Preclinical Testing of Neuroprotective Neurotrophic Factors in a Model of Chronic Motor Neuron Degeneration

Corse, Andrea M.; Bilak, Masako M.; Bilak, Stephan R.; Lehar, Mohamed; Rothstein, Jeffrey D.; Kuncl, Ralph W.

doi:10.1006/nbdi.1999.0253

Cited by 92 publications

(57 citation statements)

References 67 publications

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“…High levels of expression achieved via AAV2 delivery most likely provides a sufficient level of local IGF-1 to overcome loss of IGF-1 signaling associated with disease. The present results coincide with previous studies that have shown that IGF-1 exerts pro-survival effects specifically on motor neurons: 1) in dissociated culture [57], 2) in the organotypic spinal cord model of excitotoxicity [19], 3) during developmental programmed cell death [37], 4) following spinal cord ischemia [44], spinal transaction [51], peripheral axotomy [38], crush injury [47] and root avulsion [29], 5) in the wobbler mouse [30] and in the SOD1 mouse [20,34].…”

Section: Therapeutic Actions Of Igf-1 In Alssupporting

confidence: 92%

Intraparenchymal spinal cord delivery of adeno-associated virus IGF-1 is protective in the SOD1G93A model of ALS

Lepore

Haenggeli

Gasmi³

et al. 2007

Brain Research

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113

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The potent neuroprotective activities of neurotrophic factors, including insulin-like growth factor 1 (IGF-1), make them promising candidates for treatment of amyotrophic lateral sclerosis (ALS). In an effort to maximize rate of motor neuron transduction, achieve high levels of spinal IGF-1, and thus enhance therapeutic benefit, we injected an adeno-associated virus 2 (AAV2)-based vector encoding human IGF-1 (CERE-130) into lumbar spinal cord parenchyma of SOD1 G93A mice. We observed robust and long-term intraspinal IGF-1 expression and partial rescue of lumbar spinal cord motor neurons, as well as sex-specific delayed disease onset, weight loss, decline in hindlimb grip strength and increased animal survival.

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Section: Therapeutic Actions Of Igf-1 In Alssupporting

confidence: 92%

Intraparenchymal spinal cord delivery of adeno-associated virus IGF-1 is protective in the SOD1G93A model of ALS

Lepore

Haenggeli

Gasmi³

et al. 2007

Brain Research

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113

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“…However, there is no direct evidence showing the neuroprotective effect of endogenous TDP-43 in neuronal injury and neurodegeneration. Our study provides the first evidence that nuclear TDP-43 expression is increased at the early stages in an in vitro glutamate accumulation-induced neurodegeneration model (Corse et al, 1999;Kidd and Isaac 2000;Matyja et al, 2006;Nagańska et al, 2010;Tolosa et al, 2008;Van Westerlaak et al, 2001). We demonstrate that glutamate accumulation results in an (right) show that overexpression of TDP-43 or treatment with bpV(pic) reduces NR2AR inhibition-mediated increase of neuronal death at 3 days after 100 mM THA treatment (means 6 s.e.m.…”

Section: Discussionmentioning

confidence: 64%

“…DL-threo-betahydroxyaspartate (THA), an inhibitor of glutamate transporters, was used to induce neuronal injury. By promoting extracellular glutamate accumulation, THA treatment causes glutamate neurotoxicity and has been used to induce neuronal injury in vitro (Corse et al, 1999;Kidd and Isaac, 2000;Matyja et al, 2006;Nagańska et al, 2010;Tolosa et al, 2008;Van Westerlaak et al, 2001). To characterize this model, we first performed a lactate dehydrogenase (LDH) release assay to measure THAinduced neuronal damage in the cortical cultures.…”

