Neuroprotective effect of sonic hedgehog up‐regulated in Schwann cells following sciatic nerve injury

Hashimoto, Manabu; Ishii, Kayoko; Nakamura, Yasuko; Watabe, Kazuhiko; Kohsaka, Shinichi; Akazawa, Chihiro

doi:10.1111/j.1471-4159.2008.05666.x

Cited by 81 publications

(89 citation statements)

References 33 publications

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“…We found up-regulation of BDNF in respond to the SHH pre-treatment and its down-regulation after cyclopamine treatment. It has been reported that SHH expression is up-regulated prior to the induction of BDNF mRNA, and blocking SHH signals suppresses BDNF expression [24]. It is therefore that activation of the SHH pathway induces the increase of BDNF and results in neuroprotective to oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

Sonic Hedgehog Protects Cortical Neurons Against Oxidative Stress

et al. 2010

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The cerebellum undergoes rapid growth during the third trimester and is vulnerable to injury and deficient growth in infants born prematurely. Factors associated with preterm cerebellar hypoplasia include chronic lung disease and post-natal glucocorticoid administration. We modeled chronic hyp-oxemia and glucocorticoid administration in neonatal mice to study whole cerebellar and cell type-specific effects of dual exposure. Chronic neonatal hypoxia resulted in permanent cerebellar hypoplasia. This was compounded by administration of prednisolone as shown by greater volume loss and Purkinje cell death. In the setting of hypoxia and prednisolone, administration of a small molecule Smoothened-Hedgehog agonist (SAG) preserved cerebellar volume and protected against Purkinje cell death. Such protective effects were observed even when SAG was given as a one-time dose after dual insult. To model complex injury and determine cell type-specific roles for the hypoxia inducible factor (HIF) pathway, we performed conditional knockout of von Hippel Lindau (VHL) to hyperactivate HIF1α in cerebellar granule neuron precursors (CGNP) or Purkinje cells. Surprisingly, HIF activation in either cell type resulted in no cerebellar deficit. However, in mice administered prednisolone, HIF overactivation in CGNPs resulted in significant cerebellar hy-poplasia, whereas HIF overactivation in Purkinje cells caused cell death. Together, these findings indicate that HIF primes both cell types for injury via glucocorticoids, and that hypoxia/HIF + postnatal glucocorticoid administration act on distinct cellular pathways to cause cerebellar injury. They further suggest that SAG is neuroprotective in the setting of complex neonatal cerebellar injury. Highlights • Chronic hypoxia results in cerebellar hypoplasia in neonatal mice • Hypoxia/HIF plus glucocorticoid activation exacerbates neuronal damage • Smoothened agonist (SAG) is protective in complex neonatal cerebellar injury Electronic supplementary material The online version of this article (https://doi.

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Section: Discussionmentioning

confidence: 99%

Sonic Hedgehog Protects Cortical Neurons Against Oxidative Stress

et al. 2010

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“…Wnt/β-catenin and Sonic HedgeHog (SHH) morphogen signallings both regulate embryonic neurogenesis and angiogenesis [123,124] and are variably associated with the remyelination process [125] and BBB integrity [126]. Nogo-A is an axonal growth inhibitor, and negative regulator of CNS angiogenesis [127]; anti-Nogo IgGs have been shown to suppress EAE through an immunomodulatory activity and the removal of remyelination obstacles between axons and new myelinating membranes [128].…”

Section: Other Angiogenic Molecules Potentially Involved In Ms and Eamentioning

confidence: 99%

Angiogenesis in multiple sclerosis and experimental autoimmune encephalomyelitis

Girolamo

Coppola

Ribatti

et al. 2014

Acta Neuropathologica Communications

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Angiogenesis, the formation of new vessels, is found in Multiple Sclerosis (MS) demyelinating lesions following Vascular Endothelial Growth Factor (VEGF) release and the production of several other angiogenic molecules. The increased energy demand of inflammatory cuffs and damaged neural cells explains the strong angiogenic response in plaques and surrounding white matter. An angiogenic response has also been documented in an experimental model of MS, experimental allergic encephalomyelitis (EAE), where blood-brain barrier disruption and vascular remodelling appeared in a pre-symptomatic disease phase. In both MS and EAE, VEGF acts as a pro-inflammatory factor in the early phase but its reduced responsivity in the late phase can disrupt neuroregenerative attempts, since VEGF naturally enhances neuron resistance to injury and regulates neural progenitor proliferation, migration, differentiation and oligodendrocyte precursor cell (OPC) survival and migration to demyelinated lesions. Angiogenesis, neurogenesis and oligodendroglia maturation are closely intertwined in the neurovascular niches of the subventricular zone, one of the preferential locations of inflammatory lesions in MS, and in all the other temporary vascular niches where the mutual fostering of angiogenesis and OPC maturation occurs. Angiogenesis, induced either by CNS inflammation or by hypoxic stimuli related to neurovascular uncoupling, appears to be ineffective in chronic MS due to a counterbalancing effect of vasoconstrictive mechanisms determined by the reduced axonal activity, astrocyte dysfunction, microglia secretion of free radical species and mitochondrial abnormalities. Thus, angiogenesis, that supplies several trophic factors, should be promoted in therapeutic neuroregeneration efforts to combat the progressive, degenerative phase of MS.

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“…The activation of c-Jun inhibits Krox-20, thereby suppressing myelination. c-Jun also promotes the level of transcription factor SHH, trophic factors such as GDNF and BDNF, cell surface molecules such as NCAM, N-cadherin, and the neurotrophin receptor p75 NTR (Ahmad et al, 2014;Arthur-Farraj et al, 2012;Coulson et al, 2000;Coulson et al, 1999;Fontana et al, 2012;Hashimoto et al, 2008;Jiang et al, 2005;Klein et al, 2014;Parkinson et al, 2008;Pham et al, 2009;Shy et al, 1996;Topilko et al, 1997;Topilko et al, 1994). SCs are then entering a unique active stage normally named dedifferentiation.…”

Section: Gdf-15 and Schwann Cells/fibroblasts/macrophagesmentioning

confidence: 99%