Here, we describe efficient in vitro derivation and purification of TG neurons from human iPSCs via a cranial placode intermediate. The resulting TG neurons are of sensory identity and exhibit robust responses to heat (capsaicin), cold (icilin), and inflammatory pain (ATP). Unlike control cortical neurons, both control and TLR3-deficient TG neurons were highly susceptible to HSV-1. However, pretreatment of control TG neurons with poly(I:C) induced the cells into an anti-HSV-1 state. Moreover, both control and TLR3-deficient TG neurons developed resistance to HSV-1 following pretreatment with IFN-ß but not IFN-λ. These data indicate that TG neurons are vulnerable to HSV-1 because they require preemptive stimulation of the TLR3 or IFN-α/ß receptors to induce antiviral immunity, whereas cortical neurons possess a TLR3-dependent constitutive resistance that is sufficient to block incoming HSV-1 in the absence of prior antiviral signals. The lack of constitutive resistance in TG neurons in vitro is consistent with their exploitation as a latent virus reservoir in vivo. Our results incriminate deficiencies in the constitutive TLR3-dependent response of cortical neurons in the pathogenesis of HSE.


Assuntos
Imunidade/imunologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Neurônios/metabolismo , Receptor 3 Toll-Like/metabolismo , Antivirais/farmacologia , Diferenciação Celular/genética , Células Cultivadas , Córtex Cerebral/citologia , Criança , Herpesvirus Humano 1/imunologia , Herpesvirus Humano 1/fisiologia , Humanos , Imunidade/genética , Células-Tronco Pluripotentes Induzidas/citologia , Interferon beta/farmacologia , Mutação , Neurônios/efeitos dos fármacos , Neurônios/virologia , Poli I-C/farmacologia , Receptor 3 Toll-Like/genética , Gânglio Trigeminal/citologia
4.
Stem Cells ; 32(8): 2201-14, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24578327

RESUMO

Novel environmental stimuli, such as running and learning, increase proliferation of adult hippocampal neural stem cells (NSCs) and enlarge the population of new neurons. However, it remains unclear how increased numbers of new neurons can be generated in a time frame far shorter than the time required for proliferating stem cells to generate these neurons. Here, we show that bone morphogenetic protein (BMP) signaling in the subgranular zone regulates the tempo of neural progenitor cell (NPC) maturation by directing their transition between states of quiescence and activation at multiple stages along the lineage. Virally mediated overexpression of BMP4 caused NPC cell cycle exit and slowed the normal maturation of NPCs, resulting in a long-term reduction in neurogenesis. Conversely, overexpression of the BMP inhibitor noggin promoted NPC cell cycle entry and accelerated NPC maturation. Similarly, BMP receptor type 2 (BMPRII) ablation in Ascl1(+) intermediate NPCs accelerated their maturation into neurons. Importantly, ablation of BMPRII in GFAP(+) stem cells accelerated maturation without depleting the NSC pool, indicating that an increased rate of neurogenesis does not necessarily diminish the stem cell population. Thus, inhibition of BMP signaling is a mechanism for rapidly expanding the pool of new neurons in the adult hippocampus by tipping the balance between quiescence/activation of NPCs and accelerating the rate at which they mature into neurons.


Assuntos
Células-Tronco Adultas/citologia , Proteínas Morfogenéticas Ósseas/metabolismo , Diferenciação Celular/fisiologia , Células-Tronco Neurais/citologia , Neurogênese/fisiologia , Células-Tronco Adultas/metabolismo , Animais , Western Blotting , Linhagem da Célula , Hipocampo/citologia , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Microscopia Confocal , Células-Tronco Neurais/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/fisiologia
5.
J Neuroimmunol ; 262(1-2): 53-61, 2013 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-23899666

RESUMO

Myelin-associated glycoprotein (MAG) expressed by oligodendrocytes promotes the stability of axons but also impedes neural repair by inhibiting axon extension through lesioned white matter. We previously reported exacerbated axon losses in MAGKO as compared to wild type mice, 30days into experimental autoimmune encephalitis (EAE). Here, we report the time course of axon losses in EAE and show this occurs as early as 7days post-immunization, confirming MAG is protective against immune-mediated axon transection events. MAGKO mice also exhibit increased microglial activation prior to EAE, which is not seen in B4galnt1KO mice that also have axon loss, suggesting that the microglial activation may be a consequence of the loss of MAG inhibitory influence, and not a simple result of axonal degeneration.