Section: Resultsmentioning

confidence: 99%

Regulation of nuclear TDP-43 by NR2A-containing NMDA receptors and PTEN

Liao

Cui

et al. 2012

Journal of Cell Science

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SummaryThe dysfunction of TAR DNA-binding protein-43 (TDP-43) is implicated in neurodegenerative diseases. However, the function of TDP-43 is not fully elucidated. Here we show that the protein level of endogenous TDP-43 in the nucleus is increased in mouse cortical neurons in the early stages, but return to basal level in the later stages after glutamate accumulation-induced injury. The elevation of TDP-43 results from a downregulation of phosphatase and tensin homolog (PTEN). We further demonstrate that activation of NR2A-containing NMDA receptors (NR2ARs) leads to PTEN downregulation and subsequent reduction of PTEN import from the cytoplasm to the nucleus after glutamate accumulation. The decrease of PTEN in the nucleus contributes to its reduced association with TDP-43, and thereby mediates the elevation of nuclear TDP-43. We provide evidence that the elevation of nuclear TDP-43, mediated by NR2AR activation and PTEN downregulation, confers protection against cortical neuronal death in the late stages after glutamate accumulation. Thus, this study reveals a NR2AR-PTEN-TDP-43 signaling pathway by which nuclear TDP-43 promotes neuronal survival. These results suggest that upregulation of nuclear TDP-43 represents a self-protection mechanism to delay neurodegeneration in the early stages after glutamate accumulation and that prolonging the upregulation process of nuclear TDP-43 might have therapeutic significance.

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“…A variety of different treatment paradigms have been evaluated in this model and represent a basis for later testing in human clinical studies [8][9][10] . In order to be able to detect significant differences in an experimental treatment study in these mice, it is of eminent importance to include at least 24 litter-matched gender-balanced mice of the same genetic background and follow a double-blinded design 8 shall be prepared, their skin has also to be incised.…”

Section: Representative Resultsmentioning

confidence: 99%

“…vibratome or cryotome) and can finally be subjected to immunohistological analysis. Here, basic evaluation parameters are the numbers of spinal cord motoneurons and activated or infiltrating glial cells 10,15 . Depending on the original research question, additional immunohistochemical markers like SOD aggregates or CNS endothelium integrity can be evaluated.…”

Section: Representative Resultsmentioning

confidence: 99%

Clinical Testing and Spinal Cord Removal in a Mouse Model for Amyotrophic Lateral Sclerosis (ALS)

Günther

Suhr

Koch

et al. 2012

JoVE

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder resulting in progressive degeneration of motoneurons. Peak of onset is around 60 years for the sporadic disease and around 50 years for the familial disease. Due to its progressive course, 50% of the patients die within 30 months of symptom onset. In order to evaluate novel treatment options for this disease, genetic mouse models of ALS have been generated based on human familial mutations in the SOD gene, such as the SOD1 (G93A) mutation. Most important aspects that have to be evaluated in the model are overall survival, clinical course and motor function. Here, we demonstrate the clinical evaluation, show the conduction of two behavioural motor tests and provide quantitative scoring systems for all parameters. Because an in depth analysis of the ALS mouse model usually requires an immunohistochemical examination of the spinal cord, we demonstrate its preparation in detail applying the dorsal laminectomy method. Exemplary histological findings are demonstrated. The comprehensive application of the depicted examination methods in studies on the mouse model of ALS will enable the researcher to reliably test future therapeutic options which can provide a basis for later human clinical trials. Video LinkThe video component of this article can be found at http://www.jove.com/video/3936/ Protocol Animals were purchased from Jackson Laboratory (# 002726) 1 . They are clinically scored and subjected to a test of motor function (rotarod test) and of muscular strength (hanging wire test). All these tests and the later killing of the animals in order to prepare the spinal cord have been performed in very close accordance to the local guidelines for proper conduct of animal experiments.

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Preclinical Testing of Neuroprotective Neurotrophic Factors in a Model of Chronic Motor Neuron Degeneration

Cited by 92 publications

References 67 publications

Intraparenchymal spinal cord delivery of adeno-associated virus IGF-1 is protective in the SOD1G93A model of ALS

Intraparenchymal spinal cord delivery of adeno-associated virus IGF-1 is protective in the SOD1G93A model of ALS

Regulation of nuclear TDP-43 by NR2A-containing NMDA receptors and PTEN

Clinical Testing and Spinal Cord Removal in a Mouse Model for Amyotrophic Lateral Sclerosis (ALS)

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