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One Universal Common Endpoint in Mouse Models of Amyotrophic Lateral Sclerosis

  • Jesse A. Solomon,

    Affiliation School of Kinesiology and Health Science, Faculty of Health, York University, Toronto, Ontario, Canada

  • Mark A. Tarnopolsky,

    Affiliations Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada, Department of Medicine, McMaster University, Hamilton, Ontario, Canada

  • Mazen J. Hamadeh

    hamadeh@yorku.ca

    Affiliations School of Kinesiology and Health Science, Faculty of Health, York University, Toronto, Ontario, Canada, Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada

One Universal Common Endpoint in Mouse Models of Amyotrophic Lateral Sclerosis

  • Jesse A. Solomon, 
  • Mark A. Tarnopolsky, 
  • Mazen J. Hamadeh
PLOS
x

Abstract

There is no consensus among research laboratories around the world on the criteria that define endpoint in studies involving rodent models of amyotrophic lateral sclerosis (ALS). Data from 4 nutrition intervention studies using 162 G93A mice, a model of ALS, were analyzed to determine if differences exist between the following endpoint criteria: CS 4 (functional paralysis of both hindlimbs), CS 4+ (CS 4 in addition to the earliest age of body weight loss, body condition deterioration or righting reflex), and CS 5 (CS 4 plus righting reflex >20 s). The age (d; mean ± SD) at which mice reached endpoint was recorded as the unit of measurement. Mice reached CS 4 at 123.9±10.3 d, CS 4+ at 126.6±9.8 d and CS 5 at 127.6±9.8 d, all significantly different from each other (P<0.001). There was a significant positive correlation between CS 4 and CS 5 (r = 0.95, P<0.001), CS 4 and CS 4+ (r = 0.96, P<0.001), and CS 4+ and CS 5 (r = 0.98, P<0.001), with the Bland-Altman plot showing an acceptable bias between all endpoints. Logrank tests showed that mice reached CS 4 24% and 34% faster than CS 4+ (P = 0.046) and CS 5 (P = 0.006), respectively. Adopting CS 4 as endpoint would spare a mouse an average of 4 days (P<0.001) from further neuromuscular disability and poor quality of life compared to CS 5. Alternatively, CS 5 provides information regarding proprioception and severe motor neuron death, both could be important parameters in establishing the efficacy of specific treatments. Converging ethics and discovery, would adopting CS 4 as endpoint compromise the acquisition of insight about the effects of interventions in animal models of ALS?

Introduction

The endpoints used in research studies involving mouse models of amyotrophic lateral sclerosis (ALS) vary widely between laboratories around the world [1][97]. Not all endpoints are in perfect agreement with each other; that is, depending on the endpoint, the age at which mice are euthanized (time point at which age is used to establish lifespan) may differ independently of the intervention treatment used in research studies (Table 1). Because specific endpoints inherently occur early or later in disease progression, researchers may not be able to directly compare the effectiveness of treatments on disease severity and progression, as well as functional outcomes, in animal models of ALS conducted in one research laboratory with similar treatments conducted in different laboratories. Identifying the proper endpoint is important, because it impacts lifespan and marks the end of data collection. A solution would be a universal endpoint which would allow researchers to follow disease progression and identify the effectiveness of an intervention treatment, while still meeting stringent ethical standards. Of relevance, this impacts the adoption of results from animal-based research for human randomized clinical trials, as well as the implications of adopting new recommendations, nutrition or pharmaceutical, for people with ALS.

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Table 1. Raw data and summary of endpoint criteria for 162 B6SJL-TgN-(SOD1-G93A)1Gur autosomal hemizygous female (F) and male (M) mice.

https://doi.org/10.1371/journal.pone.0020582.t001

ALS is a devastating neuromuscular disease characterized by death of motor neurons in the brain [98] and spinal cord [99]. Symptoms of ALS begin with muscle weakness, ultimately leading to paralysis and death [100]. The first mouse model used to study ALS was created by Gurney et al in 1994 [100] who discovered that a glycine to alanine substitution on the 93rd position in the human Cu,Zn superoxide dismutase (Cu/Zn-SOD) gene produced the phenotype of ALS. Mice testing positive for this mutation begin to overtly exhibit signs of motor degeneration through a change in gait between 85–110 d of life [15], [82], [83]. As the disease progresses, the hindlimbs become paralyzed, paw grip strength and endurance deteriorate, bony structures become palpable due to severe muscle and tissue loss, mobility is limited, and an inability to groom and scavenge for food and water become apparent [20], [49], [54], [73], [82]. Researchers conducting intervention studies in mouse models of ALS monitor the above changes to track the effectiveness of their intervention, however at what point is it no longer ethical to keep these mice alive?

Research ethics committees and animal care organizations/agencies serve to maintain standards for the care and use of animals used in research, including transgenic mice used in models of ALS [101]. Standards of care include the selection of “endpoint” which is the point at which an experimental animal is killed humanely to terminate pain, distress and/or suffering [101]. Hence, research ethics committees and animal care organizations/agencies must consult with ALS researchers to decide on a case-by-case basis which endpoint is suitable for a specific intervention study, while maintaining compatibility with the objectives and the integrity of the research project. Different laboratories using mouse models of ALS have chosen varying endpoints, some reflecting more advanced stages of the disease, including the righting reflex (mice are placed on their sides and are euthanized if they cannot right themselves to sternum in 3–30 s, time chosen depends on the laboratory), an inability to splay the hindlimbs due to paralysis, a percentage decrease in motor performance or grip strength from initial values, an inability to obtain food or water, a defined percentage of body weight loss from peak weight, serious eye infection, an inability to self-groom, no spontaneous breathing or movement for a predetermined time with no response to pain, complete hindlimb paralysis, or combinations of two or more of these criteria. The most commonly used endpoint is a righting reflex of at least 3 s [1], [4], [5], [7], [10][15], [17][23], [25], [27], [28], [30][32], [36], [38][47], [49][51], [53], [57][59], [61], [62], [64], [65], [68], [70][72], [74], [77], [79][83], [84], [86][89], [91], [94][97], however some studies did not specify the length of time used as the cutoff for the righting reflex [26], [54], [60], [73], [78], [85], [90], [93]. The popularity of the righting reflex is possibly due to its relative simplicity, value as an indicator of proprioception deterioration [102], [103], and/or history as the first endpoint used in an intervention study in this particular disease model [79].

To date, a universal endpoint has not been established among researchers using rodent models of ALS. An ideal endpoint would meet strict ethical standards, could be adopted by all research laboratories, and would allow researchers to properly study the progression of ALS and the effectiveness of treatments tested. A consistent endpoint across research laboratories would reduce inter-laboratory variability that may be attributed at least partially to the selection of endpoint. Thus, our objective was to determine whether an earlier endpoint could replace the righting reflex, sparing mice undue suffering, while preserving the integrity of research in rodent models of ALS. To do this, we used the G93A transgenic mouse model of ALS to validate if functional paralysis in both hindlimbs (CS 4) could replace other later endpoints, including the righting reflex (CS 5).

Materials and Methods

Ethics Statement

The experimental protocols of all 4 studies followed the guidelines of the Canadian Council of Animal Care and were approved by the McMaster University Animal Research Ethics Board. All necessary steps were taken to minimize suffering and distress to the mice in the studies.

Animals

Raw data for clinical score (CS), body condition and body weight were compiled from 4 previously published [15], [82], [83], [104], [105] nutrition intervention studies using a total of 162 B6SJL-TgN-(SOD1-G93A)1Gur autosomal hemizygous mice (100 females, 62 males) that reached endpoint at a clinical score of 5 (CS 5). All mice expressed the phenotype of ALS due to the G93A mutation in the SOD1 (Cu/Zn-SOD) gene. Raw data were used to determine the following endpoint criteria, with age (d) at which mice reached endpoint as the unit of measurement:

  1. CS 4 = both hindlimbs are functionally paralyzed
  2. CS 4+ = CS 4 plus the earliest time mice attained one of the following:
    1. weight loss ≥20% vs. body weight immediately prior to a clinical score of 2 (CS 2 is considered disease onset) = 20%CS2
    2. weight loss ≥20% vs. peak body weight = 20%Peak
    3. body condition score <2 = BC<2
    4. righting reflex >20 s (clinical score of 5) = CS 5
  3. CS 5 = CS 4 plus a righting reflex >20 s (considered as the endpoint in the previous 4 studies)

Body Weight and Body Condition

Body weights of mice in the 4 intervention studies were measured starting at age 35–40 d until mice reached CS 5. Body condition was assessed following a 5-point scale: 5 = obese mice, 4 = overconditioned mice (spine is a continuous column and the vertebrae are palpable only with firm pressure), 3 = well-conditioned mice (the vertebrae and dorsal pelvis are not prominent and are palpable with slight pressure), 2 = underconditioned mice (the segmentation of the vertebral column is evident and the dorsal pelvic bones are easily palpable), and 1 = emaciated mice (the skeletal structure is extremely prominent and the vertebrae are distinctly segmented). Body condition was recorded starting at age 43–79 d until mice reached CS 5.

Clinical Score

Using an 8-point scale, clinical score measurements for mice in the 4 intervention studies started at age 50–81 d until mice reached CS 5. The clinical score was based on signs exhibited by the mice to identify the severity of the disease: 0 = no evidence of disease, 1 = shaking or splaying of the hindlimbs when suspended by the tail (an indication of weakness in the hindlimbs), 1.5 = weakness in one hindlimb (compensation for footdrop), 2 = change in gait (used as disease onset when attained on two consecutive days), 2.5 = extreme weakness in one hindlimb (inability to dorsiflex), 3 = extreme weakness in both hindlimbs, 3.5 = functional paralysis in one hindlimb, 4 = functional paralysis in both hindlimbs but can right themselves in less than 20 s after being placed on their side, and 5 = cannot right themselves to sternum within 20 s after being placed on their sides (endpoint).