Assuntos
Axônios/patologia , Encefalomielite Autoimune Experimental/patologia , Microglia/metabolismo , Glicoproteína Associada a Mielina/deficiência , Animais , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/genética , Feminino , Masculino , Camundongos , Camundongos Congênicos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/patologia , Fatores de Tempo
6.
Exp Neurol ; 237(1): 153-9, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22688009

RESUMO

Axon degeneration is a common hallmark of many neurodegenerative diseases. There is now an abundance of spontaneous and genetically engineered mice available to study the mechanisms of axonal degeneration and to screen for axonal protective agents. However, many of these mouse models exhibit slow progressive axonal loss which can span over many months. Consequently, there is a pressing need to accelerate the pace of axonal loss over a short interval for high-throughput screening of pharmacological and genetic therapies. Here, we present a novel technique using acrylamide, an axonal neurotoxin, to provoke rapid axonal degeneration in murine models of neuropathies. The progressive axonal loss which typically occurs over 8 months was reproduced within 7 to 10 days of the acrylamide intoxication. This approach was successfully applied to Myelin Associated Glycoprotein knockout (MAG-/-) mouse and Trembler-J mouse, a popular murine model of Charcot-Marie-Tooth disease type 1 (CMT-1). Acrylamide intoxication in transgenic mouse models offers a novel experimental approach to accelerate the rate of axonal loss over short intervals for timely in vivo studies of nerve degeneration. This report also provides for the first time an animal model for medication or toxin-induced exacerbation of pre-existing neuropathies, a phenomenon widely reported in patients with neuropathies.


Assuntos
Modelos Animais de Doenças , Progressão da Doença , Degeneração Neural/patologia , Degeneração Neural/fisiopatologia , Doenças do Sistema Nervoso Periférico/patologia , Doenças do Sistema Nervoso Periférico/fisiopatologia , Acrilamida/toxicidade , Animais , Axônios/patologia , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Mutantes Neurológicos , Camundongos Transgênicos , Proteínas da Mielina/deficiência , Proteínas da Mielina/genética , Glicoproteína Mielina-Oligodendrócito , Degeneração Neural/etiologia , Doenças do Sistema Nervoso Periférico/etiologia , Distribuição Aleatória
7.
FASEB J ; 22(11): 3757-67, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18644839

RESUMO

Matrix metalloproteinases (MMPs) are zinc-dependent enzymes that play a role in the inflammatory response. These enzymes have been well studied in the context of cancer biology and inflammation. Recent studies, however, suggest that these enzymes also play roles in brain development and neurodegenerative disease. Select MMPs can target proteins critical to synaptic structure and neuronal survival, including integrins and cadherins. Here, we show that one member of the MMP family, MMP-7, which may be released from cells, including microglia, can target a protein critical to synaptic function. Through analysis of extracts from murine cortical slice preparations, we show that MMP-7 cleaves the NR1 subunit of the N-methyl-d-aspartate (NMDA) receptor to generate an N-terminal fragment of approximately 65 kDa. Moreover, studies with recombinant protein show that MMP-7-mediated cleavage of NR1 occurs at amino acid 517, which is extracellular and just distal to the first transmembrane domain. Data suggest that NR2A, which shares sequence homology with NR1, is also cleaved following treatment of slices with MMP-7, while select AMPA receptor subunits are not. Consistent with a potential effect of MMP-7 on ligand binding, additional experiments demonstrate that NMDA-mediated calcium flux is significantly diminished by MMP-7 pretreatment of cultures. In addition, the AMPA/NMDA ratio is increased by MMP-7 pretreatment. These data suggest that synaptic function may be altered in neurological conditions associated with increased levels of MMP-7.


Assuntos
Química Encefálica/fisiologia , Sinalização do Cálcio/fisiologia , Metaloproteinase 7 da Matriz/metabolismo , Microglia/enzimologia , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Células Cultivadas , Humanos , Inflamação/enzimologia , Camundongos , Microglia/citologia , Neoplasias/enzimologia , Estrutura Terciária de Proteína/fisiologia , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/metabolismo
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