Neuroprotective Effects of 4-phenylbutyric Acid and Its Derivatives: Possible Therapeutics for Neurodegenerative Diseases

Abstract

The pathogenesis of neurodegenerative diseases such as Alzheimer's and Parkinson's diseases involves the aggregation of denatured and misfolded nascent proteins. Consequently, many pharmacological approaches have been developed to prevent protein aggregation. 4-Phenylbutyric acid (4-PBA) is a chemical chaperone that shows potential as a candidate drug for the treatment of neurodegenerative diseases. The main actions of chemical chaperones are the amelioration of unfolded proteins and the suppression of their aggregation, which result in protective effects against endoplasmic reticulum stress-induced neuronal cell death. Furthermore, 4-PBA exhibits inhibitory activity against histone deacetylases (HDACs). However, owing to the problematically high doses of 4-PBA currently required for therapeutic efficacy, the optimization of 4-PBA is crucial for its effective medicinal application. In the present review, we summarize the recent advances in research on the basic actions of 4-PBA and its derivatives. We also discuss whether these compounds could be viable therapeutic agents against neurodegenerative diseases.