Statistical Analysis

Data for all 162 mice were submitted to a one-way repeated measures ANOVA to determine significant differences between CS4, CS4+ and CS5. When ANOVA indicated significance, a Tukey's HSD post hoc was used to determine the source of difference. A Pearson product-moment correlation coefficient (r) was determined to establish the relationship between the different endpoints. A Bland-Altman plot was used to analyze the agreement between the different endpoints. A logrank test was used to determine whether there was a difference in the rate at which mice reached CS4, CS4+ and CS 5. For all logrank tests, CS 4 was used as the reference when comparing CS 4 vs. CS 4+ and CS 4 vs. CS 5, whereas CS 4+ was used as the reference when comparing CS 4+ vs. CS 5. All ANOVA, linear regression and logrank test comparisons were planned. All statistical analyses were completed using GraphPad Prism (version 4.0, GraphPad Software, La Jolla, CA). Significance was established at P≤0.05. Data are presented as means ± SD, unless otherwise indicated.

Results

Mice reached CS 4 at 123.9±10.3 d, CS 4+ at 126.6±9.8 d and CS 5 at 127.6±9.8 d (Table 1). There was a significant main effect between endpoints (P<0.001), all being significantly different from each other (P<0.001 for all).

There was a strong positive correlation between CS 4 and CS 5 (r = 0.95; slope = 0.91; P<0.001; Figure 1A), CS 4 and CS 4+ (r = 0.96; slope = 0.92; P<0.001; Figure 2A), and CS 4+ and CS 5 (r = 0.98; slope = 0.98; P<0.001; Figure 3A). The Bland-Altman plot revealed acceptable bias between CS 4 and CS 5 (3.0±2.5%; lower limit = −2.0%, upper limit = 7.9%; Figure 1B), between CS 4 and CS 4+ (2.2±2.3%; lower limit = −2.4%, upper limit = 6.7%; Figure 2B), and between CS 4+ and CS 5 (0.8±1.7%; lower limit = −2.5%, upper limit = 4.1%; Figure 3B).

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Figure 1. Correlation between CS 4 and CS 5 and the Bland-Altman plot for CS 4 vs. CS 5.

(A) Correlation between CS 4 (clinical score of 4 = functional paralysis of both hindlimbs) and CS 5 (clinical score of 5 = CS 4 plus a righting reflex >20 s). There was a strong positive relationship between CS 4 and CS 5 (r = 0.95, slope = 0.91, P<0.001). CS 5 (d) = (14.80±2.83)+[(0.91±0.02)×(CS 4 in d)], mean ± SEM. Dashed line indicates line of identity. (B) A Bland-Altman plot comparing CS 4 to CS 5. Mean bias ± SD = 3.0±2.5%, lower limit = −2.0%, upper limit = 7.9%.

https://doi.org/10.1371/journal.pone.0020582.g001

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Figure 2. Correlation between CS 4 and CS 4+ and the Bland-Altman plot for CS 4 and CS 4+.

(A) Correlation between CS 4 (clinical score of 4 = functional paralysis of both hindlimbs) and CS 4+ [CS 4 plus the earliest of a) weight loss ≥20% vs. body weight immediately prior to a clinical score of 2, b) weight loss ≥20% vs. peak body weight, c) body condition score <2, or d) a righting reflex >20 s (CS 5)]. There was a strong positive relationship between CS 4 and CS 4+ (r = 0.96, slope = 0.92, P<0.001). CS 4+ (d) = (12.79±2.56)+[(0.92±0.02)×(CS 4 in d)], mean ± SEM. Dashed line indicates line of identity. (B) A Bland-Altman plot comparing CS 4 to CS 4+. Mean bias ± SD = 2.2±2.3%, lower limit = −2.4%, upper limit = 6.7%.

https://doi.org/10.1371/journal.pone.0020582.g002

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Figure 3. Correlation between CS 5 and CS 4+ and the Bland-Altman plot for CS 5 and CS 4+.

(A) Correlation between CS 5 (clinical score of 5 = CS 4 and righting reflex >20 s) and CS 4+ [CS 4 plus the earliest of a) weight loss ≥20% vs. body weight immediately prior to a clinical score of 2, b) weight loss ≥20% loss vs. peak body weight, c) body condition score <2, or d) a righting reflex >20 s (CS 5)]. There was a strong positive relationship between CS 5 and CS 4+ (r = 0.98, slope = 0.98, P<0.001). CS5 (d) = (3.93±2.15)+[(0.98±0.02)×(CS 4+ in d)], mean ± SEM. Dashed line indicates line of identity. (B) A Bland-Altman plot comparing CS 5 to CS 4+. Mean bias ± SD = 0.8±1.7%, lower limit = −2.5%, upper limit = 4.1%.

https://doi.org/10.1371/journal.pone.0020582.g003

A logrank test showed a significant difference in the rate at which endpoint was reached between CS 4, CS 4+ and CS 5 (P = 0.021; Figure 4). Mice reached CS 4 at a rate 34% faster vs. CS 5 (HR = 1.34; 95% CI 1.10, 1.74; P = 0.006) and 24% faster vs. CS 4+ (HR = 1.24; 95% CI 1.00, 1.59; P = 0.046). Mice reached CS 4+ at a non-significant rate of 9% faster vs. CS 5 (HR = 1.09; 95% CI 0.88, 1.38; P = 0.410).

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Figure 4. Probability of survival for CS 4, CS 4+ and CS 5.

Probability of survival for the 3 different endpoints (CS 4, black line; CS 4+, blue line; CS 5, red line). For all logrank tests, CS 4 was used as the reference when comparing CS 4 vs. CS 4+ and CS 4 vs. CS 5, whereas CS 4+ was used as the reference when comparing CS 4+ vs. CS 5. The rate of reaching endpoint is significantly different (P = 0.021) between CS 4 (clinical score of 4 = functional paralysis of both hindlimbs), CS 4+ [CS 4 plus the earliest of a) weight loss ≥20% vs. body weight immediately prior to a clinical score of 2, b) weight loss ≥20% vs. peak body weight, c) body condition score <2, or d) a righting reflex >20 s (CS 5)], and CS 5 (clinical score of 5 = CS 4 and righting reflex >20 s). Mice reached CS 4 at a rate of 34% faster vs. CS 5 (HR = 1.34; 95% CI 1.10, 1.74; P = 0.006) and 24% faster vs. CS 4+ (HR = 1.24; 95% CI 1.00, 1.59; P = 0.046). Mice reached CS 4+ at a non-significant rate of 9% faster vs. CS 5 (HR = 1.09; 95% CI 0.88, 1.38; P = 0.410).

https://doi.org/10.1371/journal.pone.0020582.g004

Statistical analyses were conducted for the same 3 endpoints within each sex. Differences between endpoints within each sex were similar as above.

Discussion

Our objective was to determine whether an earlier endpoint could replace the most commonly used righting reflex in a transgenic mouse model of ALS. This was done to validate the use of an endpoint that would meet the strict standards set by research ethics boards to decrease suffering and distress in mice, as well as to allow researchers from different laboratories the use of a uniform and consistent endpoint to directly compare the effectiveness of treatments in this particular animal model. We found strong positive correlations between all endpoints with an acceptable mean bias as measured by a Bland- Altman plot. Using CS 4+ and CS 5 would prolong life span by 2% and 3%, respectively, as compared to CS 4. Additionally, mice reached CS 4 at a rate 24% faster compared to CS 4+ and 34% faster compared to CS 5.

Once mice reach CS 4, they must rely on the strength of their forelimbs to obtain food and water which may place them at risk of starvation and dehydration [43]. Some studies have used the inability to scrounge for food and water as endpoint [11], [13], [28], [43], [63], [67], [73], [106], however establishing this is time consuming and indicates an advanced disease state possibly well beyond CS 5. As well, research ethics committees may institute policy requiring mice to have access to food and water-based gels at cage floor level when mice reach a pre-defined disease severity, which actually prolongs disease exposure of mice due to easier access to nutrients.

Paw grip endurance and motor performance scores will have decreased precipitously by the time mice reached CS 4, as compared to scores prior to disease onset, due to hindlimb paralysis and weakness in the forelimbs [15], [82], [83]. A decrease in motor performance and/or paw grip strength has been previously used as endpoint in mouse models of ALS [3], [20]. Adoption of such endpoints requires expensive, specialized equipment such as the rotarod apparatus [20] and commercial grip strength meters [3]. Also, there is no standardization for the percent decrease in paw grip strength among laboratories using this as a criterion for endpoint [3], [20].

All mice in our analyses met the criteria for CS 4+, however when each additional criterion was assessed in isolation from CS 4, that is, as standalone criterion for endpoint (data collection ended at CS 5), only 29% of mice lost greater than 20% body weight versus their weight immediately prior to disease onset (20%CS2), 43% lost greater than 20% body weight versus peak weight (20%Peak), 26% had a body condition score of less than 2 (BC<2), while 100% met the criteria for CS 5 (Table 1). These results suggest that studies using any one of 20%CS2, 20%Peak, or BC<2 as a standalone criterion to establish endpoint would be keeping at least 57% of their mice alive past CS 5, prolonging disease exposure beyond what is considered humane. Alternatively, another interpretation of these results is that mice could die past CS 5 without meeting the standalone criteria 20%CS2, 20%Peak, or BC<2. Past CS 5, motor neuron degeneration is so far advanced that mice can no longer right themselves to scrounge for food and water and would be at a pronounced risk of starvation and dehydration. Our analyses also reveal that fewer than 9% of all mice met the standalone criteria 20%CS2, 20%Peak, or BC<2 prior to reaching CS 4 (Table 2). Hence, we conclude that CS 4 does not prolong disease exposure compared to 20%CS2, 20%Peak, or BC<2 in a mouse model of ALS. More male mice met 20%CS2, 20%Peak, or BC<2 prior to reaching CS 4 compared to females, however this result is expected since male mice have greater muscle mass than females and muscle atrophy is a result of disease progression [107].

