Genome-Wide Expression Analysis of Valproate Action: A Systems Level Synthesis

Abhay      Sharma

Abstract

The molecular mechanisms underlying neuroprotective effect of valproate, a widely used antiepileptic and mood stabilizing drug, are not clearly understood. The acute biochemical effects of valproate on neurotransmitter systems and ion channels do not provide simple mechanistic interpretation of its long-term neuroprotective action. The latter is instead considered to result from drug induced gene expression changes. To this end, expression profiles of mouse and rat brain, and cultured rat cortical neurons and human neuroblastoma cells following valproate treatment have previously been analyzed. The present review aims to examine if there exists converging evidence of genes and pathways in valproate action. A synthesis of the available transcriptomic data revealed enrichment of processes related to cell death/apoptosis, learning or memory, and antigen processing and presentation of peptide antigen via MHC class I in valproate regulated genes. An independent set of valproate regulated genes described in diverse non-transcriptomic studies also enriched these processes. Further, previously identified differentially expressed genes in multiple transcriptomic studies in epilepsy and bipolar disorder showed enrichment of apoptosis. Literature search also revealed that several apoptotic pathways targeting drugs possess therapeutic potential in epilepsy or bipolar disorder. The present analysis therefore implicates apoptosis in the neuroprotective mechanism of valproate. This is consistent with a recently described interaction network analysis of valproate responsive transcriptome, genes and enzymes reported in a variety of cell/tissue types in different organisms.

Keywords: Valproate, gene expression, antiepileptic, mood stabilizing, microarray, transcriptome, neuroprotective, apoptosis, bipolar disorder, valproic acid, CNS diseases, NMR spectroscopy, Pharmacogenomics, Cell signaling, excitotoxic neuronal death, CNS synapses