Sonic hedgehog protects cortical neurons against oxidative stress.
ABSTRACT Oxidative stress is one of the most important pathological mechanisms in neurodegenerative diseases and ischemia. Recent studies have indicated that the sonic hedgehog (SHH) signaling pathway is involved in these diseases, but the underlying mechanisms remains elusive. Here we report that the SHH pathway was activated in primary cultured cortical neurons after exposure to hydrogen peroxide (H₂O₂). H₂O₂ treatment decreased the cell viability of neurons, and inhibition of endogenous SHH signaling exacerbated its neurotoxicity. Activation of SHH signaling protected neurons from H₂O₂-induced apoptosis and increased the cell viability while those effects were partially reversed by blocking SHH signals. Exogenous SHH increased the activities of Superoxide dismutase (SOD) and Glutathione peroxidase (GSH-PX) in H₂O₂-treated neurons and decreased production of Malondialdehyde (MDA). It also promoted expression of the anti-apoptotic gene Bcl-2 and inhibited expression of pro-apoptotic gene Bax. Activation of SHH signals upregulated both Neurotrophic factors vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF). Pretreatment with SHH inhibited the activation of ERK (extracellular signal-regulated kinases) signals induced by H₂O₂. Our findings demonstrate that activation of SHH signaling protects cortical neurons against oxidative stress and suggest a potential role of SHH for the clinic treatments of brain ischemia and neurodegenerative disorders.
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ABSTRACT: Sonic hedgehog (Shh) protein is required for the maintenance of neural progenitor cells (NPCs) in the embryonic and adult hippocampus. Brain ischemia causes increased proliferation of hippocampal NPCs. We therefore examined whether Shh regulates the increase in proliferation of NPCs after ischemia/hypoxia. Male SV129 mice were exposed to a 20-minute middle cerebral artery occlusion; hippocampi were then analyzed for Shh mRNA and protein expression by real-time polymerase chain reaction, immunoblot, and immunohistochemistry. Primary cell cultures of neurons, astrocytes, and NPCs were exposed to 16 hours of hypoxia (1% O(2)) and analyzed by real-time polymerase chain reaction and immunoblot for Shh expression. Proliferation of NPCs, in vivo and in vitro, was measured by bromodeoxyuridine incorporation. Among the cell types examined in vitro, only NPC and neurons increased Shh mRNA under hypoxic conditions. Furthermore, hypoxia increased proliferation of NPCs and this proliferation was enhanced by the addition of recombinant Shh or blocked by the pathway-specific inhibitor, cyclopamine. Middle cerebral artery occlusion was associated with a transient 2-fold increase in the mRNA encoding both Shh and its transcription factor, Gli1, 0.5 days after ischemia. Within the hippocampus, Shh protein was increased approximately 3-fold 3 and 7 days after ischemia and was observed predominantly within cells in the CA3 and hilar regions. Shh was expressed only in mature neurons. In vivo, cyclopamine suppressed ischemia-induced proliferation of subgranular NPCs. The Shh pathway plays a role in the proliferation of NPCs induced by ischemia/hypoxia and might participate in injury remodeling.Stroke 09/2009; 40(11):3618-26. · 6.16 Impact Factor
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ABSTRACT: Extracellular signal-regulated kinases (ERKs) are traditionally viewed as a survival factor in the mitogen-activated protein kinase (MAPK) family. On the other hand, some recent reports have suggested that ERK can also be responsible for neuronal cell death in various neurodegeneration models. In-depth studies on the action of ERK in apoptosis, however, have not been done. A recent study has revealed that ERK is a key apoptotic factor in potassium deprivation-induced neuronal cell death by showing that ERK inhibitors protect neurons from low potassium conditions, whereas constitutively activated ERK activates cell death. Most important, this study shows how ERK can promote neuronal cell death by causing plasma membrane and DNA damage that is independent of caspase-3 activity. Further studies on the mechanism of ERK in neuronal cell death will shed light on the possibility of using ERK as a therapeutic target in treating neurodegeneration.Science s STKE 10/2004; 2004(251):PE45.
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ABSTRACT: Activation of the Hedgehog (Hh) pathway has been identified in several cancers, including medulloblastoma, but the mechanisms by which this pathway affects tumor survival and growth are incompletely understood. We investigated whether Hedgehog might promote survival of medulloblastoma cells via up-regulation of BclII. We found that mRNA levels of the Hedgehog pathway effector Gli1 were significantly associated with BclII expression in medulloblastoma and that Gli1 and BclII are both present in regions of decreased apoptosis in nodular medulloblastoma. Transient overexpression of Gli1 and Gli2 in medulloblastoma cultures induced a BclII transcriptional reporter and increased BclII protein levels, whereas stable overexpression of Gli1 was associated with increased BclII mRNA. The Hedgehog antagonist cyclopamine blocked expression of the Hh pathway targets PTCH1 and Gli1, lowered BclII levels, and increased apoptosis in DAOY and UW228 medulloblastoma cells. Apoptotic induction caused by cyclopamine could be rescued in part by enforced expression of Gli1 or BclII. Hh pathway blockade also sensitized medulloblastoma to the effects of the proapoptotic agent lovastatin. These data demonstrate that BclII is an important mediator of Hh activity in medulloblastoma and suggest new strategies for combined chemotherapeutic regimens.American Journal Of Pathology 02/2007; 170(1):347-55. · 4.52 Impact Factor