Antioxidants and anti-inflammatory drugs in the treatment of motor neuron disease

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive, lethal neurodegenerative disorder, which causes the selective death of motor neurons in the brain and spinal cord, leading to paralysis of voluntary muscles and eventually to death. The etiology and the cause(s) of most cases of ALS remain unknown. Furthermore, it is also not understood how motor neurons degenerate in ALS. For the small percentage of familial ALS that is caused by mutation in superoxide dismutase (SOD1), the precise mechanism(s) by which the mutant SOD1 protein leads to motor neuron degeneration in humans and animal models for ALS has not been defined with certainty. Among pathways that are shown to be involved in motor neuron degeneration, protein misfoldings, glutamate excitotoxicity, oxidative stress, and inflammatory pathways attract special attention across the board, and accumulating evidence suggests that the degeneration of motor neurons is associated with the activation and proliferation of astrocytes and microglial cells and mitochondrial dysfunction. These lead to the rationale to test compounds to block oxidative damage and inflammatory injuries. Although some antioxidants and anti-inflammatory compounds have shown potentially beneficial effects in animal models, human clinical trials with antioxidant, anti-inflammatory drugs have thus far been disappointing. In this chapter, we discuss the past, present, and future for oxidative and inflammatory pathways in ALS and highlight some of the therapeutic studies carried out in the past decade. We also review and discuss our recent discoveries for the development of small molecules to stimulate a master pathway that is potentially capable of regulating and controlling oxidative stress, inflammation, and mitochondrial dysfunction. This master pathway is the Nrf2/ARE signaling pathway; its downstream molecules can simultaneously block multiple pathogenic pathways against ALS.