Benefit of vitamin E, riluzole, and gababapentin in a transgenic model of familial amyotrophic lateral sclerosis

Gurney, Mark E.; Cutting, Frank B.; Zhai, Ping; Doble, Adam; Taylor, Charles P.; Andrus, Paula K.; Hall, Edward D.

doi:10.1002/ana.410390203

Cited by 619 publications

(355 citation statements)

References 52 publications

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“…Previous research into the pathogenesis of ALS supports the hypothesis that the production of free radicals precipitates, or at least facilitates, motor neuron loss, while multiple antioxidants attenuate this deleterious progression [ (Gurney et al 1996;Henderson et al 1996)]. By crossing the SOD G93A mouse model of ALS with a reporter of ARE activation, we were able to discern that the Nrf2-ARE pathway is indeed active within the hindlimb muscle at a very early timepoint (30 days, Figure 1).…”

Section: Discussionmentioning

confidence: 57%

“…In humans, as well as animal models, it has been clearly shown that oxidative stress plays a central role in the progression of this motor neuron loss, possibly in concert with a chronically enhanced excitotoxin profile [ (Rothstein et al 1990;Gurney et al 1996;Andrus et al 1998;Heath and Shaw 2002;Agar and Durham 2003)]. Five to 10% of all human ALS cases have a familial cause (fALS), of which about 20% are caused by a mutation in the gene encoding Cu/Zn superoxide dismutase (SOD1) [ (Rosen 1993;Gurney et al 1994)].…”

Section: Introductionmentioning

confidence: 99%

“…Therapeutically, the molecular avenues targeted for treatment of fALS include neurotrophic factors, antioxidants, modifiers of the proteasome system, as well as inhibitors of inflammation or excitotoxicity [(Gurney et al 1996;Bruijn et al 1998;Drachman et al 2002;Guo et al 2003;Valentine and Hart 2003;Wang et al 2003;Ascherio et al 2005;McGeer and McGeer 2005)]. A recent study suggests that reconfiguration of the muscle alone is sufficient for trophic support of endangered spinal cord neurons [ (Dobrowolny et al 2005)].…”

Section: Introductionmentioning

confidence: 99%

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Activation of the Nrf2–ARE pathway in muscle and spinal cord during ALS-like pathology in mice expressing mutant SOD1

Kraft

Resch

Johnson

et al. 2007

Experimental Neurology

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Oxidative stress plays a key role in the neuronal loss exhibited in amyotrophic lateral sclerosis (ALS), an event precipitating irreversible muscle atrophy. By crossing ALS mouse models (SOD G93A and SOD H46RH48Q ) with an antioxidant response element (ARE) reporter mouse, we identified activation characteristics of the ARE system throughout the timecourse of motor neuron disease. Surprisingly, the earliest and most significant activation of this genetic sensor of oxidative stress occurred in the distal muscles of mutant SOD mice. The resultant data supports existing hypotheses that the muscle is somehow implicated during the initial pathology of these mice. Subsequently, Nrf2-ARE activation appears to progress in a retrograde fashion along the motor pathway. These data provide timely information concerning the contributions of the Nrf2-ARE pathway in ALS disease progression.

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Section: Discussionmentioning

confidence: 57%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Activation of the Nrf2–ARE pathway in muscle and spinal cord during ALS-like pathology in mice expressing mutant SOD1

Kraft

Resch

Johnson

et al. 2007

Experimental Neurology

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“…Furthermore, it resulted in a significant prolongation for 16 and 11 days in survival of female and male SOD1 G93A mice, respectively. Therefore, sigma-1R modulation produces important functional benefits in terms of spinal MN function, locomotion, and survival in the SOD1 G93A mouse model, even comparatively better than silencing the mutant SOD1 expression [38] or other pharmacological treatments previously reported [39], such as riluzole [40].…”