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Table 2. Raw data and summary of 162 B6SJL-TgN-(SOD1-G93A)1Gur autosomal hemizygous female (F) and male (M) mice meeting the additional endpoint criteria prior to reaching CS 4.

https://doi.org/10.1371/journal.pone.0020582.t002

The righting reflex, either as a standalone criterion or used in conjunction with other parameters, has long been used to establish endpoint in a mouse model of ALS [1], [4], [5], [7], [10][15], [17][23], [25][28], [30][32], [36], [38][47], [49][51], [53], [54], [57][62], [64], [65], [68], [70][74], [77][91], [93][97]. The righting reflex has its advantages. Failure to right within a pre-defined period of time (at least >3 s) demonstrates severe muscle weakness, an indication of advanced motor neuron degeneration, as mice must use their strength to right themselves when placed on their side. The righting reflex may also be a measure of declining proprioception. Evidence suggests the dorsal root [102], dorsal root ganglia [102], [108][110], dorsal funiculus [102], Clarke's nuclei [103], [109], [111], [112] and spinocerebellar tract [103], [109], [111][113], the regions of the spinal cord responsible for processing proprioception, may be affected in humans with ALS [103], [108][112] and animal models of ALS [102], [113], however some researchers failed to ascertain this association [113]. It is important to note that the magnitude of diminished proprioception and muscle loss may be different depending on the time used as the cutoff for the righting reflex, with greater atrophy of motor neurons occurring when longer cutoffs are used [113]. Although the righting reflex may provide insight into muscle wasting and proprioception deficits, no studies have used the righting reflex to quantify proprioception and motor neuron loss. Rather, the righting reflex is simply used to identify endpoint. Moreover, the time used to establish the righting reflex is not standardized (at least 3 s), introducing a confounding within the righting reflex methodology. Some studies did not specify the length of time used as the cutoff for the righting reflex [26], [54], [60], [73], [78], [85], [90], [93].

The criteria for the ideal endpoint would meet strict ethical standards, be easily adopted by research laboratories, and ensure researchers are able to gather information regarding the progression of ALS and the effectiveness of treatments in intervention studies. Also, it would represent a point in the progression of the disease beyond which additional insight into the nature of disease or into the effectiveness of an intervention is absent, or at least nominal. CS 4, representing functional paralysis in both hindlimbs, occurs in all mice used in mouse models of ALS. CS 4 is reached earlier than both CS 4+ and CS 5, satisfying standards set by research ethics committees by shortening the time of disease exposure. A more difficult challenge arises when addressing the final criterion required to establish an ideal endpoint, that is, does CS 4 permit investigators the acquisition of sufficient data relating to disease progression? In rodent models of ALS, functional paralysis marks the beginning of the end in disease progression. Once paralysis is established in the hindlimbs, it will spread to the diaphragm, ultimately resulting in death due to respiratory failure. Between disease onset and hindlimb paralysis, changes in gait, paw grip strength and endurance, and motor performance deteriorate measurably allowing scientists to track these changes throughout the course of the disease [15], [82], [83]. These changes continue to occur past CS 4, but in severely disabled mice with compromised quality of life. Our analysis has yielded an equation that will allow researchers to predict the age at which CS 4+ and/or CS 5 are attained, on average, from CS 4. Animal models of multiple sclerosis (experimental autoimmune encephalomyelitis; EAE) [114][116] follow a similar disease progression, including hindlimb weakness and paralysis, and use similar endpoint criteria as mouse models of ALS, suggesting our findings may be used in mouse models of EAE.

Is CS 4 the “ideal” endpoint? The righting reflex may provide information regarding muscle loss and proprioception deficits beyond that of CS 4. For those specific studies whereby severe muscle loss and compromised proprioception are inherent outcome measures reflecting the effectiveness of a specific intervention, CS 5 should be adopted as an endpoint. Alternatively, we have shown that CS 4, occurring on average 4 days sooner than CS 5, can predict the age at CS 4+ or CS 5. These 4 days will lessen the suffering and distress experienced by mice used in mouse models of ALS. Adopting CS 4 as endpoint negotiates an acceptable agreement between scientific discovery and ethics, a partnership that serves to protect scientific integrity and ethical standards in the humane treatment of research animals. At the forefront is the strength of the data extrapolated from animal-based research to serve as the background for potential recommendations adopted for people with ALS.

Acknowledgments

We thank Bart Hettinga for technical support, Dabin Jones for research assistance, Babitha Thampinathan for data confirmation, and Hailey Cho for supplementary research.

Author Contributions

Conceived and designed the experiments: MJH. Performed the experiments: MJH. Analyzed the data: JAS MJH. Contributed reagents/materials/analysis tools: MAT MJH. Wrote the paper: JAS MJH.

