Structure-function studies for the panacea, valproic acid.
The anticonvulsant properties of VPA (valproic acid), a branched short-chain fatty acid, were serendipitously discovered in 1963. Since then, therapeutic roles of VPA have increased to include bipolar disorder and migraine prophylaxis, and have more recently been proposed in cancer, Alzheimer's disease and HIV treatment. These numerous therapeutic roles elevate VPA to near 'panacea' level. Surprisingly, the mechanisms of action of VPA in the treatment of many of these disorders remain unclear, although it has been shown to alter a wide variety of signalling pathways and a small number of direct targets. To analyse the mechanism of action of VPA, a number of studies have defined the structural characteristics of VPA-related compounds giving rise to distinct therapeutic and cellular effects, including adverse effects such as teratogenicity and hepatotoxicity. These studies raise the possibility of identifying target-specific novel compounds, providing better therapeutic action or reduced side effects. This short review will describe potential therapeutic pathways targeted by VPA, and highlight studies showing structural constraints necessary for these effects.
Terbach
Nicole
N
Centre for Biomedical Sciences, School of Biological Sciences, Royal Holloway University of London, Egham, UK.
Williams
Robin S B
RS
D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D001714:Bipolar Disorder / Q000188:drug therapy*; D004827:Epilepsy / Q000188:drug therapy*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D006801:Humans; D007294:Inositol / Q000378:metabolism; D007473:Ion Channels / Q000378:metabolism; D008881:Migraine Disorders / Q000188:drug therapy; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D015394:Molecular Structure; D054467:Phospholipases A2 / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013329:Structure-Activity Relationship; D013723:Teratogens; D014635:Valproic Acid / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D017735:Virus Latency / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000927:Anticonvulsants; D007473:Ion Channels; D010743:Phospholipids; D013723:Teratogens; D007294:Inositol; D005680:gamma-Aminobutyric Acid; D014635:Valproic Acid; D020928:Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; D054467:Phospholipases A2