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Ana Garcera - One of the best experts on this subject based on the ideXlab platform.
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Regulation of Survival Motor Neuron Protein by the Nuclear Factor-Kappa B Pathway in Mouse Spinal Cord Motoneurons
Molecular Neurobiology, 2018Co-Authors: Saravanan Arumugam, Stefka Mincheva-tasheva, Ambika Periyakaruppiah, Sandra Fuente, Rosa M. Soler, Ana GarceraAbstract:Survival motor neuron (SMN) protein deficiency causes the genetic neuromuscular disorder Spinal muscular atrophy (SMA), characterized by Spinal Cord Motoneuron degeneration. Since SMN protein level is critical to disease onset and severity, analysis of the mechanisms involved in SMN stability is one of the central goals of SMA research. Here, we describe the role of several members of the NF-κB pathway in regulating SMN in Motoneurons. NF-κB is one of the main regulators of Motoneuron survival and pharmacological inhibition of NF-κB pathway activity also induces mouse survival motor neuron (Smn) protein decrease. Using a lentiviral-based shRNA approach to reduce the expression of several members of NF-κB pathway, we observed that IKK and RelA knockdown caused Smn reduction in mouse-cultured Motoneurons whereas IKK or RelB knockdown did not. Moreover, isolated Motoneurons obtained from the severe SMA mouse model showed reduced protein levels of several NF-κB members and RelA phosphorylation. We describe the alteration of NF-κB pathway in SMA cells. In the context of recent studies suggesting regulation of altered intracellular pathways as a future pharmacological treatment of SMA, we propose the NF-κB pathway as a candidate in this new therapeutic approach.
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The Canonical Nuclear Factor-κB Pathway Regulates Cell Survival in a Developmental Model of Spinal Cord Motoneurons
The Journal of Neuroscience, 2011Co-Authors: Stefka Mincheva, Ana Garcera, Myriam Gou-fabregas, Mario Encinas, Xavier Dolcet, Rosa M. SolerAbstract:In vivo and in vitro Motoneuron survival depends on the support of neurotrophic factors. These factors activate signaling pathways related to cell survival or inactivate proteins involved in neuronal death. In the present work, we analyzed the involvement of the nuclear factor-κB (NF-κB) pathway in mediating mouse Spinal Cord Motoneuron survival promoted by neurotrophic factors. This pathway comprises ubiquitously expressed transcription factors that could be activated by two different routes: the canonical pathway, associated with IKKα/IKKβ kinase phosphorylation and nuclear translocation RelA (p65)/p50 transcription factors; and the noncanonical pathway, related to IKKα kinase homodimer phosphorylation and RelB/p52 transcription factor activation. In our system, we show that neurotrophic factors treatment induced IKKα and IKKβ phosphorylation and RelA nuclear translocation, suggesting NF-κB pathway activation. Protein levels of different members of the canonical or noncanonical pathways were reduced in a primary culture of isolated embryonic Motoneurons using an interference RNA approach. Even in the presence of neurotrophic factors, selective reduction of IKKα, IKKβ, or RelA proteins induced cell death. In contrast, RelB protein reduction did not have a negative effect on Motoneuron survival. Together these results demonstrated that the canonical NF-κB pathway mediates Motoneuron survival induced by neurotrophic factors, and the noncanonical pathway is not related to this survival effect. Canonical NF-κB blockade induced an increase of Bim protein level and apoptotic cell death. Bcl-x(L) overexpression or Bax reduction counteracted this apoptotic effect. Finally, RelA knockdown causes changes of CREB and Smn protein levels.
Douglas M Bradley - One of the best experts on this subject based on the ideXlab platform.