References

  1. 1. Mahoney DJ, Rodriguez C, Devries M, Yasuda N, Tarnopolsky MA (2004) Effects of high-intensity endurance exercise training in the G93A mouse model of amyotrophic lateral sclerosis. Muscle Nerve 29: 656–662.DJ MahoneyC. RodriguezM. DevriesN. YasudaMA Tarnopolsky2004Effects of high-intensity endurance exercise training in the G93A mouse model of amyotrophic lateral sclerosis.Muscle Nerve29656662
  2. 2. Lee J, Ryu H, Kowall NW (2009) Motor neuronal protection by L-arginine prolongs survival of mutant SOD1 (G93A) ALS mice. Biochem Biophys Res Commun 384: 524–529.J. LeeH. RyuNW Kowall2009Motor neuronal protection by L-arginine prolongs survival of mutant SOD1 (G93A) ALS mice.Biochem Biophys Res Commun384524529
  3. 3. Liebetanz D, Hagemann K, von Lewinski F, Kahler E, Paulus W (2004) Extensive exercise is not harmful in amyotrophic lateral sclerosis. Eur J Neurosci 20: 3115–20.D. LiebetanzK. HagemannF. von LewinskiE. KahlerW. Paulus2004Extensive exercise is not harmful in amyotrophic lateral sclerosis.Eur J Neurosci20311520
  4. 4. Martinez JA, Francis GJ, Liu WQ, Pradzinsky N, Fine J, et al. (2008) Intranasal delivery of insulin and a nitric oxide synthase inhibitor in an experimental model of amyotrophic lateral sclerosis. Neuroscience 157: 908–925.JA MartinezGJ FrancisWQ LiuN. PradzinskyJ. Fine2008Intranasal delivery of insulin and a nitric oxide synthase inhibitor in an experimental model of amyotrophic lateral sclerosis.Neuroscience157908925
  5. 5. Matthews RT, Yang L, Browne S, Baik M, Beal MF (1998) Coenzyme Q10 administration increases brain mitochondrial concentrations and exerts neuroprotective effects. Proc Natl Acad Sci U S A 95: 8892–8897.RT MatthewsL. YangS. BrowneM. BaikMF Beal1998Coenzyme Q10 administration increases brain mitochondrial concentrations and exerts neuroprotective effects.Proc Natl Acad Sci U S A9588928897
  6. 6. Mattson MP, Cutler RG, Camandola S (2007) Energy intake and amyotrophic lateral sclerosis. Neuromolecular Med 9: 17–20.MP MattsonRG CutlerS. Camandola2007Energy intake and amyotrophic lateral sclerosis.Neuromolecular Med91720
  7. 7. Moges H, Vasconcelos OM, Campbell WW, Borke RC, McCoy JA, et al. (2009) Light therapy and supplementary Riboflavin in the SOD1 transgenic mouse model of familial amyotrophic lateral sclerosis (FALS). Lasers Surg Med 41: 52–59.H. MogesOM VasconcelosWW CampbellRC BorkeJA McCoy2009Light therapy and supplementary Riboflavin in the SOD1 transgenic mouse model of familial amyotrophic lateral sclerosis (FALS).Lasers Surg Med415259
  8. 8. Nagano S, Fujii Y, Yamamoto T, Taniyama M, Fukada K, et al. (2003) The efficacy of trientine or ascorbate alone compared to that of the combined treatment with these two agents in familial amyotrophic lateral sclerosis model mice. Exp Neurol 179: 176–180.S. NaganoY. FujiiT. YamamotoM. TaniyamaK. Fukada2003The efficacy of trientine or ascorbate alone compared to that of the combined treatment with these two agents in familial amyotrophic lateral sclerosis model mice.Exp Neurol179176180
  9. 9. Nagano S, Ogawa Y, Yanagihara T, Sakoda S (1999) Benefit of a combined treatment with trientine and ascorbate in familial amyotrophic lateral sclerosis model mice. Neurosci Lett 265: 159–162.S. NaganoY. OgawaT. YanagiharaS. Sakoda1999Benefit of a combined treatment with trientine and ascorbate in familial amyotrophic lateral sclerosis model mice.Neurosci Lett265159162
  10. 10. Neymotin A, Petri S, Calingasan NY, Wille E, Schafer P, et al. (2009) Lenalidomide (Revlimid) administration at symptom onset is neuroprotective in a mouse model of amyotrophic lateral sclerosis. Exp Neurol 220: 191–197.A. NeymotinS. PetriNY CalingasanE. WilleP. Schafer2009Lenalidomide (Revlimid) administration at symptom onset is neuroprotective in a mouse model of amyotrophic lateral sclerosis.Exp Neurol220191197
  11. 11. Ohnishi S, Ito H, Suzuki Y, Adachi Y, Wate R, et al. (2009) Intra-bone marrow-bone marrow transplantation slows disease progression and prolongs survival in G93A mutant SOD1 transgenic mice, an animal model mouse for amyotrophic lateral sclerosis. Brain Res 1296: 216–224.S. OhnishiH. ItoY. SuzukiY. AdachiR. Wate2009Intra-bone marrow-bone marrow transplantation slows disease progression and prolongs survival in G93A mutant SOD1 transgenic mice, an animal model mouse for amyotrophic lateral sclerosis.Brain Res1296216224
  12. 12. Ohta Y, Kamiya T, Nagai M, Nagata T, Morimoto N, et al. (2008) Therapeutic benefits of intrathecal protein therapy in a mouse model of amyotrophic lateral sclerosis. J Neurosci Res 86: 3028–3037.Y. OhtaT. KamiyaM. NagaiT. NagataN. Morimoto2008Therapeutic benefits of intrathecal protein therapy in a mouse model of amyotrophic lateral sclerosis.J Neurosci Res8630283037
  13. 13. Pamphlett R, Todd E, Vink R, McQuilty R, Cheema SS (2003) Magnesium supplementation does not delay disease onset or increase survival in a mouse model of familial ALS. J Neurol Sci 216: 95–98.R. PamphlettE. ToddR. VinkR. McQuiltySS Cheema2003Magnesium supplementation does not delay disease onset or increase survival in a mouse model of familial ALS.J Neurol Sci2169598
  14. 14. Park JH, Hong YH, Kim HJ, Kim SM, Kim MJ, et al. (2007) Pyruvate slows disease progression in a G93A SOD1 mutant transgenic mouse model. Neurosci Lett 413: 265–269.JH ParkYH HongHJ KimSM KimMJ Kim2007Pyruvate slows disease progression in a G93A SOD1 mutant transgenic mouse model.Neurosci Lett413265269
  15. 15. Patel BP, Safdar A, Raha S, Tarnopolsky MA, Hamadeh MJ (2010) Caloric restriction shortens lifespan through an increase in lipid peroxidation, inflammation and apoptosis in the G93A mouse, an animal model of ALS. PLoS One Feb 24;5(2): e9386.BP PatelA. SafdarS. RahaMA TarnopolskyMJ Hamadeh2010Caloric restriction shortens lifespan through an increase in lipid peroxidation, inflammation and apoptosis in the G93A mouse, an animal model of ALS.PLoS OneFeb 24;52e9386
  16. 16. Pedersen WA, Mattson MP (1999) No benefit of dietary restriction on disease onset or progression in amyotrophic lateral sclerosis Cu/Zn-superoxide dismutase mutant mice. Brain Res 833: 117–120.WA PedersenMP Mattson1999No benefit of dietary restriction on disease onset or progression in amyotrophic lateral sclerosis Cu/Zn-superoxide dismutase mutant mice.Brain Res833117120
  17. 17. Petri S, Kiaei M, Wille E, Calingasan NY, Flint Beal M (2006) Loss of Fas ligand-function improves survival in G93A-transgenic ALS mice. J Neurol Sci 251: 44–49.S. PetriM. KiaeiE. WilleNY CalingasanM. Flint Beal2006Loss of Fas ligand-function improves survival in G93A-transgenic ALS mice.J Neurol Sci2514449
  18. 18. Petri S, Calingasan NY, Alsaied OA, Wille E, Kiaei M, et al. (2007) The lipophilic metal chelators DP-109 and DP-460 are neuroprotective in a transgenic mouse model of amyotrophic lateral sclerosis. J Neurochem 102: 991–1000.S. PetriNY CalingasanOA AlsaiedE. WilleM. Kiaei2007The lipophilic metal chelators DP-109 and DP-460 are neuroprotective in a transgenic mouse model of amyotrophic lateral sclerosis.J Neurochem1029911000
  19. 19. Petri S, Kiaei M, Kipiani K, Chen J, Calingasan NY, et al. (2006) Additive neuroprotective effects of a histone deacetylase inhibitor and a catalytic antioxidant in a transgenic mouse model of amyotrophic lateral sclerosis. Neurobiol Dis 22: 40–49.S. PetriM. KiaeiK. KipianiJ. ChenNY Calingasan2006Additive neuroprotective effects of a histone deacetylase inhibitor and a catalytic antioxidant in a transgenic mouse model of amyotrophic lateral sclerosis.Neurobiol Dis224049
  20. 20. Pitzer C, Kruger C, Plaas C, Kirsch F, Dittgen T, et al. (2008) Granulocyte-colony stimulating factor improves outcome in a mouse model of amyotrophic lateral sclerosis. Brain 131: 3335–3347.C. PitzerC. KrugerC. PlaasF. KirschT. Dittgen2008Granulocyte-colony stimulating factor improves outcome in a mouse model of amyotrophic lateral sclerosis.Brain13133353347
  21. 21. Pizzasegola C, Caron I, Daleno C, Ronchi A, Minoia C, et al. (2009) Treatment with lithium carbonate does not improve disease progression in two different strains of SOD1 mutant mice. Amyotroph Lateral Scler 10: 221–228.C. PizzasegolaI. CaronC. DalenoA. RonchiC. Minoia2009Treatment with lithium carbonate does not improve disease progression in two different strains of SOD1 mutant mice.Amyotroph Lateral Scler10221228
  22. 22. Poduslo JF, Whelan SL, Curran GL, Wengenack TM (2000) Therapeutic benefit of polyamine-modified catalase as a scavenger of hydrogen peroxide and nitric oxide in familial amyotrophic lateral sclerosis transgenics. Ann Neurol 48: 943–947.JF PodusloSL WhelanGL CurranTM Wengenack2000Therapeutic benefit of polyamine-modified catalase as a scavenger of hydrogen peroxide and nitric oxide in familial amyotrophic lateral sclerosis transgenics.Ann Neurol48943947
  23. 23. Reinholz MM, Merkle CM, Poduslo JF (1999) Therapeutic benefits of putrescine-modified catalase in a transgenic mouse model of familial amyotrophic lateral sclerosis. Exp Neurol 159: 204–216.MM ReinholzCM MerkleJF Poduslo1999Therapeutic benefits of putrescine-modified catalase in a transgenic mouse model of familial amyotrophic lateral sclerosis.Exp Neurol159204216
