Spinal and bulbar muscular atrophy, also known as
Kennedy's disease, is an adult-onset hereditary
neurodegenerative disorder caused by an expansion of the
polyglutamine repeat in the first exon in the
androgen receptor gene. Pathologically, the disease is defined by selective loss of spinal and bulbar motor neurons causing bulbar, facial and limb weakness. Although the precise disease pathophysiology is largely unknown, it appears to be related to abnormal accumulation of the pathogenic
androgen receptor protein within the nucleus, leading to disruption of cellular processes. Using a mouse model of
spinal and bulbar muscular atrophy that exhibits many of the characteristic features of the human disease, in vivo physiological assessment of muscle function revealed that mice with the pathogenic expansion of the
androgen receptor develop a motor deficit characterized by a reduction in muscle force, abnormal muscle contractile characteristics, loss of functional motor units and motor neuron degeneration. We have previously shown that treatment with
arimoclomol, a co-inducer of the heat shock stress response, delays
disease progression in the mutant
superoxide dismutase 1 mouse model of
amyotrophic lateral sclerosis, a fatal
motor neuron disease. We therefore evaluated the therapeutic potential of
arimoclomol in mice with
spinal and bulbar muscular atrophy.
Arimoclomol was administered orally, in
drinking water, from symptom onset and the effects established at 18 months of age, a late stage of disease.
Arimoclomol significantly improved hindlimb muscle force and contractile characteristics, rescued motor units and, importantly, improved motor neuron survival and upregulated the expression of the
vascular endothelial growth factor which possess neurotrophic activity. These results provide evidence that upregulation of the heat shock response by treatment with
arimoclomol may have therapeutic potential in the treatment of
spinal and bulbar muscular atrophy and may also be a possible approach for the treatment of other
neurodegenerative diseases.