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prenatal ethanol exposure reduces Spinal Cord Motoneuron number in the fetal rat but does not affect gdnf target tissue protein
Developmental Neuroscience, 1999Co-Authors: M Barrow B Heaton, Kara Kidd, Douglas M Bradley, Michael Paiva, Jean J Mitchell, Don W WalkerAbstract:Fetal rats were exposed throughout gestation to one of three diets: an ethanol-containing liquid diet, a liquid diet with the isocaloric substitution of sucrose for ethanol or a laboratory chow control diet. At postnatal day 1 (P1), the Spinal Cords were taken for analyses of Motoneuron number and size. These analyses revealed a significant loss of Motoneurons and a reduction of Motoneuron size in the ethanol-exposed animals, compared to both sucrose and chow controls. Spinal Cord length and ventral horn volume were not altered as a result of ethanol treatment, so the change in Motoneuron number cannot be attributed to volumetric changes. The content of the Motoneuron survival factor glial cell-line-derived neurotrophic factor (GDNF) was also assessed in the P1 limb Motoneuron target tissue. This analysis was undertaken because GDNF is a potent survival factor for developing Motoneurons and has been shown to protect this population from ethanol neurotoxicity. Thus, its depletion could contribute to Motoneuron loss. These analyses, using the ELISA assay, did not detect reductions in GDNF in the ethanol-exposed animals. Therefore, alterations in other neurotrophic factors or ethanol neurotoxicity by other means appear to be responsible for the Motoneuron loss. These results are consistent with earlier studies in the chick embryo, which also found reduced Motoneuron numbers as a function of developmental ethanol exposure, and point again to the general lethality of ethanol to the developing nervous system.
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ethanol influences on the chick embryo Spinal Cord motor system analyses of Motoneuron cell death motility and target trophic factor activity and in vitro analyses of neurotoxicity and trophic factor neuroprotection
Journal of Neurobiology, 1995Co-Authors: Marieta Barrow Heaton, Douglas M BradleyAbstract:A series of in vivo and in vitro experiments were conducted to determine the influence of prenatally administered ethanol on several aspects of the developing chick embryo Spinal Cord motor system. Specifically, we examined: (1) the effect of chronic ethanol administration during the natural cell death period on Spinal Cord Motoneuron numbers; (2) the influence of ethanol on ongoing embryonic motility; (3) the effect of ethanol exposure on neurotrophic activity in Motoneuron target tissue (limbbud); and (4) the responsiveness of cultured Spinal Cord neurons to ethanol, and the potential of target-derived neurotrophic factors to ameliorate ethanol neurotoxicity. These studies revealed the following: Chronic prenatal ethanol exposure reduces the number of Motoneurons present in the lateral motor column after the cell death period [embryonic day 12 (E12)]. Ethanol tends to inhibit embryonic motility, particularly during the later stages viewed (E9-E11). Chronic ethanol exposure reduces the neurotrophic activity contained in target muscle tissue. Such diminished support could contribute to the observed Motoneuron loss. Direct exposure of Spinal Cord neurons to ethanol decreases neuronal survival and process outgrowth in a dose-dependent manner, but the addition of target muscle extract to ethanol-containing cultures can ameliorate this ethanol neurotoxicity. These studies demonstrate ethanol toxicity in a population not previously viewed in this regard and suggest a mechanism that may be related to this cell loss (i.e., decreased neurotrophic support). © 1995 John Wiley & Sons, Inc.
Rosa M. Soler - One of the best experts on this subject based on the ideXlab platform.
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Regulation of Survival Motor Neuron Protein by the Nuclear Factor-Kappa B Pathway in Mouse Spinal Cord Motoneurons
Molecular Neurobiology, 2018Co-Authors: Saravanan Arumugam, Stefka Mincheva-tasheva, Ambika Periyakaruppiah, Sandra Fuente, Rosa M. Soler, Ana GarceraAbstract:Survival motor neuron (SMN) protein deficiency causes the genetic neuromuscular disorder Spinal muscular atrophy (SMA), characterized by Spinal Cord Motoneuron degeneration. Since SMN protein level is critical to disease onset and severity, analysis of the mechanisms involved in SMN stability is one of the central goals of SMA research. Here, we describe the role of several members of the NF-κB pathway in regulating SMN in Motoneurons. NF-κB is one of the main regulators of Motoneuron survival and pharmacological inhibition of NF-κB pathway activity also induces mouse survival motor neuron (Smn) protein decrease. Using a lentiviral-based shRNA approach to reduce the expression of several members of NF-κB pathway, we observed that IKK and RelA knockdown caused Smn reduction in mouse-cultured Motoneurons whereas IKK or RelB knockdown did not. Moreover, isolated Motoneurons obtained from the severe SMA mouse model showed reduced protein levels of several NF-κB members and RelA phosphorylation. We describe the alteration of NF-κB pathway in SMA cells. In the context of recent studies suggesting regulation of altered intracellular pathways as a future pharmacological treatment of SMA, we propose the NF-κB pathway as a candidate in this new therapeutic approach.