  24. 24. Rembach A, Turner BJ, Bruce S, Cheah IK, Scott RL, et al. (2004) Antisense peptide nucleic acid targeting GluR3 delays disease onset and progression in the SOD1 G93A mouse model of familial ALS. J Neurosci Res 77: 573–582.A. RembachBJ TurnerS. BruceIK CheahRL Scott2004Antisense peptide nucleic acid targeting GluR3 delays disease onset and progression in the SOD1 G93A mouse model of familial ALS.J Neurosci Res77573582
  25. 25. Ryu H, Smith K, Camelo SI, Carreras I, Lee J, et al. (2005) Sodium phenylbutyrate prolongs survival and regulates expression of anti-apoptotic genes in transgenic amyotrophic lateral sclerosis mice.[Erratum appears in J Neurochem. 2006 Feb;96(3):908]. J Neurochem 93: 1087–1098.H. RyuK. SmithSI CameloI. CarrerasJ. Lee2005Sodium phenylbutyrate prolongs survival and regulates expression of anti-apoptotic genes in transgenic amyotrophic lateral sclerosis mice.[Erratum appears in J Neurochem. 2006 Feb;96(3):908].J Neurochem9310871098
  26. 26. Sekiya M, Ichiyanagi T, Ikeshiro Y, Yokozawa T (2009) The Chinese prescription Wen-Pi-Tang extract delays disease onset in amyotrophic lateral sclerosis model mice while attenuating the activation of glial cells in the spinal cord. Biol Pharm Bull 32: 382–388.M. SekiyaT. IchiyanagiY. IkeshiroT. Yokozawa2009The Chinese prescription Wen-Pi-Tang extract delays disease onset in amyotrophic lateral sclerosis model mice while attenuating the activation of glial cells in the spinal cord.Biol Pharm Bull32382388
  27. 27. Shimojo Y, Kosaka K, Noda Y, Shimizu T, Shirasawa T (2010) Effect of rosmarinic acid in motor dysfunction and life span in a mouse model of familial amyotrophic lateral sclerosis. J Neurosci Res 88: 896–904.Y. ShimojoK. KosakaY. NodaT. ShimizuT. Shirasawa2010Effect of rosmarinic acid in motor dysfunction and life span in a mouse model of familial amyotrophic lateral sclerosis.J Neurosci Res88896904
  28. 28. Shoemaker JL, Seely KA, Reed RL, Crow JP, Prather PL (2007) The CB2 cannabinoid agonist AM-1241 prolongs survival in a transgenic mouse model of amyotrophic lateral sclerosis when initiated at symptom onset. J Neurochem 101: 87–98.JL ShoemakerKA SeelyRL ReedJP CrowPL Prather2007The CB2 cannabinoid agonist AM-1241 prolongs survival in a transgenic mouse model of amyotrophic lateral sclerosis when initiated at symptom onset.J Neurochem1018798
  29. 29. Snow RJ, Turnbull J, da Silva S, Jiang F, Tarnopolsky MA (2003) Creatine supplementation and riluzole treatment provide similar beneficial effects in copper, zinc superoxide dismutase (G93A) transgenic mice. Neuroscience 119: 661–667.RJ SnowJ. TurnbullS. da SilvaF. JiangMA Tarnopolsky2003Creatine supplementation and riluzole treatment provide similar beneficial effects in copper, zinc superoxide dismutase (G93A) transgenic mice.Neuroscience119661667
  30. 30. Suchy J, Lee S, Ahmed A, Shea TB (2010) Dietary supplementation with S-adenosyl methionine delays the onset of motor neuron pathology in a murine model of amyotrophic lateral sclerosis. Neuromolecular Med 12: 86–97.J. SuchyS. LeeA. AhmedTB Shea2010Dietary supplementation with S-adenosyl methionine delays the onset of motor neuron pathology in a murine model of amyotrophic lateral sclerosis.Neuromolecular Med128697
  31. 31. Teng YD, Choi H, Huang W, Onario RC, Frontera WR, et al. (2006) Therapeutic effects of clenbuterol in a murine model of amyotrophic lateral sclerosis. Neurosci Lett 397: 155–158.YD TengH. ChoiW. HuangRC OnarioWR Frontera2006Therapeutic effects of clenbuterol in a murine model of amyotrophic lateral sclerosis.Neurosci Lett397155158
  32. 32. Tokuda E, Ono S, Ishige K, Watanabe S, Okawa E, et al. (2008) Ammonium tetrathiomolybdate delays onset, prolongs survival, and slows progression of disease in a mouse model for amyotrophic lateral sclerosis. Exp Neurol 213: 122–128.E. TokudaS. OnoK. IshigeS. WatanabeE. Okawa2008Ammonium tetrathiomolybdate delays onset, prolongs survival, and slows progression of disease in a mouse model for amyotrophic lateral sclerosis.Exp Neurol213122128
  33. 33. Turner BJ, Parkinson NJ, Davies KE, Talbot K (2009) Survival motor neuron deficiency enhances progression in an amyotrophic lateral sclerosis mouse model. Neurobiol Dis 34: 511–517.BJ TurnerNJ ParkinsonKE DaviesK. Talbot2009Survival motor neuron deficiency enhances progression in an amyotrophic lateral sclerosis mouse model.Neurobiol Dis34511517
  34. 34. Turner BJ, Rembach A, Spark R, Lopes EC, Cheema SS (2003) Opposing effects of low and high-dose clozapine on survival of transgenic amyotrophic lateral sclerosis mice. J Neurosci Res 74: 605–613.BJ TurnerA. RembachR. SparkEC LopesSS Cheema2003Opposing effects of low and high-dose clozapine on survival of transgenic amyotrophic lateral sclerosis mice.J Neurosci Res74605613
  35. 35. Turner BJ, Murray SS, Piccenna LG, Lopes EC, Kilpatrick TJ, et al. (2004) Effect of p75 neurotrophin receptor antagonist on disease progression in transgenic amyotrophic lateral sclerosis mice. J Neurosci Res 78: 193–199.BJ TurnerSS MurrayLG PiccennaEC LopesTJ Kilpatrick2004Effect of p75 neurotrophin receptor antagonist on disease progression in transgenic amyotrophic lateral sclerosis mice.J Neurosci Res78193199
  36. 36. Van Damme P, Leyssen M, Callewaert G, Robberecht W, Van Den Bosch L (2003) The AMPA receptor antagonist NBQX prolongs survival in a transgenic mouse model of amyotrophic lateral sclerosis. Neurosci Lett 343: 81–84.P. Van DammeM. LeyssenG. CallewaertW. RobberechtL. Van Den Bosch2003The AMPA receptor antagonist NBQX prolongs survival in a transgenic mouse model of amyotrophic lateral sclerosis.Neurosci Lett3438184
  37. 37. Veldink JH, Bar PR, Joosten EAJ, Otten M, Wokke JHJ, et al. (2003) Sexual differences in onset of disease and response to exercise in a transgenic model of ALS. Neuromuscul Disord 13: 737–743.JH VeldinkPR BarEAJ JoostenM. OttenJHJ Wokke2003Sexual differences in onset of disease and response to exercise in a transgenic model of ALS.Neuromuscul Disord13737743
  38. 38. Vercelli A, Mereuta OM, Garbossa D, Muraca G, Mareschi K, et al. (2008) Human mesenchymal stem cell transplantation extends survival, improves motor performance and decreases neuroinflammation in mouse model of amyotrophic lateral sclerosis. Neurobiol Dis 31: 395–405.A. VercelliOM MereutaD. GarbossaG. MuracaK. Mareschi2008Human mesenchymal stem cell transplantation extends survival, improves motor performance and decreases neuroinflammation in mouse model of amyotrophic lateral sclerosis.Neurobiol Dis31395405
  39. 39. Waibel S, Reuter A, Malessa S, Blaugrund E, Ludolph AC (2004) Rasagiline alone and in combination with riluzole prolongs survival in an ALS mouse model. J Neurol 251: 1080–1084.S. WaibelA. ReuterS. MalessaE. BlaugrundAC Ludolph2004Rasagiline alone and in combination with riluzole prolongs survival in an ALS mouse model.J Neurol25110801084
  40. 40. Wang R, Zhang D (2005) Memantine prolongs survival in an amyotrophic lateral sclerosis mouse model. Eur J Neurosci 22: 2376–2380.R. WangD. Zhang2005Memantine prolongs survival in an amyotrophic lateral sclerosis mouse model.Eur J Neurosci2223762380
  41. 41. Weishaupt JH, Bartels C, Polking E, Dietrich J, Rohde G, et al. (2006) Reduced oxidative damage in ALS by high-dose enteral melatonin treatment. J Pineal Res 41: 313–323.JH WeishauptC. BartelsE. PolkingJ. DietrichG. Rohde2006Reduced oxidative damage in ALS by high-dose enteral melatonin treatment.J Pineal Res41313323
  42. 42. West M, Mhatre M, Ceballos A, Floyd RA, Grammas P, et al. (2004) The arachidonic acid 5-lipoxygenase inhibitor nordihydroguaiaretic acid inhibits tumor necrosis factor alpha activation of microglia and extends survival of G93A-SOD1 transgenic mice. J Neurochem 91: 133–143.M. WestM. MhatreA. CeballosRA FloydP. Grammas2004The arachidonic acid 5-lipoxygenase inhibitor nordihydroguaiaretic acid inhibits tumor necrosis factor alpha activation of microglia and extends survival of G93A-SOD1 transgenic mice.J Neurochem91133143
  43. 43. Wu AS, Kiaei M, Aguirre N, Crow JP, Calingasan NY, et al. (2003) Iron porphyrin treatment extends survival in a transgenic animal model of amyotrophic lateral sclerosis. J Neurochem 85: 142–150.AS WuM. KiaeiN. AguirreJP CrowNY Calingasan2003Iron porphyrin treatment extends survival in a transgenic animal model of amyotrophic lateral sclerosis.J Neurochem85142150
  44. 44. Xu Z, Chen S, Li X, Luo G, Li L, et al. (2006) Neuroprotective effects of (-)-epigallocatechin-3-gallate in a transgenic mouse model of amyotrophic lateral sclerosis. Neurochem Res 31: 1263–1269.Z. XuS. ChenX. LiG. LuoL. Li2006Neuroprotective effects of (-)-epigallocatechin-3-gallate in a transgenic mouse model of amyotrophic lateral sclerosis.Neurochem Res3112631269
  45. 45. Zhang X, Chen S, Li L, Wang Q, Le W (2008) Folic acid protects motor neurons against the increased homocysteine, inflammation and apoptosis in SOD1 G93A transgenic mice. Neuropharmacology 54: 1112–1119.X. ZhangS. ChenL. LiQ. WangW. Le2008Folic acid protects motor neurons against the increased homocysteine, inflammation and apoptosis in SOD1 G93A transgenic mice.Neuropharmacology5411121119
