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Increased motor neuron resilience by small molecule compounds that regulate IGF-II expression.
Teresia M Osborn1, Jonathan Beagan1, Ole Isacson1
1Neuroregeneration Research Institute, McLean Hospital and Harvard Medical School, Belmont, MA, USA.
Neurobiology of Disease
|November 9, 2017
Summary
Researchers identified vardenafil, a compound that increases insulin-like growth factor II (IGF-II) levels, offering significant protection to motor neurons. This discovery provides a potential therapeutic strategy for motor neuron diseases like ALS.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Amyotrophic lateral sclerosis (ALS) selectively affects motor neurons, with some populations showing resilience.
- Understanding the molecular basis of this selective vulnerability is key to developing treatments.
- Insulin-like growth factor II (IGF-II) is upregulated in resilient motor neurons and has demonstrated protective effects.
Purpose of the Study:
- To identify small molecules that induce IGF-II expression.
- To evaluate the neuroprotective potential of these compounds against excitotoxicity.
- To assess the therapeutic efficacy of identified compounds in preclinical models of ALS.
Main Methods:
- Screening of a small molecule library to identify IGF-II inducers.
- In vitro testing of compounds for motor neuron protection against glutamate excitotoxicity.
- In vivo studies in rats and SOD1 transgenic mice to assess vardenafil's effects.
- Analysis of IGF-II expression and promoter activity in iPSC-derived motor neurons from healthy and ALS patients.
Main Results:
- Several compounds induced IGF-II expression and protected motor neurons in vitro.
- Vardenafil demonstrated complete motor neuron protection, which was reversible by blocking IGF-II receptors.
- Vardenafil increased spinal cord IGF-II mRNA in rats and delayed symptom onset and prolonged survival in SOD1 transgenic mice.
- Vardenafil enhanced IGF-II levels and protected ALS patient-derived motor neurons in vitro.
Conclusions:
- Modulating differentially expressed genes, such as through IGF-II induction, is a promising therapeutic avenue for motor neuron diseases.
- Vardenafil shows potential as a therapeutic agent for ALS by increasing IGF-II.
- Targeting molecular pathways involved in motor neuron resilience may offer new treatment strategies for neurodegenerative disorders.
