Transcriptome bioinformatic analysis identifies potential therapeutic mechanism of pentylenetetrazole in down...

Pentylenetetrazole (PTZ) has recently been found to ameliorate cognitive impairment in rodent models of Down syndrome (DS). The mechanism underlying PTZ's therapeutic effect in DS is however not clear. Microarray profiling has previously reported differential expression, both up- and down-regulation, of genes in DS. Given this, transcriptomic data related to PTZ treatment, if available, could be used to understand the drug's therapeutic mechanism in DS. No such mammalian data however exists. Nevertheless, a Drosophila model inspired by PTZ induced kindling plasticity in rodents has recently been described. Microarray profiling has shown PTZ's downregulatory effect on gene expression in the fly heads.

In a comparative transcriptomics approach, I have analyzed the available microarray data in order to identify potential therapeutic mechanism of PTZ in DS. In the analysis, summary data of up- and down-regulated genes reported in human DS studies and of down-regulated genes reported in the Drosophila model has been used.

I find that transcriptomic correlate of chronic PTZ in Drosophila counteracts that of DS. Genes downregulated by PTZ significantly over-represent genes upregulated in DS and under-represent genes downregulated in DS. Further, the genes which are common in the downregulated and upregulated DS set show enrichment for MAP kinase pathway.

My analysis suggests that downregulation of MAP kinase pathway may mediate therapeutic effect of PTZ in DS. Existing evidence implicating MAP kinase pathway in DS supports this observation.