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

Neurotherapeutics, 2012 · DOI: 10.1007/s13311-012-0140-y · Published: August 31, 2012

Simple Explanation

Amyotrophic lateral sclerosis (ALS) is a disease that causes muscle weakness and paralysis because motor neurons are lost. This study looked at whether a drug that activates sigma-1 receptors (sigma-1R), called PRE-084, could help mice with ALS. The researchers gave PRE-084 to mice with ALS and found that it improved their motor function, protected their motor neurons, and helped them live longer. The drug seemed to work by affecting certain pathways in the motor neurons and reducing inflammation in the spinal cord. The study suggests that drugs that activate sigma-1R, like PRE-084, could be a promising way to treat ALS in humans.

Study Duration

8 weeks

Participants

SOD1G93A transgenic mice

Evidence Level

Not specified

Key Findings

1
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.
2
It extended survival in both female and male mice by more than 15 %.
3
PRE-084 exerts a dual therapeutic contribution, modulating NMDA Ca2+ influx to protect MNs, and the microglial reactivity to ameliorate the MN environment.

Research Summary

This study investigates the therapeutic potential of the sigma-1R agonist PRE-084 in the SOD1G93A mouse model of ALS. The results demonstrate that PRE-084 administration significantly improves motor neuron function, preserves neuromuscular connections, and extends survival in ALS mice. The mechanism of action involves the modulation of NMDA receptor-mediated calcium influx and the reduction of microglial reactivity in the spinal cord. These findings suggest that sigma-1R agonists may be promising therapeutic candidates for ALS. Delayed administration of PRE-084 also showed significant improvements, suggesting potential for treatment even after the onset of symptoms.

Practical Implications

Therapeutic Potential

Sigma-1R agonists, such as PRE-084, may represent a novel therapeutic strategy for ALS, offering a potential avenue for slowing disease progression and improving patient outcomes.

Drug Development

The study provides a rationale for further development and clinical evaluation of sigma-1R agonists as a treatment for ALS.

Understanding ALS Pathology

The findings contribute to a better understanding of the role of NMDA receptor modulation and microglial reactivity in the pathogenesis of ALS.

Study Limitations

1
The study was conducted on a mouse model of ALS, which may not fully replicate the complexity of the human disease.
2
Further research is needed to determine the optimal dosage and timing of sigma-1R agonist administration.
3
The long-term effects and potential side effects of sigma-1R agonist treatment need to be investigated.

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