Treatment with arimoclomol, a coinducer of heat shock proteins, delays disease progression in ALS mice.

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition in which motoneurons of the spinal cord and motor cortex die, resulting in progressive paralysis. This condition has no cure and results in eventual death, usually within 1-5 years of diagnosis. Although the specific etiology of ALS is unknown, 20% of familial cases of the disease carry mutations in the gene encoding Cu/Zn superoxide dismutase-1 (SOD1). Transgenic mice overexpressing human mutant SOD1 have a phenotype and pathology that are very similar to that seen in human ALS patients. Here we show that treatment with arimoclomol, a coinducer of heat shock proteins (HSPs), significantly delays disease progression in mice expressing a SOD1 mutant in which glycine is substituted with alanine at position 93 (SOD1(G93A)). Arimoclomol-treated SOD1(G93A) mice show marked improvement in hind limb muscle function and motoneuron survival in the later stages of the disease, resulting in a 22% increase in lifespan. Pharmacological activation of the heat shock response may therefore be a successful therapeutic approach to treating ALS, and possibly other neurodegenerative diseases.

• Authors: Dairin Kieran, Bernadett Kalmar, James R T Dick, Joanna Riddoch-Contreras, Geoffrey Burnstock, Linda Greensmith
• Journal: Nature medicine (Nat Med) Vol. 10 Issue 4 Pg. 402-5 (Apr 2004) ISSN: 1078-8956 [Print] United States
• PMID: 15034571 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Heat-Shock Proteins
• Hydroxylamines
• Superoxide Dismutase
• arimoclomol

Topics

• Amyotrophic Lateral Sclerosis (drug therapy, enzymology, pathology, physiopathology)
• Animals
• Disease Progression
• Heat-Shock Proteins (biosynthesis)
• Humans
• Hydroxylamines (pharmacology, therapeutic use)
• Mice
• Mice, Transgenic
• Motor Neurons (pathology)
• Mutation
• Superoxide Dismutase (genetics)