Amyotrophic Lateral Sclerosis: Drug Therapy from the Bench to the Bedside

Gibson, Summer; Bromberg, Mark B.

doi:10.1055/s-0032-1329193

Cited by 20 publications

(9 citation statements)

References 80 publications

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“…Riluzole is licensed for MND and has two modes of action of relevance to SPMS: reducing glutamate release and antagonism of voltage dependent sodium channels [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Drug Repurposing: A Systematic Approach to Evaluate Candidate Oral Neuroprotective Interventions for Secondary Progressive Multiple Sclerosis

et al. 2015

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ObjectiveTo develop and implement an evidence based framework to select, from drugs already licenced, candidate oral neuroprotective drugs to be tested in secondary progressive multiple sclerosis.DesignSystematic review of clinical studies of oral putative neuroprotective therapies in MS and four other neurodegenerative diseases with shared pathological features, followed by systematic review and meta-analyses of the in vivo experimental data for those interventions. We presented summary data to an international multi-disciplinary committee, which assessed each drug in turn using pre-specified criteria including consideration of mechanism of action.ResultsWe identified a short list of fifty-two candidate interventions. After review of all clinical and pre-clinical evidence we identified ibudilast, riluzole, amiloride, pirfenidone, fluoxetine, oxcarbazepine, and the polyunsaturated fatty-acid class (Linoleic Acid, Lipoic acid; Omega-3 fatty acid, Max EPA oil) as lead candidates for clinical evaluation.ConclusionsWe demonstrate a standardised and systematic approach to candidate identification for drug rescue and repurposing trials that can be applied widely to neurodegenerative disorders.

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“…Riluzole is licensed for MND and has two modes of action of relevance to SPMS: reducing glutamate release and antagonism of voltage dependent sodium channels [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Drug Repurposing: A Systematic Approach to Evaluate Candidate Oral Neuroprotective Interventions for Secondary Progressive Multiple Sclerosis

et al. 2015

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“…ALS results in muscle paralysis caused by the degeneration of the motor neurons and neuromuscular junctions in the cortico-motor-neuronal system, however it is not clear why these neurons are selectively vulnerable. Although it is likely that ALS is a multifactorial disease, potentially involving RNA dysfunction, protein misfolding and aggregation, autophagy, ER stress and axonal disruption (Gibson and Bromberg, 2012 ), there is increasing evidence for a pivotal role for excitotoxicity in the pathogenesis, with a significant period of neuronal dysfunction occurring prior to frank cell loss (Corona et al, 2007 ; Kiernan et al, 2011 ). Indeed, hyperexcitability of both upper and lower motor neurons has been reported prior to the onset of motor symptoms(Pieri et al, 2003 ; Vucic and Kiernan, 2006 ; van Zundert et al, 2008 ; Menon et al, 2015 ) and the only current treatment available for ALS, riluzole, involves inhibition of this excitotoxic pathway (Miller et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

Inducing Chronic Excitotoxicity in the Mouse Spinal Cord to Investigate Lower Motor Neuron Degeneration

2016

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We report the methodology for the chronic delivery of an excitotoxin to the mouse spinal cord via surgically implanted osmotic mini-pumps. Previous studies have investigated the effect of chronic application of excitotoxins in the rat, however there has been little translation of this model to the mouse. Using mice that express yellow fluorescent protein (YFP), motor neuron and neuromuscular junction alterations can be investigate following targeted, long-term (28 days) exposure to the α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor excitotoxin, kainic acid. By targeting the L3-4 region of the lumbar spinal cord, with insertion of an intrathecal catheter into the subarachnoid space at L5, chronic application of the kainic acid results in slow excitotoxic death in the anterior ventral horn, with a significant (P < 0.05) reduction in the number of SMI-32 immunopositive neurons present after 28 days infusion. Use of the Thy1-YFP mice provides unrivaled visualization of the neuromuscular junction and enables the resultant distal degeneration in skeletal muscle to be observed. Both neuromuscular junction retraction at the gastrocnemius muscle and axonal fragmentation in the sciatic nerve were observed after chronic infusion of kainic acid for 28 days. Lower motor neuron, and distal neuromuscular junction, degeneration are pathological hallmarks of the devastating neurodegenerative disease Amyotrophic Lateral Sclerosis (ALS). This mouse model will be advantageous for increasing our understanding of how the pathophysiological phenomena associated with this disease can lead to lower motor neuron loss and distal pathology, as well as providing a robust in vivo platform to test therapeutic interventions directed at excitotoxic mechanisms.

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“…Although 10% of ALS cases have an inherited genetic mutation ( Kiernan et al, 2011 ; Ajroud-Driss and Siddique, 2014 ), the majority of cases are sporadic. ALS is a multifactorial disease involving RNA dysfunction, protein misfolding and aggregation, ER stress, axonal disruption and excitotoxicity ( Gibson and Bromberg, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

Identifying the primary site of pathogenesis in amyotrophic lateral sclerosis – vulnerability of lower motor neurons to proximal excitotoxicity

Blizzard

Southam

Dawkins

et al. 2015

Disease Models &Amp; Mechanisms

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There is a desperate need for targeted therapeutic interventions that slow the progression of amyotrophic lateral sclerosis (ALS). ALS is a disorder with heterogeneous onset, which then leads to common final pathways involving multiple neuronal compartments that span both the central and peripheral nervous system. It is believed that excitotoxic mechanisms might play an important role in motor neuron death in ALS. However, little is known about the mechanisms by which excitotoxicity might lead to the neuromuscular junction degeneration that characterizes ALS, or about the site at which this excitotoxic cascade is initiated. Using a novel compartmentalised model of site-specific excitotoxin exposure in lower motor neurons in vitro, we found that spinal motor neurons are vulnerable to somatodendritic, but not axonal, excitotoxin exposure. Thus, we developed a model of somatodendritic excitotoxicity in vivo using osmotic mini pumps in Thy-1-YFP mice. We demonstrated that in vivo cell body excitotoxin exposure leads to significant motor neuron death and neuromuscular junction (NMJ) retraction. Using confocal real-time live imaging of the gastrocnemius muscle, we found that NMJ remodelling preceded excitotoxin-induced NMJ degeneration. These findings suggest that excitotoxicity in the spinal cord of individuals with ALS might result in a die-forward mechanism of motor neuron death from the cell body outward, leading to initial distal plasticity, followed by subsequent pathology and degeneration.

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Amyotrophic Lateral Sclerosis: Drug Therapy from the Bench to the Bedside

Cited by 20 publications

References 80 publications

Drug Repurposing: A Systematic Approach to Evaluate Candidate Oral Neuroprotective Interventions for Secondary Progressive Multiple Sclerosis

Drug Repurposing: A Systematic Approach to Evaluate Candidate Oral Neuroprotective Interventions for Secondary Progressive Multiple Sclerosis

Inducing Chronic Excitotoxicity in the Mouse Spinal Cord to Investigate Lower Motor Neuron Degeneration

Identifying the primary site of pathogenesis in amyotrophic lateral sclerosis – vulnerability of lower motor neurons to proximal excitotoxicity

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