BDNF Protects the Neonatal Brain from Hypoxic-Ischemic Injury<i>In Vivo</i>via the ERK Pathway

Han, Byung Hee; Holtzman, David M.

doi:10.1523/jneurosci.20-15-05775.2000

Cited by 484 publications

(399 citation statements)

References 51 publications

(64 reference statements)

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“…Importantly, these neurotrophic factors are known to support neuronal survival and plasticity in various models of axonopathy and neuropathy. [42][43][44][45][46] Quantitative analysis of constitutive neurotrophic factor release from NSCs is relatively rarely reported in the literature, despite the popular theory that release of these proteins and their effects on compromised host tissue is a potential mechanism behind the cells' restorative capacity. 8,9,11,14,16 Time courses of release are generally lacking, as are release profiles from scaffolded cells.…”

Section: Discussionmentioning

confidence: 99%

Alginate Composition Effects on a Neural Stem Cell–Seeded Scaffold

Purcell

Singh

Kipke

2009

Tissue Engineering Part C: Methods

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The purpose of this study was to evaluate the effects of alginate composition on the neurotrophic factor release, viability, and proliferation of encapsulated neural stem cells (NSCs), as well as on the mechanical stability of the scaffold itself. Four compositions were tested: a high guluronic acid (68%) and a high mannuronic acid (54%) content alginate, with or without a poly-L-lysine (PLL) coating layer. Enzyme-linked immunosorbent assay was used to quantify the release of brain-derived neurotrophic factor, glial-derived neurotrophic factor, and nerve growth factor from the encapsulated cells. All three factors were detected from encapsulated cells only when a high L-guluronic acid alginate without PLL was used. Additionally, capsules with this composition remained intact more frequently when exposed to solutions of low osmolarity, potentially indicating superior mechanical stability. Alginate beads with a PLL-coated, high D-mannuronic acid composition were the most prone to breakage in the osmotic pressure test, and were too fragile for histology and proliferation assays after 1 week in vitro. NSCs survived and proliferated in the three remaining alginate compositions similarly over the 21-day study course irrespective of scaffold condition. NSC-seeded alginate beads with a high L-guluronic acid, non-PLL-coated composition may be useful in the repair of injured nervous tissue, where the mechanism is the secretion of neuroprotective factors. We verify the neuroprotective effects of medium conditioned by NSCseeded alginate beads on the serum withdrawal-mediated death of PC-12 cells here.

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Section: Discussionmentioning

confidence: 99%

Alginate Composition Effects on a Neural Stem Cell–Seeded Scaffold

Purcell

Singh

Kipke

2009

Tissue Engineering Part C: Methods

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“…14,15 Activation of the extracellular-regulated kinases (ERKs) pathway by BDNF is important for neuronal survival. 16,17 BDNF mediates activity dependent synaptic plasticity by mechanisms that involve receptor regulation and localized gene transcription. 18,19 At present, it is unclear whether the neuroprotection, synaptic remodeling and plasticity effects of BDNF are related to each other through common downstream elements.…”

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confidence: 99%

GAP-43 is essential for the neurotrophic effects of BDNF and positive AMPA receptor modulator S18986

et al. 2009

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Positive a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor modulators include benzamide compounds that allosterically modulate AMPA glutamate receptors. These small molecules that cross the blood-brain barrier have been shown to act as a neuroprotectant by increasing the levels of endogenous brain-derived neurotrophic factor (BDNF). Positive AMPA receptor modulators have also been shown to increase the levels of growth-associated protein-43 (GAP-43). GAP-43 plays a major role in many aspects of neuronal function in vertebrates. The goal of this study was to determine whether GAP-43 was important in mediating the actions of positive AMPA receptor modulator (S18986) and BDNF. Using cortical cultures from GAP-43 knockout and control mice, we show that (1) GAP-43 is upregulated in response to S18986 and BDNF in control cultures; (2) this upregulation of GAP-43 is essential for mediating the neuroprotective effects of S18986 and BDNF; (3) administration of S18986 and BDNF leads to an increase in the expression of the glutamate transporters GLT-1 and GLAST that are key to limiting excitotoxic cell death and this increase in GLT-1 and GLAST expression is completely blocked in the absence of GAP-43. Taken together this study concludes that GAP-43 is an important mediator of the neurotrophic effects of S18986 and BDNF on neuronal survival and plasticity, and is essential for the success of positive AMPA receptor modulator-BDNF-based neurotrophin therapy. Positive a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor modulators allosterically modulate AMPA-type glutamate receptors and facilitate fast excitatory transmission, 1,2 and have been shown to enhance learning and memory. [3][4][5] Positive AMPA receptor modulators also decrease neuronal loss in excitotoxic neonatal brain lesions. 6 Thus, positive AMPA receptor modulators are potential candidates for treatment of diseases characterized by cognitive dysfunction and neuronal loss. 7,8 Some of the effects of positive AMPA receptor modulators are mediated via increased BDNF expression. 9,10 Positive AMPA receptor modulators however are preferred over direct administration of BDNF itself as this class of molecules readily crosses the blood-brain barrier. 11 Brain-derived neurotrophic factor is important for appropriate development and connectivity of neurons as well as their survival. 12,13 In adults, activity dependent modulation of BDNF levels is important for synaptic plasticity and remodeling. 14,15 Activation of the extracellular-regulated kinases (ERKs) pathway by BDNF is important for neuronal survival. 16,17 BDNF mediates activity dependent synaptic plasticity by mechanisms that involve receptor regulation and localized gene transcription. 18,19 At present, it is unclear whether the neuroprotection, synaptic remodeling and plasticity effects of BDNF are related to each other through common downstream elements.Growth-associated protein-43 (GAP-43) is a nervous system specific F-actin regulating phosphoprotein expressed during de...

