Enoxacin Elevates MicroRNA Levels in Rat Frontal Cortex and Prevents Learned Helplessness

Neil R Smalheiser,Hui Zhang,Yogesh Dwivedi

doi:10.3389/fpsyt.2014.00006

Abstract

Major depressive disorder (MDD) is a major public health concern. Despite tremendous advancement, the pathogenic mechanisms associated with MDD are still unclear. Moreover, a significant number of MDD subjects do not respond to the currently available medication. MicroRNAs (miRNAs) are a class of small non-coding RNAs that control gene expression by modulating translation, mRNA degradation or stability of mRNA targets. The role of miRNAs in disease pathophysiology is emerging rapidly. Recently, we reported that miRNA expression is down-regulated in frontal cortex of depressed suicide subjects, and that rats exposed to repeated inescapable shock show differential miRNA changes depending on whether they exhibited normal adaptive responses or learned helpless (LH) behavior. Enoxacin, a fluoroquinolone used clinically as an anti-bacterial compound, enhances the production of miRNAs in vitro and in peripheral tissues in vivo, but has not yet been tested as an experimental tool to study the relation of miRNA expression to neural functions or behavior. Treatment of rats with 10 or 25 mg/kg enoxacin for 1 week increased the expression of miRNAs in frontal cortex and decreased the proportion of rats exhibiting LH behavior following inescapable shock. Further studies are warranted to learn whether enoxacin may ameliorate depressive behavior in other rodent paradigms and in human clinical situations, and if so whether its mechanism is due to upregulation of miRNAs.

Highlights

Major depressive disorder (MDD) is one of the most prevalent psychiatric disorders
When rats were pretreated with enoxacin and subjected to inescapable shock, the learned helpless (LH) phenotype was suppressed at both doses (Table 2)
Enoxacin belongs to a family of synthetic anti-bacterial compounds, the fluoroquinolones, which function as bacterial type II topoisomerase inhibitors [25]

Summary

Introduction

Major depressive disorder (MDD) is one of the most prevalent psychiatric disorders. It affects about 17% of Americans during their lifetime [1] and is associated with psychosocial impairment, poor quality of life, significant disability [2], morbidity, and mortality [3,4,5]. Much work has been done to characterize MDD, about 40% of MDD patients do not respond to the currently available medications [6]. This is partially a result of poor understanding of the molecular pathophysiology underlying MDD. The cellular mechanisms that underlie such compromised neural plasticity and structural impairments in MDD are not clearly understood and no single mechanism appears to be responsible for MDD etiopathogenesis; it is becoming increasingly evident that MDD may result from disruptions across whole cellular networks, leading to aberrant information processing in the circuits that regulate mood, cognition, and neurovegetative functions [7]. Evidence demonstrating impaired cellular networks that regulate neural plasticity has reshaped our views about the neurobiological underpinnings of MDD [8]

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