  46. 46. Zhao Z, Lange DJ, Voustianiouk A, MacGrogan D, Ho L, et al. (2006) A ketogenic diet as a potential novel therapeutic intervention in amyotrophic lateral sclerosis. BMC Neurosci 7: 29.Z. ZhaoDJ LangeA. VoustianioukD. MacGroganL. Ho2006A ketogenic diet as a potential novel therapeutic intervention in amyotrophic lateral sclerosis.BMC Neurosci729
  47. 47. Amante DJ, Kim J, Carreiro ST, Cooper AC, Jones SW, et al. (2010) Uridine ameliorates the pathological phenotype in transgenic G93A-ALS mice. Amyotroph Lateral Scler. DJ AmanteJ. KimST CarreiroAC CooperSW Jones2010Uridine ameliorates the pathological phenotype in transgenic G93A-ALS mice.Amyotroph Lateral Scler2010 Jun 22 [Epub ahead of print]. 2010 Jun 22 [Epub ahead of print].
  48. 48. Amodio R, Esposito E, De Ruvo C, Bellavia V, Amodio E, et al. (2006) Red wine extract prevents neuronal apoptosis in vitro and reduces mortality of transgenic mice. Ann N Y Acad Sci 1089: 88–97.R. AmodioE. EspositoC. De RuvoV. BellaviaE. Amodio2006Red wine extract prevents neuronal apoptosis in vitro and reduces mortality of transgenic mice.Ann N Y Acad Sci10898897
  49. 49. Andreassen OA, Dedeoglu A, Klivenyi P, Beal MF, Bush AI (2000) N-acetyl-L-cysteine improves survival and preserves motor performance in an animal model of familial amyotrophic lateral sclerosis. Neuroreport 11: 2491–2493.OA AndreassenA. DedeogluP. KlivenyiMF BealAI Bush2000N-acetyl-L-cysteine improves survival and preserves motor performance in an animal model of familial amyotrophic lateral sclerosis.Neuroreport1124912493
  50. 50. Andreassen OA, Jenkins BG, Dedeoglu A, Ferrante KL, Bogdanov MB, et al. (2001) Increases in cortical glutamate concentrations in transgenic amyotrophic lateral sclerosis mice are attenuated by creatine supplementation. J Neurochem 77: 383–390.OA AndreassenBG JenkinsA. DedeogluKL FerranteMB Bogdanov2001Increases in cortical glutamate concentrations in transgenic amyotrophic lateral sclerosis mice are attenuated by creatine supplementation.J Neurochem77383390
  51. 51. Andreassen OA, Dedeoglu A, Friedlich A, Ferrante KL, Hughes D, et al. (2001) Effects of an inhibitor of poly(ADP-ribose) polymerase, desmethylselegiline, trientine, and lipoic acid in transgenic ALS mice. Exp Neurol 168: 419–424.OA AndreassenA. DedeogluA. FriedlichKL FerranteD. Hughes2001Effects of an inhibitor of poly(ADP-ribose) polymerase, desmethylselegiline, trientine, and lipoic acid in transgenic ALS mice.Exp Neurol168419424
  52. 52. Azari MF, Profyris C, Le Grande MR, Lopes EC, Hirst J, et al. (2005) Effects of intraperitoneal injection of Rofecoxib in a mouse model of ALS. Eur J Neurol 12: 357–364.MF AzariC. ProfyrisMR Le GrandeEC LopesJ. Hirst2005Effects of intraperitoneal injection of Rofecoxib in a mouse model of ALS.Eur J Neurol12357364
  53. 53. Azzouz M, Ralph GS, Storkebaum E, Walmsley LE, Mitrophanous KA, et al. (2004) VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model. Nature 429: 413–417.M. AzzouzGS RalphE. StorkebaumLE WalmsleyKA Mitrophanous2004VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model.Nature429413417
  54. 54. Barbeito AG, Martinez-Palma L, Vargas MR, Pehar M, Manay N, et al. (2010) Lead exposure stimulates VEGF expression in the spinal cord and extends survival in a mouse model of ALS. Neurobiol Dis 37: 574–580.AG BarbeitoL. Martinez-PalmaMR VargasM. PeharN. Manay2010Lead exposure stimulates VEGF expression in the spinal cord and extends survival in a mouse model of ALS.Neurobiol Dis37574580
  55. 55. Bruce KM, Narayan K, Kong HC, Larmour I, Lopes EC, et al. (2004) Chemotherapy delays progression of motor neuron disease in the SOD1 G93A transgenic mouse. Chemotherapy 50: 138–142.KM BruceK. NarayanHC KongI. LarmourEC Lopes2004Chemotherapy delays progression of motor neuron disease in the SOD1 G93A transgenic mouse.Chemotherapy50138142
  56. 56. Bruestle DA, Cutler RG, Telljohann RS, Mattson MP (2009) Decline in daily running distance presages disease onset in a mouse model of ALS. Neuromolecular Med 11: 58–62.DA BruestleRG CutlerRS TelljohannMP Mattson2009Decline in daily running distance presages disease onset in a mouse model of ALS.Neuromolecular Med115862
  57. 57. Caraganis A, Benn S, Cudkowicz M, Brown RH Jr (2008) Thrombopoietin is ineffective in a mouse model of motor neuron disease. Amyotroph Lateral Scler 9: 354–358.A. CaraganisS. BennM. CudkowiczRH Brown Jr2008Thrombopoietin is ineffective in a mouse model of motor neuron disease.Amyotroph Lateral Scler9354358
  58. 58. Chiba T, Yamada M, Sasabe J, Terashita K, Aiso S, et al. (2006) Colivelin prolongs survival of an ALS model mouse. Biochem Biophys Res Commun 343: 793–798.T. ChibaM. YamadaJ. SasabeK. TerashitaS. Aiso2006Colivelin prolongs survival of an ALS model mouse.Biochem Biophys Res Commun343793798
  59. 59. Choi CI, Lee YD, Gwag BJ, Cho SI, Kim SS, et al. (2008) Effects of estrogen on lifespan and motor functions in female hSOD1 G93A transgenic mice. J Neurol Sci 268: 40–47.CI ChoiYD LeeBJ GwagSI ChoSS Kim2008Effects of estrogen on lifespan and motor functions in female hSOD1 G93A transgenic mice.J Neurol Sci2684047
  60. 60. Chritin M, Savasta M, Besson G (2006) Benefit of tianeptine and morphine in a transgenic model of familial amyotrophic lateral sclerosis. Amyotroph Lateral Scler 7: 32–37.M. ChritinM. SavastaG. Besson2006Benefit of tianeptine and morphine in a transgenic model of familial amyotrophic lateral sclerosis.Amyotroph Lateral Scler73237
  61. 61. Ciriza J, Moreno-Igoa M, Calvo AC, Yague G, Palacio J, et al. (2008) A genetic fusion GDNF-C fragment of tetanus toxin prolongs survival in a symptomatic mouse ALS model. Restor Neurol Neurosci 26: 459–465.J. CirizaM. Moreno-IgoaAC CalvoG. YagueJ. Palacio2008A genetic fusion GDNF-C fragment of tetanus toxin prolongs survival in a symptomatic mouse ALS model.Restor Neurol Neurosci26459465
  62. 62. Corti S, Locatelli F, Papadimitriou D, Del Bo R, Nizzardo M, et al. (2007) Neural stem cells LewisX+ CXCR4+ modify disease progression in an amyotrophic lateral sclerosis model. Brain 130: 1289–1305.S. CortiF. LocatelliD. PapadimitriouR. Del BoM. Nizzardo2007Neural stem cells LewisX+ CXCR4+ modify disease progression in an amyotrophic lateral sclerosis model.Brain13012891305
  63. 63. Crochemore C, Virgili M, Bonamassa B, Canistro D, Pena-Altamira E, et al. (2009) Long-term dietary administration of valproic acid does not affect, while retinoic acid decreases, the lifespan of G93A mice, a model for amyotrophic lateral sclerosis. Muscle Nerve 39: 548–552.C. CrochemoreM. VirgiliB. BonamassaD. CanistroE. Pena-Altamira2009Long-term dietary administration of valproic acid does not affect, while retinoic acid decreases, the lifespan of G93A mice, a model for amyotrophic lateral sclerosis.Muscle Nerve39548552
  64. 64. Crow JP, Calingasan NY, Chen J, Hill JL, Beal MF (2005) Manganese porphyrin given at symptom onset markedly extends survival of ALS mice. Ann Neurol 58: 258–265.JP CrowNY CalingasanJ. ChenJL HillMF Beal2005Manganese porphyrin given at symptom onset markedly extends survival of ALS mice.Ann Neurol58258265
  65. 65. Del Signore SJ, Amante DJ, Kim J, Stack EC, Goodrich S, et al. (2009) Combined riluzole and sodium phenylbutyrate therapy in transgenic amyotrophic lateral sclerosis mice. Amyotroph Lateral Scler 10: 85–94.SJ Del SignoreDJ AmanteJ. KimEC StackS. Goodrich2009Combined riluzole and sodium phenylbutyrate therapy in transgenic amyotrophic lateral sclerosis mice.Amyotroph Lateral Scler108594
  66. 66. Derave W, Van Den Bosch L, Lemmens G, Eijnde BO, Robberecht W, et al. (2003) Skeletal muscle properties in a transgenic mouse model for amyotrophic lateral sclerosis: effects of creatine treatment. Neurobiol Dis 13: 264–272.W. DeraveL. Van Den BoschG. LemmensBO EijndeW. Robberecht2003Skeletal muscle properties in a transgenic mouse model for amyotrophic lateral sclerosis: effects of creatine treatment.Neurobiol Dis13264272
  67. 67. Ende N, Weinstein F, Chen R, Ende M, Ende N (2000) Human umbilical cord blood effect on sod mice (amyotrophic lateral sclerosis). Life Sci 67: 53–59.N. EndeF. WeinsteinR. ChenM. EndeN. Ende2000Human umbilical cord blood effect on sod mice (amyotrophic lateral sclerosis).Life Sci675359
  68. 68. Ermilova IP, Ermilov VB, Levy M, Ho E, Pereira C, et al. (2005) Protection by dietary zinc in ALS mutant G93A SOD transgenic mice. Neurosci Lett 379: 42–46.IP ErmilovaVB ErmilovM. LevyE. HoC. Pereira2005Protection by dietary zinc in ALS mutant G93A SOD transgenic mice.Neurosci Lett3794246
  69. 69. Esposito E, Rossi C, Amodio R, Di Castelnuovo A, Bendotti C, et al. (2000) Lyophilized red wine administration prolongs survival in an animal model of amyotrophic lateral sclerosis. Ann Neurol 48: 686–687.E. EspositoC. RossiR. AmodioA. Di CastelnuovoC. Bendotti2000Lyophilized red wine administration prolongs survival in an animal model of amyotrophic lateral sclerosis.Ann Neurol48686687
