Neural stem cells protect against glutamate-induced excitotoxicity and promote survival of injured motor neurons through the secretion of neurotrophic factors

Lladó, Jerònia; Haenggeli, Christine; Maragakis, Nicholas J.; Snyder, Evan Y.; Rothstein, Jeffrey D.

doi:10.1016/j.mcn.2004.07.010

Cited by 186 publications

(136 citation statements)

References 41 publications

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“…These results are consistent with the hypothesis that, in neural stem cells, SOX9 expression promotes a glial rather than a neuronal cell fate and that, in Sox9 conditional knock-outs, neural stem cells activated by the injury may adopt a neuronal as opposed to a glial fate. If astrocytes newly-born after injury contribute to CSPG production, or if newly-born neuroblasts are able to generate new neurons or produce growth factors that support neuronal survival (Behrstock et al, 2006;Llado et al, 2004;Madhavan et al, 2008), then the effect of Sox9 ablation on neural stem cell behavior (decreasing the number of newborn astrocytes and increasing the number of neuroblasts or neurons) may explain the improved recovery of Sox9 conditional knock-out mice after SCI. This possibility is being evaluated by fate mapping studies in the Sox9 conditional knock-outs after SCI.…”

Section: Discussionmentioning

confidence: 99%

Conditional Sox9 ablation reduces chondroitin sulfate proteoglycan levels and improves motor function following spinal cord injury

McKillop

Dragan

Schedl

et al. 2012

Glia

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Chondroitin sulfate proteoglycans (CSPGs) found in perineuronal nets and in the glial scar after spinal cord injury have been shown to inhibit axonal growth and plasticity. Since we have previously identified SOX9 as a transcription factor that upregulates the expression of a battery of genes associated with glial scar formation in primary astrocyte cultures, we predicted that conditional Sox9 ablation would result in reduced CSPG expression after spinal cord injury and that this would lead to increased neuroplasticity and improved locomotor recovery. Control and Sox9 conditional knock-out mice were subject to a 70 kdyne contusion spinal cord injury at thoracic level 9. One week after injury, Sox9 conditional knock-out mice expressed reduced levels of CSPG biosynthetic enzymes (Xt-1 and C4st), CSPG core proteins (brevican, neurocan, and aggrecan), collagens 2a1 and 4a1, and Gfap, a marker of astrocyte activation, in the injured spinal cord compared with controls. These changes in gene expression were accompanied by improved hind limb function and locomotor recovery as evaluated by the Basso Mouse Scale (BMS) and rodent activity boxes. Histological assessments confirmed reduced CSPG deposition and collagenous scarring at the lesion of Sox9 conditional knock-out mice, and demonstrated increased neurofilament-positive fibers in the lesion penumbra and increased serotonin immunoreactivity caudal to the site of injury. These results suggest that SOX9 inhibition is a potential strategy for the treatment of SCI.

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Section: Discussionmentioning

confidence: 99%

Conditional Sox9 ablation reduces chondroitin sulfate proteoglycan levels and improves motor function following spinal cord injury

McKillop

Dragan

Schedl

et al. 2012

Glia

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“…Control experiments were performed with the omission of the primary antibodies yielding negative results. Finally, to reveal whether NSI‐189 induced secretion of neurogenic factors in cultured hippocampal cells which might have facilitated cell proliferation and neurogenesis, we measured from the conditioned media (harvested from NSI‐189 supplemented and standard growth medium) trophic factors such as SCF, brain derived‐neurotrophic factor (BDNF), glial cell line‐derived neurotrophic factor (GDNF), and vascular endothelial growth factor (VEGF) which have been implicated as critical secretory factors associated with stemness properties (Lladó, Haenggeli, Maragakis, Snyder, & Rothstein, 2004; Sieber‐Blum, 1998). The levels of BDNF, GDNF, VEGF, and SCF were determined using ELISA kits according to the protocols of the manufacturer (BDNF and GDNF from Promega; human VEGF and human SCF from R & D Systems).…”

Section: Methodsmentioning

confidence: 99%

NSI‐189, a small molecule with neurogenic properties, exerts behavioral, and neurostructural benefits in stroke rats

Tajiri

Quach

Kaneko

et al. 2017

Journal Cellular Physiology

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Enhancing neurogenesis may be a powerful stroke therapy. Here, we tested in a rat model of ischemic stroke the beneficial effects of NSI‐189, an orally active, new molecular entity (mol. wt. 366) with enhanced neurogenic activity, and indicated as an anti‐depressant drug in a clinical trial (Fava et al., 2015, Molecular Psychiatry, DOI: 10.1038/mp.2015.178) and being tested in a Phase 2 efficacy trial (ClinicalTrials.gov, 2016, ClinicalTrials.gov Identifier: NCT02695472) for treatment of major depression. Oral administration of NSI‐189 in adult Sprague–Dawley rats starting at 6 hr after middle cerebral artery occlusion, and daily thereafter over the next 12 weeks resulted in significant amelioration of stroke‐induced motor and neurological deficits, which was maintained up to 24 weeks post‐stroke. Histopathological assessment of stroke brains from NSI‐189‐treated animals revealed significant increments in neurite outgrowth as evidenced by MAP2 immunoreactivity that was prominently detected in the hippocampus and partially in the cortex. These results suggest NSI‐189 actively stimulated remodeling of the stroke brain. Parallel in vitro studies further probed this remodeling process and demonstrated that oxygen glucose deprivation and reperfusion (OGD/R) initiated typical cell death processes, which were reversed by NSI‐189 treatment characterized by significant attenuation of OGD/R‐mediated hippocampal cell death and increased Ki67 and MAP2 expression, coupled with upregulation of neurogenic factors such as BDNF and SCF. These findings support the use of oral NSI‐189 as a therapeutic agent well beyond the initial 6‐hr time window to accelerate and enhance the overall functional improvement in the initial 6 months post stroke.

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“…Trophic factors such as SCF, brain derived-neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and vascular endothelial growth factor (VEGF) have been detected as critical secretory factors in immature NSCs (SieberBlum, 1998; Lu et al, 2003;Llado et al, 2004). Thus, we measured these molecules as possible neurotrophic factors secreted by HB1.F3 cells.…”

Section: In Vitro Studymentioning

confidence: 99%

Transplantation of Human Neural Stem Cells Exerts Neuroprotection in a Rat Model of Parkinson's Disease

Yasuhara¹,

Matsukawa²,

Hara³

et al. 2006

J. Neurosci.

262

200

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Neural stem cells protect against glutamate-induced excitotoxicity and promote survival of injured motor neurons through the secretion of neurotrophic factors

Cited by 186 publications

References 41 publications

Conditional Sox9 ablation reduces chondroitin sulfate proteoglycan levels and improves motor function following spinal cord injury

Conditional Sox9 ablation reduces chondroitin sulfate proteoglycan levels and improves motor function following spinal cord injury

NSI‐189, a small molecule with neurogenic properties, exerts behavioral, and neurostructural benefits in stroke rats

Transplantation of Human Neural Stem Cells Exerts Neuroprotection in a Rat Model of Parkinson's Disease

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