Abstract
BackgroundThe molecular and biological mechanisms by which many antidepressants function are based on the monoamine depletion hypothesis. However, the entire cascade of mechanisms responsible for the therapeutic effect of antidepressants has not yet been elucidated.ResultsWe used a genome-wide microarray system containing 30,000 clones to evaluate total RNA that had been isolated from the brains of treated rats to identify the genes involved in the therapeutic mechanisms of various antidepressants, a tricyclic antidepressant (imipramine). a selective serotonin reuptake inhibitor (fluoxetine), a monoamine oxidase inhibitor (phenelzine) and psychoactive herbal extracts of Nelumbinis Semen (NS). To confirm the differential expression of the identified genes, we analyzed the amount of mRNA that was isolated from the hippocampus of rats that had been treated with antidepressants by real-time RT-PCR using primers specific for selected genes of interest. These data demonstrate that antidepressants interfere with the expression of a large array of genes involved in signaling, survival and protein metabolism, suggesting that the therapeutic effect of these antidepressants is very complex. Surprisingly, unlike other antidepressants, we found that the standardized herbal medicine, Nelumbinis Semen, is free of factors that can induce neurodegenerative diseases such as caspase 8, α-synuclein, and amyloid precursor protein. In addition, the production of the inflammatory cytokine, IFNγ, was significantly decreased in rat hippocampus in response to treatment with antidepressants, while the inhibitory cytokine, TGFβ, was significantly enhanced.ConclusionsThese results suggest that antidepressants function by regulating neurotransmission as well as suppressing immunoreactivity in the central nervous system.
Highlights
The molecular and biological mechanisms by which many antidepressants function are based on the monoamine depletion hypothesis
DNA microarray analysis of RNA isolated from pretreated rat hippocampus We used a genome-wide microarray analysis to examine changes in the gene expression profile of rats after treatment with antidepressants or Nelumbinis Semen for one, three and seven days
Of the 30,000 genes evaluated in the present study, the expression of 35, 49, 37 and 44 genes decreased, whereas that of 21, 20, 35 and 27 genes were over-expressed in response to treatment with imipramine, fluoxetine, phenelzine and Nelumbinis Semen, respectively (Figure 1)
Summary
The molecular and biological mechanisms by which many antidepressants function are based on the monoamine depletion hypothesis. When MAO attempts to oxidize phenelzine, the hydrazine-moiety binds covalently to the enzyme, thereby irreversibly inactivating it. This may contribute to its anxiolytic properties and superior efficacy when treating severe anxiety [6]. Nelumbinis Semen (NS) is a traditional medicine that has been used for hundreds of years in East-Asia to treat insomnia, anxiety and women’s post-menstrualpause depression [9]. In previous studies, this herbal medicine was found to exert an antidepressant-like effect in rats when examined by the Porsolt forced swim test. The results of that study suggested that Nelumbinis Semen could increase local cholinergic and dopaminergic or norephinergic neurotransmission via activation of cAMP formation in the hippocampus and pre-frontal cortex [10,11]
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