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The Canonical Nuclear Factor-κB Pathway Regulates Cell Survival in a Developmental Model of Spinal Cord Motoneurons
The Journal of Neuroscience, 2011Co-Authors: Stefka Mincheva, Ana Garcera, Myriam Gou-fabregas, Mario Encinas, Xavier Dolcet, Rosa M. SolerAbstract:In vivo and in vitro Motoneuron survival depends on the support of neurotrophic factors. These factors activate signaling pathways related to cell survival or inactivate proteins involved in neuronal death. In the present work, we analyzed the involvement of the nuclear factor-κB (NF-κB) pathway in mediating mouse Spinal Cord Motoneuron survival promoted by neurotrophic factors. This pathway comprises ubiquitously expressed transcription factors that could be activated by two different routes: the canonical pathway, associated with IKKα/IKKβ kinase phosphorylation and nuclear translocation RelA (p65)/p50 transcription factors; and the noncanonical pathway, related to IKKα kinase homodimer phosphorylation and RelB/p52 transcription factor activation. In our system, we show that neurotrophic factors treatment induced IKKα and IKKβ phosphorylation and RelA nuclear translocation, suggesting NF-κB pathway activation. Protein levels of different members of the canonical or noncanonical pathways were reduced in a primary culture of isolated embryonic Motoneurons using an interference RNA approach. Even in the presence of neurotrophic factors, selective reduction of IKKα, IKKβ, or RelA proteins induced cell death. In contrast, RelB protein reduction did not have a negative effect on Motoneuron survival. Together these results demonstrated that the canonical NF-κB pathway mediates Motoneuron survival induced by neurotrophic factors, and the noncanonical pathway is not related to this survival effect. Canonical NF-κB blockade induced an increase of Bim protein level and apoptotic cell death. Bcl-x(L) overexpression or Bax reduction counteracted this apoptotic effect. Finally, RelA knockdown causes changes of CREB and Smn protein levels.
Saravanan Arumugam - One of the best experts on this subject based on the ideXlab platform.
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Regulation of Survival Motor Neuron Protein by the Nuclear Factor-Kappa B Pathway in Mouse Spinal Cord Motoneurons
Molecular Neurobiology, 2018Co-Authors: Saravanan Arumugam, Stefka Mincheva-tasheva, Ambika Periyakaruppiah, Sandra Fuente, Rosa M. Soler, Ana GarceraAbstract:Survival motor neuron (SMN) protein deficiency causes the genetic neuromuscular disorder Spinal muscular atrophy (SMA), characterized by Spinal Cord Motoneuron degeneration. Since SMN protein level is critical to disease onset and severity, analysis of the mechanisms involved in SMN stability is one of the central goals of SMA research. Here, we describe the role of several members of the NF-κB pathway in regulating SMN in Motoneurons. NF-κB is one of the main regulators of Motoneuron survival and pharmacological inhibition of NF-κB pathway activity also induces mouse survival motor neuron (Smn) protein decrease. Using a lentiviral-based shRNA approach to reduce the expression of several members of NF-κB pathway, we observed that IKK and RelA knockdown caused Smn reduction in mouse-cultured Motoneurons whereas IKK or RelB knockdown did not. Moreover, isolated Motoneurons obtained from the severe SMA mouse model showed reduced protein levels of several NF-κB members and RelA phosphorylation. We describe the alteration of NF-κB pathway in SMA cells. In the context of recent studies suggesting regulation of altered intracellular pathways as a future pharmacological treatment of SMA, we propose the NF-κB pathway as a candidate in this new therapeutic approach.
Henry H. Zhou - One of the best experts on this subject based on the ideXlab platform.