  70. 70. Esposito E, Capasso M, di Tomasso N, Corona C, Pellegrini F, et al. (2007) Antioxidant strategies based on tomato-enriched food or pyruvate do not affect disease onset and survival in an animal model of amyotrophic lateral sclerosis. Brain Res Sep 7;1168: 90–6 Epub 2007 Jul 31.E. EspositoM. CapassoN. di TomassoC. CoronaF. Pellegrini2007Antioxidant strategies based on tomato-enriched food or pyruvate do not affect disease onset and survival in an animal model of amyotrophic lateral sclerosis.Brain ResSep 7;1168906 Epub 2007 Jul 31
  71. 71. Ferrante RJ, Klein AM, Dedeoglu A, Beal MF (2001) Therapeutic efficacy of EGb761 (Gingko biloba extract) in a transgenic mouse model of amyotrophic lateral sclerosis. J Mol Neurosci 17: 89–96.RJ FerranteAM KleinA. DedeogluMF Beal2001Therapeutic efficacy of EGb761 (Gingko biloba extract) in a transgenic mouse model of amyotrophic lateral sclerosis.J Mol Neurosci178996
  72. 72. Fischer LR, Culver DG, Davis AA, Tennant P, Wang M, et al. (2005) The WldS gene modestly prolongs survival in the SOD1G93A fALS mouse. Neurobiol Dis 19: 293–300.LR FischerDG CulverAA DavisP. TennantM. Wang2005The WldS gene modestly prolongs survival in the SOD1G93A fALS mouse.Neurobiol Dis19293300
  73. 73. Ghoddoussi F, Galloway MP, Jambekar A, Bame M, Needleman R, et al. (2010) Methionine sulfoximine, an inhibitor of glutamine synthetase, lowers brain glutamine and glutamate in a mouse model of ALS. J Neurol Sci 290: 41–47.F. GhoddoussiMP GallowayA. JambekarM. BameR. Needleman2010Methionine sulfoximine, an inhibitor of glutamine synthetase, lowers brain glutamine and glutamate in a mouse model of ALS.J Neurol Sci2904147
  74. 74. Gifondorwa DJ, Robinson MB, Hayes CD, Taylor AR, Prevette DM, et al. (2007) Exogenous delivery of heat shock protein 70 increases lifespan in a mouse model of amyotrophic lateral sclerosis. J Neurosci 27: 13173–13180.DJ GifondorwaMB RobinsonCD HayesAR TaylorDM Prevette2007Exogenous delivery of heat shock protein 70 increases lifespan in a mouse model of amyotrophic lateral sclerosis.J Neurosci271317313180
  75. 75. Groeneveld GJ, de Leeuw van Weenen J, van Muiswinkel FL, Veldman H, Veldink JH, et al. (2003) Zinc amplifies mSOD1-mediated toxicity in a transgenic mouse model of amyotrophic lateral sclerosis. Neurosci Lett 352: 175–178.GJ GroeneveldJ. de Leeuw van WeenenFL van MuiswinkelH. VeldmanJH Veldink2003Zinc amplifies mSOD1-mediated toxicity in a transgenic mouse model of amyotrophic lateral sclerosis.Neurosci Lett352175178
  76. 76. Groeneveld GJ, Van Muiswinkel FL, Sturkenboom JM, Wokke JH, Bar PR, et al. (2004) Ovariectomy and 17beta-estradiol modulate disease progression of a mouse model of ALS. Brain Res 1021: 128–131.GJ GroeneveldFL Van MuiswinkelJM SturkenboomJH WokkePR Bar2004Ovariectomy and 17beta-estradiol modulate disease progression of a mouse model of ALS.Brain Res1021128131
  77. 77. Gros-Louis F, Soucy G, Lariviere R, Julien JP, Gros-Louis F, et al. (2010) Intracerebroventricular infusion of monoclonal antibody or its derived Fab fragment against misfolded forms of SOD1 mutant delays mortality in a mouse model of ALS. J Neurochem 113: 1188–1199.F. Gros-LouisG. SoucyR. LariviereJP JulienF. Gros-Louis2010Intracerebroventricular infusion of monoclonal antibody or its derived Fab fragment against misfolded forms of SOD1 mutant delays mortality in a mouse model of ALS.J Neurochem11311881199
  78. 78. Gurney ME, Fleck TJ, Himes CS, Hall ED (1998) Riluzole preserves motor function in a transgenic model of familial amyotrophic lateral sclerosis. Neurology 50: 62–66.ME GurneyTJ FleckCS HimesED Hall1998Riluzole preserves motor function in a transgenic model of familial amyotrophic lateral sclerosis.Neurology506266
  79. 79. Gurney ME, Cutting FB, Zhai P, Doble A, Taylor CP, et al. (1996) Benefit of vitamin E, riluzole, and gabapentin in a transgenic model of familial amyotrophic lateral sclerosis. Ann Neurol 39: 147–157.ME GurneyFB CuttingP. ZhaiA. DobleCP Taylor1996Benefit of vitamin E, riluzole, and gabapentin in a transgenic model of familial amyotrophic lateral sclerosis.Ann Neurol39147157
  80. 80. Habisch HJ, Schwalenstocker B, Danzeisen R, Neuhaus O, Hartung HP, et al. (2007) Limited effects of glatiramer acetate in the high-copy number hSOD1-G93A mouse model of ALS. Exp Neurol 206: 288–295.HJ HabischB. SchwalenstockerR. DanzeisenO. NeuhausHP Hartung2007Limited effects of glatiramer acetate in the high-copy number hSOD1-G93A mouse model of ALS.Exp Neurol206288295
  81. 81. Haenggeli C, Julien JP, Mosley RL, Perez N, Dhar A, et al. (2007) Therapeutic immunization with a glatiramer acetate derivative does not alter survival in G93A and G37R SOD1 mouse models of familial ALS. Neurobiol Dis 26: 146–152.C. HaenggeliJP JulienRL MosleyN. PerezA. Dhar2007Therapeutic immunization with a glatiramer acetate derivative does not alter survival in G93A and G37R SOD1 mouse models of familial ALS.Neurobiol Dis26146152
  82. 82. Hamadeh MJ, Tarnopolsky MA (2006) Transient caloric restriction in early adulthood hastens disease endpoint in male, but not female, Cu/Zn-SOD mutant G93A mice. Muscle Nerve 34: 709–719.MJ HamadehMA Tarnopolsky2006Transient caloric restriction in early adulthood hastens disease endpoint in male, but not female, Cu/Zn-SOD mutant G93A mice.Muscle Nerve34709719
  83. 83. Hamadeh MJ, Rodriguez MC, Kaczor JJ, Tarnopolsky MA (2005) Caloric restriction transiently improves motor performance but hastens clinical onset of disease in the Cu/Zn-superoxide dismutase mutant G93A mouse. Muscle Nerve 31: 214–220.MJ HamadehMC RodriguezJJ KaczorMA Tarnopolsky2005Caloric restriction transiently improves motor performance but hastens clinical onset of disease in the Cu/Zn-superoxide dismutase mutant G93A mouse.Muscle Nerve31214220
  84. 84. Ito H, Wate R, Zhang J, Ohnishi S, Kaneko S, et al. (2008) Treatment with edaravone, initiated at symptom onset, slows motor decline and decreases SOD1 deposition in ALS mice. Exp Neurol 213: 448–455.H. ItoR. WateJ. ZhangS. OhnishiS. Kaneko2008Treatment with edaravone, initiated at symptom onset, slows motor decline and decreases SOD1 deposition in ALS mice.Exp Neurol213448455
  85. 85. Jaarsma D, Guchelaar HJ, Haasdijk E, de Jong JM, Holstege JC (1998) The antioxidant N-acetylcysteine does not delay disease onset and death in a transgenic mouse model of amyotrophic lateral sclerosis. Ann Neurol 44: 293.D. JaarsmaHJ GuchelaarE. HaasdijkJM de JongJC Holstege1998The antioxidant N-acetylcysteine does not delay disease onset and death in a transgenic mouse model of amyotrophic lateral sclerosis.Ann Neurol44293
  86. 86. Jiang F, DeSilva S, Turnbull J (2000) Beneficial effect of ginseng root in SOD-1 (G93A) transgenic mice. J Neurol Sci 180: 52–54.F. JiangS. DeSilvaJ. Turnbull2000Beneficial effect of ginseng root in SOD-1 (G93A) transgenic mice.J Neurol Sci1805254
  87. 87. Joo IS, Hwang DH, Seok JI, Shin SK, Kim SU (2007) Oral administration of memantine prolongs survival in a transgenic mouse model of amyotrophic lateral sclerosis. J Clin Neurol 3: 181–186.IS JooDH HwangJI SeokSK ShinSU Kim2007Oral administration of memantine prolongs survival in a transgenic mouse model of amyotrophic lateral sclerosis.J Clin Neurol3181186
  88. 88. Kalmar B, Novoselov S, Gray A, Cheetham ME, Margulis B, et al. (2008) Late stage treatment with arimoclomol delays disease progression and prevents protein aggregation in the SOD1 mouse model of ALS. J Neurochem 107: 339–350.B. KalmarS. NovoselovA. GrayME CheethamB. Margulis2008Late stage treatment with arimoclomol delays disease progression and prevents protein aggregation in the SOD1 mouse model of ALS.J Neurochem107339350
  89. 89. Kiaei M, Kipiani K, Chen J, Calingasan NY, Beal MF (2005) Peroxisome proliferator-activated receptor-gamma agonist extends survival in transgenic mouse model of amyotrophic lateral sclerosis. Exp Neurol 191: 331–336.M. KiaeiK. KipianiJ. ChenNY CalingasanMF Beal2005Peroxisome proliferator-activated receptor-gamma agonist extends survival in transgenic mouse model of amyotrophic lateral sclerosis.Exp Neurol191331336
  90. 90. Kieran D, Kalmar B, Dick JR, Riddoch-Contreras J, Burnstock G, et al. (2004) Treatment with arimoclomol, a coinducer of heat shock proteins, delays disease progression in ALS mice. Nat Med 10: 402–405.D. KieranB. KalmarJR DickJ. Riddoch-ContrerasG. Burnstock2004Treatment with arimoclomol, a coinducer of heat shock proteins, delays disease progression in ALS mice.Nat Med10402405
  91. 91. Kim K, Moore DH, Makriyannis A, Abood ME (2006) AM1241, a cannabinoid CB2 receptor selective compound, delays disease progression in a mouse model of amyotrophic lateral sclerosis. Eur J Pharmacol 542: 100–105.K. KimDH MooreA. MakriyannisME Abood2006AM1241, a cannabinoid CB2 receptor selective compound, delays disease progression in a mouse model of amyotrophic lateral sclerosis.Eur J Pharmacol542100105
  92. 92. Kira Y, Nishikawa M, Ochi A, Sato E, Inoue M (2006) L-carnitine suppresses the onset of neuromuscular degeneration and increases the life span of mice with familial amyotrophic lateral sclerosis. Brain Res 1070: 206–214.Y. KiraM. NishikawaA. OchiE. SatoM. Inoue2006L-carnitine suppresses the onset of neuromuscular degeneration and increases the life span of mice with familial amyotrophic lateral sclerosis.Brain Res1070206214
