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Published on: October 6, 2015
CGP 3466B has no effect on disease course of (G93A) mSOD1 transgenic mice
Geert J Groeneveld1, Freek L van Muiswinkel, Judith de Leeuw van Weenen
1Department of Neurology, Laboratory for Experimental Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, Utrecht, The Netherlands. g.j.groeneveld@neuro.azu.nl
Background:
There is an accumulating body of evidence that apoptosis is involved in the motor neuron death that occurs in ALS, and in the (G93A) mSOD1 transgenic mouse model (mSOD1 mice). CGP 3466B, a tricyclic propargylamine structurally related to (-)-deprenyl, was found to inhibit apoptosis in a wide variety of in vitro and in vivo models. We therefore studied the effect of CGP 3466B in mSOD1 mice.
Methods:
As the effect of CGP 3466B was previously reported to have a bell-shaped curve, we performed a dose-ranging study. High-copy G93A mSOD1 mice were treated subcutaneously from the age of 50 days until death with four concentrations of CGP 3466B (0.39 microg kg(-1), 3.9 microg kg(-1), 39 microg kg(-1), and 390 microg kg(-1)). Behavioural tests were performed daily to determine disease onset, disease progression and survival. At the age of 110 days, two mice per group were sacrificed for histopathological analysis of the lumbar ventral horn and for semiquantitative analysis of motor neuron number.
Results:
We observed no effect on disease onset, disease progression, or survival of the mice. We also did not observe a significant effect on the number of motor neurons due to CGP 3466B.
Conclusions:
We conclude that in high-copy G93A mSOD1 mice, chronic subcutaneous treatment with CGP 3466B offers no clinical benefit.
Insights
CGP 3466B did not improve survival or motor neuron count in a mouse model of Amyotrophic Lateral Sclerosis (ALS). This study found no clinical benefit of CGP 3466B in high-copy G93A mSOD1 mice.
Area of Science:
- Neuroscience
- Pharmacology
- Genetics
Background:
- Apoptosis plays a role in motor neuron death in Amyotrophic Lateral Sclerosis (ALS) and the G93A mSOD1 mouse model.
- CGP 3466B, a propargylamine derivative, inhibits apoptosis in various experimental models.
Purpose of the Study:
- To investigate the therapeutic potential of CGP 3466B in the G93A mSOD1 mouse model of ALS.
- To evaluate the effect of CGP 3466B on disease progression, survival, and motor neuron survival.
Main Methods:
- A dose-ranging study was conducted using four concentrations of CGP 3466B administered subcutaneously to high-copy G93A mSOD1 mice from 50 days of age until death.
- Daily behavioral tests assessed disease onset, progression, and survival.
- Histopathological analysis of motor neuron number was performed at 110 days of age.
Main Results:
- CGP 3466B treatment did not significantly affect disease onset, progression, or survival rates in the mSOD1 mice.
- No significant difference in motor neuron count was observed between treated and control groups.
Conclusions:
- Chronic subcutaneous administration of CGP 3466B provides no clinical benefit in high-copy G93A mSOD1 mice.
- These findings suggest CGP 3466B is not an effective therapeutic agent for this ALS mouse model.
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