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suppression of Spinal Cord Motoneuron excitability correlates with surgical immobility during isoflurane anesthesia
Anesthesiology, 1998Co-Authors: Henry H. Zhou, Tsentsen Jin, Binsheng Qin, Herman TurndorfAbstract:BACKGROUND Recent evidence suggests that the Spinal Cord is an important site of anesthetic action that produces surgical immobility. Inhalation anesthetics depress the Hoffmann's reflex (H reflex) and F wave, indicating Spinal Motoneuron suppression. The aim of this study was to assess the correlation between isoflurane-induced immobility and H- and F-wave suppression. METHODS The baseline H reflex and F wave were measured before anesthesia in 15 adult patients. After induction, 1% end-tidal isoflurane was maintained for 20 min before the H and F waves were reelicited. Using an electric stimulus applied to the forearm and grading the response as movement or no movement, the authors increased or decreased the isoflurane concentration in 0.1% steps, depending on the movement responses. The H and F waves were reCorded 20 min after each change of isoflurane concentration. The correlation between H- and F-wave suppression and surgical immobility was analyzed using a paired t test with Bonferroni correction. RESULTS H-reflex amplitude (2.74 +/- 1.63 mV) and F-wave persistence (70.69 +/- 26.19%) at the highest isoflurane concentration that allowed movement response to a stimulus are different (P < 0.01) from these (1.97 +/- 1.46 mV; 43.16 +/- 22.91%) at the lowest isoflurane concentration that suppressed response. At 0.8% isoflurane, the H-reflex amplitude was 3.69 +/- 1.83 mV with movement and 1.01 +/- 1.14 mV without movement (P < 0.01); F-wave amplitude was 0.29 +/- 0.15 mV with movement and 0.11 +/- 0.06 mV without movement (P < 0.01); F-wave persistence was 80 +/- 22.36% with movement and 34.9 +/- 25.75% without movement (P < 0.01). CONCLUSIONS The degree of H- and F-wave amplitude and F-wave persistence suppression correlates with movement response, suggesting that isoflurane-suppressive action in the Spinal Cord plays a significant role in producing surgical immobility.
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Spinal Cord Motoneuron excitability during isoflurane and nitrous oxide anesthesia.
Anesthesiology, 1997Co-Authors: Henry H. Zhou, M. P. Mehta, Arturo A. LeisAbstract:Background Recent evidence suggests that the Spinal Cord is an important site of anesthesia that is necessary for surgical immobility, but the specific effect of anesthetics within the Spinal Cord is unclear. This study assessed the effect of isoflurane and nitrous oxide on Spinal Motoneuron excitability by monitoring the H-reflex and the F wave. Methods Eight adult patients, categorized as American Society of Anesthesiologists physical status 1 or 2, who were undergoing elective orthopedic surgery were anesthetized with 0.6, 0.8, 1.0, and 1.2 times the estimated minimum alveolar concentration (MAC) of isoflurane. Nitrous oxide was added in graded concentrations of 30%, 50%, and 70%, whereas the isoflurane concentration was decreased to maintain a total MAC of 1. The H-reflex of the soleus muscle and the F wave of the abductor hallucis muscle were measured before anesthesia and 15 min after each change of anesthetic concentration. Four or more trials of the H-reflex and 18 trials of the F wave were reCorded at each concentration of anesthesia. The effect of the anesthetics on the H-reflex and F wave was analyzed using Dunnett's test. Results H-reflex amplitude was decreased to 48.4 +/- 18.6% of preanesthesia level at 0.6 MAC isoflurane and to 33.8 +/- 19.1% when isoflurane concentration increased from 0.6 MAC to 1.2 MAC. F wave amplitude and persistence decreased to 52.2 +/- 33.6% and 44.4 +/- 26% of baseline at 0.6 MAC isoflurane, and to 33.8 +/- 26% and 21.7 +/- 22.8% at 1.2 MAC isoflurane. Isoflurane plus nitrous oxide (total 1 MAC) decreased H-reflex amplitude to 30.4–33.3% and decreased F wave persistence to 42.8–56.3% of baseline. Conclusions Both isoflurane alone and isoflurane plus nitrous oxide decrease H-reflex and F-wave amplitude and F-wave persistence. These effects suggest that isoflurane and nitrous oxide decrease Motoneuronal excitability in the human Spinal Cord. This may play an important role in producing surgical immobility.