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Androgen receptor antagonism accelerates disease onset in the SOD1 G93A mouse model of amyotrophic lateral sclerosis.
British Journal of Pharmacology 2019 March 9
BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease typically more common in males, implicating androgens in progression of both patients and mouse models. Androgen effects are mediated by the androgen receptor (AR) which is highly expressed in spinal motor neurons and skeletal muscles. To clarify the role of AR in ALS, we therefore examined the effect of AR antagonism in the SOD1G93A mouse model.
EXPERIMENTAL APPROACH: The androgen receptor antagonist, flutamide, was administered to presymptomatic SOD1G93A mice as a slow-release subcutaneous implant (5 mg.d-1 ). Testosterone, flutamide and metabolite levels were measured in blood and spinal cord tissue by LC-MS-MS. Effects of AR inhibition on disease onset and progression were assessed using motor function tests, survival, muscle and neuropathological analyses.
KEY TESULTS: Flutamide was metabolized to 2-hydroxyflutamide achieving steady state plasma levels across the study duration and reached the spinal cord at pharmacologically active concentrations. AR antagonism accelerated disease onset and locomotor dysfunction in male SOD1G93A mice, but not female mice, without affecting survival. Analysis of hindlimb muscles revealed exacerbation in myofibre atrophy of male SOD1G93A mice treated with flutamide, although motor neuron pathology was not affected.
CONCLUSION AND IMPLICATIONS: Our findings suggest AR antagonism accelerates disease onset in male SOD1G93A mice leading to exacerbated muscle pathology, consistent with a role of androgens in modulating disease severity, sexual dimorphism and peripheral pathology in ALS. These results also demonstrate a key contribution of skeletal muscle pathology to disease onset, but not outcome, in this mouse model of ALS.
EXPERIMENTAL APPROACH: The androgen receptor antagonist, flutamide, was administered to presymptomatic SOD1G93A mice as a slow-release subcutaneous implant (5 mg.d-1 ). Testosterone, flutamide and metabolite levels were measured in blood and spinal cord tissue by LC-MS-MS. Effects of AR inhibition on disease onset and progression were assessed using motor function tests, survival, muscle and neuropathological analyses.
KEY TESULTS: Flutamide was metabolized to 2-hydroxyflutamide achieving steady state plasma levels across the study duration and reached the spinal cord at pharmacologically active concentrations. AR antagonism accelerated disease onset and locomotor dysfunction in male SOD1G93A mice, but not female mice, without affecting survival. Analysis of hindlimb muscles revealed exacerbation in myofibre atrophy of male SOD1G93A mice treated with flutamide, although motor neuron pathology was not affected.
CONCLUSION AND IMPLICATIONS: Our findings suggest AR antagonism accelerates disease onset in male SOD1G93A mice leading to exacerbated muscle pathology, consistent with a role of androgens in modulating disease severity, sexual dimorphism and peripheral pathology in ALS. These results also demonstrate a key contribution of skeletal muscle pathology to disease onset, but not outcome, in this mouse model of ALS.
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