Korean J Clin Neurophysiol.  2013 Dec;15(2):53-58. 10.14253/kjcn.2013.15.2.53.

Neuroprotective Effect of Rapamycin (Autophagy Enhancer) in Transgenic SOD1-G93A Mice of Amyotrophic Lateral Sclerosis

• Ahn SW
• Jeon GS
• Park KY
• Hong YH
• Lee KW
• Sung JJ

• KMID: 1863274
• DOI: http://doi.org/10.14253/kjcn.2013.15.2.53

Abstract

BACKGROUND
The autophagy is the major route for lysosomal degradation of misfolded protein aggregates and oxidative cell components. We hypothesized that rapamycin (autophagy enhancer) would prolong the survival of motor neuron and suppress the disease progression in amyotrophic lateral sclerosis (ALS).
METHODS
A total of 24 transgenic mice harboring the human G93A mutated SOD1 gene were used. The clinical status involving rotarod test and survival, and biochemical study of ALS mice model were evaluated.
RESULTS
The onset of symptoms was significantly delayed in the rapamycin administration group compared with the control group. However, after the clinical symptom developed, the rapamycin exacerbated the disease progression and shortened the survival of ALS mice model, and apoptosis signals were up-regulated compared with control group.
CONCLUSIONS
Even though further detailed studies on the relevancy between autophagy and ALS will be needed, our results revealed that the rapamycin administration was not effective for being novel promising therapeutic strategy in ALS transgenic mice and exacerbated the apoptosis.

Keyword

Autophagy; Rapamycin; Amyotrophic lateral sclerosis; ALS

MeSH Terms

Amyotrophic Lateral Sclerosis*
Animals
Apoptosis
Autophagy
Cellular Structures
Disease Progression
Humans
Mice*
Mice, Transgenic
Motor Neurons
Neuroprotective Agents*
Rotarod Performance Test
Sirolimus*
Neuroprotective Agents
Sirolimus

Figure

• 

  Figure 1. Results of rotarod test showed that coordinate and strength in G93A transgenic mice was increasingly impaired, however the motor function deficit was alleviated by 15 weeks in G93A mice administrated with rapamycin (A). In the rapamycin administration group, the behavioral function using rotarod test was significantly better in early stage of ALS (Mann-Whitney U test, *p<0.05) (A). However the decline of the rotarod function was more rapid in the rapamycin administration group than the control group after 15 weeks (A). Similarly, the onset of symptoms was significantly delayed by the rapamycin administration (B), whereas the time of rotarod failure (C) and disease end point (D) were shortened in the rapamycin administration group compared with the control group.

• 

  Figure 2. With the rapamycin administration, the levels of cleaved caspase-8 were increased in the spinal cord of 110-days-old G93A transgenic ALS mice, whereas the level of cleaved caspase-3 was not significant between two groups.

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