Section: Discussionmentioning

confidence: 94%

Sigma-1R Agonist Improves Motor Function and Motoneuron Survival in ALS Mice

et al. 2012

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Amyotrophic lateral sclerosis is a neurodegenerative disorder characterized by progressive weakness, muscle atrophy, and paralysis due to the loss of upper and lower motoneurons (MNs). Sigma-1 receptor (sigma-1R) activation promotes neuroprotection after ischemic and traumatic injuries to the central nervous system. We recently reported that sigma-1R agonist (PRE-084) improves the survival of MNs after root avulsion injury in rats. Moreover, a mutation of the sigma-1R leading to frontotemporal lobar degeneration/amyotrophic lateral sclerosis (ALS) was recently described in human patients. In the present study, we analyzed the potential therapeutic effect of the sigma-1R agonist (PRE-084) in the SOD1 G93A mouse model of ALS. Mice were daily administered with PRE-084 (0.25 mg/kg) from 8 to 16 weeks of age. Functional outcome was assessed by electrophysiological tests and computerized analysis of locomotion. Histological, immunohistochemical analyses and Western blot of the spinal cord were performed. PRE-084 administration from 8 weeks of age improved the function of MNs, which was manifested by maintenance of the amplitude of muscle action potentials and locomotor behavior, and preserved neuromuscular connections and MNs in the spinal cord. Moreover, it extended survival in both female and male mice by more than 15 %. Delayed administration of PRE-084 from 12 weeks of age also significantly improved functional outcome and preservation of the MNs. There was an induction of protein kinase C-specific phosphorylation of the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor in SOD1 G93A animals, and a reduction of the microglial reactivity compared with untreated mice. PRE-084 exerts a dual therapeutic contribution, modulating NMDA Ca 2+ influx to protect MNs, and the microglial reactivity to ameliorate the MN environment. In conclusion, sigma-1R agonists, such as PRE-084, may be promising candidates for a therapeutical strategy of ALS.

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“…However, the overall effect in ALS patients was transient in that the survival curves were unaffected when examined in prolonged follow up studies (47,48). In ALS animal models (S2), Riluzole treatment (100µg/mL water) during the presymptomatic stage was initially shown to exert no effect on delaying the onset of disease, but did significantly extend survival by 13-15 days (49). A follow-up study showed a dose-dependent preservation of motor function, while exhibiting an identical positive effect of survival at doses of 24-44 mg riluzole/kg body weight/day of 12-13 days (50).…”

Section: Murine Models Of Familial Alsmentioning

confidence: 99%

Disparity of outcomes: the limits of modeling amyotrophic lateral sclerosis in murine models and translating results clinically

Zwiegers

Shaw

2015

jcbmr

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Amyotrophic lateral sclerosis (ALS) is a devastatingly progressive neurodegenerative disorder with multiple underlying etiological factors contributing to disease pathogenesis. Despite intensive research efforts and therapeutic development, disease presentation in ALS remains largely intractable to intervention. To date, the most common rodent model used in preclinical drug development accounts for a small proportion of the affected patient population and is predicated upon the significant overexpression of a mutant form of the human antioxidant protein, superoxide dismutase 1 (mSOD1). After more than 50 clinical trials, there is an alarming paucity of positive outcomes at the clinical level of ALS therapeutics with strong supporting pre-clinical data in mSOD1 models. Potential reasons for the negative clinical results are multifactorial in nature and include an overly reductionist model system that is heavily influenced by individual transgene level variation, as well as attempting to widely apply findings derived from a model of specific genetic causality to a patient population where the majority of cases are of unknown etiology. With such a tremendous disease burden and a lack of therapeutic options, it is critical that the research community re-evaluate the dependence on mSOD1 pre-clinical models as the gold standard prior to translating findings at the clinical level. Here we briefly review both the clinical and pre-clinical findings of select therapeutics, discuss the limitations of pre-clinical mSOD1 models, and suggest future stratagems that could aid in the clinical translation of efficacious therapeutic agents.

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Benefit of vitamin E, riluzole, and gababapentin in a transgenic model of familial amyotrophic lateral sclerosis

Cited by 619 publications

References 52 publications

Activation of the Nrf2–ARE pathway in muscle and spinal cord during ALS-like pathology in mice expressing mutant SOD1

Activation of the Nrf2–ARE pathway in muscle and spinal cord during ALS-like pathology in mice expressing mutant SOD1

Sigma-1R Agonist Improves Motor Function and Motoneuron Survival in ALS Mice

Disparity of outcomes: the limits of modeling amyotrophic lateral sclerosis in murine models and translating results clinically

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