Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man

Fischer, Lindsey R.; Culver, Deborah G.; Tennant, Philip; Davis, Albert A.; Wang, Minsheng; Castellano-Sanchez, Amilcar A.; Khan, Jaffar; Polak, Meraida; Glass, Jonathan D.

doi:10.1016/j.expneurol.2003.10.004

Cited by 1,207 publications

(1,263 citation statements)

References 31 publications

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“…Abnormal function of spinal MNs, loss of neuromuscular junctions, and subsequent death of the MNs are key elements of the pathology in human patients and animal models of ALS [1,29,37]. Recently, we characterized the pattern of lower and upper MN dysfunction electrophysiologically [23] during disease progression in the SOD1 G93A mouse model, revealing that this is a reliable test to monitor the animal model, as well as human patients.…”

Section: Discussionmentioning

confidence: 99%

“…The analysis of lower MN functional activity is crucial to assess the effect of new treatments, because the loss of neuromuscular function is 1 of the hallmarks of the disease process in ALS animal models [29][30][31]. The results showed that PRE-084 administration significantly improved the amplitude of TA and plantar compound muscle action potential (CMAP), both in female and male SOD1 G93A mice from 12 weeks of age compared to untreated mice.…”

Section: Pre-084 Administration Improves Spinal Motoneuron Function Imentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Pre-084 Administration Improves Spinal Motoneuron Function Imentioning

confidence: 99%

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

et al. 2012

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“…Upper and lower MN function impairment is the main feature of ALS pathology both in human patients [1] and animal models [27,36,37]. We analyzed the amplitude of plantar and TA CMAP and MEP as a measure of lower and upper MN functional state, respectively.…”

Section: Resveratrol Administration Preserves Lower and Upper Motoneumentioning

confidence: 99%

Resveratrol Improves Motoneuron Function and Extends Survival in SOD1G93A ALS Mice

et al. 2014

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Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disease that causes progressive paralysis and death due to degeneration of motoneurons in spinal cord, brainstem and motor cortex. Nowadays, there is no effective therapy and patients die 2-5 years after diagnosis. Resveratrol (trans-3,4′,5-trihydroxystilbene) is a natural polyphenol found in grapes, with promising neuroprotective effects since it induces expression and activation of several neuroprotective pathways involving Sirtuin1 and AMPK. The objective of this work was to assess the effect of resveratrol administration on SOD1 G93A ALS mice. We determined the onset of symptoms by rotarod test and evaluated upper and lower motoneuron function using electrophysiological tests.We assessed the survival of the animals and determined the number of spinal motoneurons. Finally, we further investigated resveratrol mechanism of action by means of western blot and immunohistochemical analysis. Resveratrol treatment from 8 weeks of age significantly delayed disease onset and preserved lower and upper motoneuron function in female and male animals. Moreover, resveratrol significantly extended SOD1 G93A mice lifespan and promoted survival of spinal motoneurons. Delayed resveratrol administration from 12 weeks of age also improved spinal motoneuron function preservation and survival. Further experiments revealed that resveratrol protective effects were associated with increased expression and activation of Sirtuin 1 and AMPK in the ventral spinal cord. Both mediators promoted normalization of the autophagic flux and, more importantly, increased mitochondrial biogenesis in the SOD1 G93A spinal cord. Taken together, our findings suggest that resveratrol may represent a promising therapy for ALS.

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“…These mice replicate much of the human ALS phenotype. They develop eventual paralysis of their hindlimbs at approximately 120 days of age subsequent to mitochondrial damage, an accumulation of extracellular glutamate and intracellular filamentous inclusions, motor neuron (MN) cell death, and loss of axons innervating the muscle [(Gurney et al 1994;Klivenyi et al 1999;Alexander et al 2000;Fischer et al 2004)]. …”

Section: Introductionmentioning

confidence: 99%

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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Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man

Cited by 1,207 publications

References 31 publications

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

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

Resveratrol Improves Motoneuron Function and Extends Survival in SOD1G93A ALS Mice

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

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