  93. 93. Kirkinezos IG, Hernandez D, Bradley WG, Moraes CT (2003) Regular exercise is beneficial to a mouse model of amyotrophic lateral sclerosis. Ann Neurol 53: 804–807.IG KirkinezosD. HernandezWG BradleyCT Moraes2003Regular exercise is beneficial to a mouse model of amyotrophic lateral sclerosis.Ann Neurol53804807
  94. 94. Klivenyi P, Ferrante RJ, Matthews RT, Bogdanov MB, Klein AM, et al. (1999) Neuroprotective effects of creatine in a transgenic animal model of amyotrophic lateral sclerosis. Nat Med 5: 347–350.P. KlivenyiRJ FerranteRT MatthewsMB BogdanovAM Klein1999Neuroprotective effects of creatine in a transgenic animal model of amyotrophic lateral sclerosis.Nat Med5347350
  95. 95. Koh SH, Kim Y, Kim HY, Cho GW, Kim KS, et al. (2007) Recombinant human erythropoietin suppresses symptom onset and progression of G93A-SOD1 mouse model of ALS by preventing motor neuron death and inflammation. Eur J Neurosci 25: 1923–1930.SH KohY. KimHY KimGW ChoKS Kim2007Recombinant human erythropoietin suppresses symptom onset and progression of G93A-SOD1 mouse model of ALS by preventing motor neuron death and inflammation.Eur J Neurosci2519231930
  96. 96. Koh SH, Kim Y, Kim HY, Hwang S, Lee CH, et al. (2007) Inhibition of glycogen synthase kinase-3 suppresses the onset of symptoms and disease progression of G93A-SOD1 mouse model of ALS. Exp Neurol 205: 336–346.SH KohY. KimHY KimS. HwangCH Lee2007Inhibition of glycogen synthase kinase-3 suppresses the onset of symptoms and disease progression of G93A-SOD1 mouse model of ALS.Exp Neurol205336346
  97. 97. Koh SH, Lee SM, Kim HY, Lee KY, Lee YJ, et al. (2006) The effect of epigallocatechin gallate on suppressing disease progression of ALS model mice. Neurosci Lett 395: 103–107.SH KohSM LeeHY KimKY LeeYJ Lee2006The effect of epigallocatechin gallate on suppressing disease progression of ALS model mice.Neurosci Lett395103107
  98. 98. Shaw PJ (1999) Motor neurone disease. BMJ 318: 1118–1121.PJ Shaw1999Motor neurone disease.BMJ31811181121
  99. 99. Martin LJ (1999) Neuronal death in amyotrophic lateral sclerosis is apoptosis: possible contribution of a programmed cell death mechanism. J Neuropathol Exp Neurol 58: 459–471.LJ Martin1999Neuronal death in amyotrophic lateral sclerosis is apoptosis: possible contribution of a programmed cell death mechanism.J Neuropathol Exp Neurol58459471
  100. 100. Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY, et al. (1994) Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation.[Erratum appears in Science 1995 Jul 14;269(5221):149]. Science 264: 1772–1775.ME GurneyH. PuAY ChiuMC Dal CantoCY Polchow1994Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation.[Erratum appears in Science 1995 Jul 14;269(5221):149].Science26417721775
  101. 101. Canadian Council on Animal Care (1998) Canadian Council on Animal Care1998CCAC guidelines on: choosing an appropriate endpoint in experiments using animals for research, teaching and testing. CCAC guidelines on: choosing an appropriate endpoint in experiments using animals for research, teaching and testing.
  102. 102. Guo YS, Wu DX, Wu HR, Wu SY, Yang C, et al. (2009) Sensory involvement in the SOD1-G93A mouse model of amyotrophic lateral sclerosis. Exp Mol Med 41: 140–150.YS GuoDX WuHR WuSY WuC. Yang2009Sensory involvement in the SOD1-G93A mouse model of amyotrophic lateral sclerosis.Exp Mol Med41140150
  103. 103. Orrell RW, King AW, Hilton DA, Campbell MJ, Lane RJ, et al. (1995) Familial amyotrophic lateral sclerosis with a point mutation of SOD-1: intrafamilial heterogeneity of disease duration associated with neurofibrillary tangles. J Neurol Neurosurg Psychiatry 59: 266–270.RW OrrellAW KingDA HiltonMJ CampbellRJ Lane1995Familial amyotrophic lateral sclerosis with a point mutation of SOD-1: intrafamilial heterogeneity of disease duration associated with neurofibrillary tangles.J Neurol Neurosurg Psychiatry59266270
  104. 104. Seevaratnam R, Raha S, Tarnopolsky MA, Hamadeh MJ (2009) Coffee increases antioxidant enzyme capacity in the brain of male G93A mice, an animal model of amyotrophic lateral sclerosis (ALS). FASEB J 23: 109.6.R. SeevaratnamS. RahaMA TarnopolskyMJ Hamadeh2009Coffee increases antioxidant enzyme capacity in the brain of male G93A mice, an animal model of amyotrophic lateral sclerosis (ALS).FASEB J23109.6
  105. 105. Seevaratnam R, Raha S, Tarnopolsky MA, Hamadeh MJ (2009) Caffeine reduces motor performance and antioxidant enzyme capacity in the brain of female G93A mice, an animal model of amyotrophic lateral sclerosis (ALS). FASEB J 23: 963.3.R. SeevaratnamS. RahaMA TarnopolskyMJ Hamadeh2009Caffeine reduces motor performance and antioxidant enzyme capacity in the brain of female G93A mice, an animal model of amyotrophic lateral sclerosis (ALS).FASEB J23963.3
  106. 106. Sugai F, Yamamoto Y, Miyaguchi K, Zhou Z, Sumi H, et al. (2004) Benefit of valproic acid in suppressing disease progression of ALS model mice. Eur J Neurosci 20: 3179–3183.F. SugaiY. YamamotoK. MiyaguchiZ. ZhouH. Sumi2004Benefit of valproic acid in suppressing disease progression of ALS model mice.Eur J Neurosci2031793183
  107. 107. Holzbaur EL, Howland DS, Weber N, Wallace K, She Y, et al. (2006) Myostatin inhibition slows muscle atrophy in rodent models of amyotrophic lateral sclerosis. Neurobiol Dis 23: 697–707.EL HolzbaurDS HowlandN. WeberK. WallaceY. She2006Myostatin inhibition slows muscle atrophy in rodent models of amyotrophic lateral sclerosis.Neurobiol Dis23697707
  108. 108. Kawamura Y, Dyck PJ, Shimono M, Okazaki H, Tateishi J, et al. (1981) Morphometric comparison of the vulnerability of peripheral motor and sensory neurons in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 40: 667–675.Y. KawamuraPJ DyckM. ShimonoH. OkazakiJ. Tateishi1981Morphometric comparison of the vulnerability of peripheral motor and sensory neurons in amyotrophic lateral sclerosis.J Neuropathol Exp Neurol40667675
  109. 109. Tateishi T, Hokonohara T, Yamasaki R, Miura S, Kikuchi H, et al. (2010) Multiple system degeneration with basophilic inclusions in Japanese ALS patients with FUS mutation. Acta Neuropathol 119: 355–364.T. TateishiT. HokonoharaR. YamasakiS. MiuraH. Kikuchi2010Multiple system degeneration with basophilic inclusions in Japanese ALS patients with FUS mutation.Acta Neuropathol119355364
  110. 110. Sasaki S, Horie Y, Iwata M (2007) Mitochondrial alterations in dorsal root ganglion cells in sporadic amyotrophic lateral sclerosis. Acta Neuropathol (Berl) 114: 633–639.S. SasakiY. HorieM. Iwata2007Mitochondrial alterations in dorsal root ganglion cells in sporadic amyotrophic lateral sclerosis.Acta Neuropathol (Berl)114633639
  111. 111. Hirano A, Kurland LT, Sayre GP (1967) Familial amyotrophic lateral sclerosis. A subgroup characterized by posterior and spinocerebellar tract involvement and hyaline inclusions in the anterior horn cells. Arch Neurol 16: 232–243.A. HiranoLT KurlandGP Sayre1967Familial amyotrophic lateral sclerosis. A subgroup characterized by posterior and spinocerebellar tract involvement and hyaline inclusions in the anterior horn cells.Arch Neurol16232243
  112. 112. Suzuki M, Irie T, Watanabe T, Mikami H, Yamazaki T, et al. (2008) Familial amyotrophic lateral sclerosis with Gly93Ser mutation in Cu/Zn superoxide dismutase: a clinical and neuropathological study. J Neurol Sci 268: 140–144.M. SuzukiT. IrieT. WatanabeH. MikamiT. Yamazaki2008Familial amyotrophic lateral sclerosis with Gly93Ser mutation in Cu/Zn superoxide dismutase: a clinical and neuropathological study.J Neurol Sci268140144
  113. 113. Dal Canto MC, Gurney ME (1994) Development of central nervous system pathology in a murine transgenic model of human amyotrophic lateral sclerosis. Am J Pathol 145: 1271–1279.MC Dal CantoME Gurney1994Development of central nervous system pathology in a murine transgenic model of human amyotrophic lateral sclerosis.Am J Pathol14512711279
  114. 114. Butterfield RJ, Blankenhorn EP, Roper RJ, Zachary JF, Doerge RW, et al. (1999) Genetic Analysis of Disease Subtypes and Sexual Dimorphisms in Mouse Experimental Allergic Encephalomyelitis (EAE): Relapsing/Remitting and Monophasic Remitting/Nonrelapsing EAE Are Immunogenetically Distinct. J Immunol 162: 3096–3102.RJ ButterfieldEP BlankenhornRJ RoperJF ZacharyRW Doerge1999Genetic Analysis of Disease Subtypes and Sexual Dimorphisms in Mouse Experimental Allergic Encephalomyelitis (EAE): Relapsing/Remitting and Monophasic Remitting/Nonrelapsing EAE Are Immunogenetically Distinct.J Immunol16230963102
  115. 115. Fleming KK, Bovaird JA, Mosier MC, Emerson MR, LeVine SM, et al. (2005) Statistical analysis of data from studies on experimental autoimmune encephalomyelitis. J Neuroimmunol 170: 71–84.KK FlemingJA BovairdMC MosierMR EmersonSM LeVine2005Statistical analysis of data from studies on experimental autoimmune encephalomyelitis.J Neuroimmunol1707184
  116. 116. Thakker P, Leach MW, Kuang W, Benoit SE, Leonard JP, et al. (2007) IL-23 Is Critical in the Induction but Not in the Effector Phase of Experimental Autoimmune Encephalomyelitis. J Immunol 178: 2589–2598.P. ThakkerMW LeachW. KuangSE BenoitJP Leonard2007IL-23 Is Critical in the Induction but Not in the Effector Phase of Experimental Autoimmune Encephalomyelitis.J Immunol17825892598