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“…Once activated, Akt phosphorylates a number of pro-apoptotic molecules including the Bcl-2 protein BAD, the Forkhead transcription factor, glycogen synthase kinase-3 (GSK-3) and caspase-9 (for a review, see Brunet et al 2001) leading to their inactivation. Another signaling pathway that has been implicated in the promotion of neuronal survival, at least in some systems, is the Raf-MEK-ERK pathway (Villalba et al 1997;Anderson and Tolkovsky 1999;Bonni et al 1999;Mazzoni et al 1999;Han and Holtzman 2000). In this pathway, Raf is recruited to the plasma membrane and directly interacts with GTP-Ras.…”

mentioning

confidence: 99%

The c‐Raf inhibitor GW5074 provides neuroprotection in vitro and in an animal model of neurodegeneration through a MEK‐ERK and Akt‐independent mechanism

Chin

Liu

Morrison

et al. 2004

Journal of Neurochemistry

111

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Cerebellar granule neurons undergo apoptosis when switched from a medium containing high potassium (HK) to one that has low potassium (LK). LK-induced cell death is blocked by GW5074 {5-Iodo-3-[(3,5-dibromo-4-hydroxyphenyl) methylene]-2-indolinone}, a synthetic drug that inhibits c-Raf activity in vitro. GW5074 has no direct effect on the activities of several apoptosis-associated kinases when assayed in vitro. In contrast to its effect in vitro, treatment of neurons with GW5074 causes c-Raf activation (when measured in vitro in the absence of the drug) and stimulates the Raf-MEK-ERK pathway. Treatment of neurons with GW5074 also leads to an increase in the activity of B-Raf, which is not inhibited by GW5074 in vitro at concentrations at which the drug exerts its neuroprotective effect. PD98059 and U0126, two distinct inhibitors of MEK, block the activation of ERK by GW5074 but have no effect on its ability to prevent cell death. Overexpression of a dominant-negative form of Akt does not reduce the efficacy of GW5074, demonstrating an Akt-independent mechanism of action. Neuroprotection is inhibited by SN-50, a specific inhibitor of nuclear factor-kappa B (NF-jB) and by the Ras inhibitor S-trans, trans-farnesylthiosalicylic acid (FTS) implicating NF-jB and Ras in the neuroprotective signaling pathway activated by GW5074. In addition to preventing LK-induced apoptosis, treatment with GW5074 protects against the neurotoxic effects of MPP+ and methylmercury in cerebellar granule neurons, and glutathione depletion-induced oxidative stress in cortical neurons. Furthermore, GW5074 prevents neurodegeneration and improves behavioral outcome in an animal model of Huntington's disease. Given its neuroprotective effect on distinct types of cultured neurons, in response to different neurotoxic stimuli, and in an animal model of neurodegeneration, GW5074 could have therapeutic value against neurodegenerative pathologies in humans.

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BDNF Protects the Neonatal Brain from Hypoxic-Ischemic InjuryIn Vivovia the ERK Pathway

Cited by 484 publications

References 51 publications

Alginate Composition Effects on a Neural Stem Cell–Seeded Scaffold

Alginate Composition Effects on a Neural Stem Cell–Seeded Scaffold

GAP-43 is essential for the neurotrophic effects of BDNF and positive AMPA receptor modulator S18986

The c‐Raf inhibitor GW5074 provides neuroprotection in vitro and in an animal model of neurodegeneration through a MEK‐ERK and Akt‐independent mechanism

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