Biochemical and Behavioral Characterization of IN14, a New Inhibitor of HDACs with Antidepressant-Like Properties.

Heidy Martínez-Pacheco,Ofir Picazo,Jean-Pascal Morin,Rossana Citlali Zepeda,Karla Viridiana Castro-Cerritos,Adolfo López-Torres,Gabriel Roldán-Roldán

doi:10.3390/biom10020299

Abstract

Evidence suggests that histone deacetylases (HDACs) inhibitors could be used as an effective treatment for some psychiatric and neurological conditions such as depression, anxiety and age-related cognitive decline. However, non-specific HDAC inhibiting compounds have a clear disadvantage regarding their efficacy and safety, thus the need to develop more selective ones. The present study evaluated the toxicity, the capacity to inhibit HDAC activity and antidepressant-like activity of three recently described class I HDAC inhibitors IN01, IN04 and IN14, using A. salina toxicity test, in vitro fluorometric HDAC activity assay and forced-swimming test, respectively. Our data show that IN14 possesses a better profile than the other two. Therefore, the pro-cognitive and antidepressant effects of IN14 were evaluated. In the forced-swimming test model of depression, intraperitoneal administration of IN14 (100 mg/Kg/day) for five days decreased immobility, a putative marker of behavioral despair, significantly more than tricyclic antidepressant desipramine, while also increasing climbing behavior, a putative marker of motivational behavior. On the other hand, IN14 left the retention latency in the elevated T-maze unaltered. These results suggest that novel HDAC class I inhibitor IN14 may represent a promising new antidepressant with low toxicity and encourages further studies on this compound.

Highlights

Epigenetic mechanisms involving chromatin-modifying enzymes have been implicated in the pathophysiology of mental and neurodegenerative diseases such as depression, anxiety and cognitive deficits [1,2,3,4,5], as well as in the therapeutic mechanisms of some antidepressants [6,7,8,9,10,11,12]
The histone deacetylases (HDACs) inhibitors targeting class I, sodium butyrate and MS-275 were reported to produce antidepressant-like effects [19,20,21]
MS-275 was associated with increased histone acetylation and decreased levels of HDAC2 [19,20]

Summary

Introduction

Epigenetic mechanisms involving chromatin-modifying enzymes have been implicated in the pathophysiology of mental and neurodegenerative diseases such as depression, anxiety and cognitive deficits [1,2,3,4,5], as well as in the therapeutic mechanisms of some antidepressants [6,7,8,9,10,11,12]. Recent findings indicate that the activity of specific class I HDAC enzymes may be altered in psychiatric and neurodegenerative disorders and may constitute a target for novel pharmacological treatments. Recent studies by two distinct groups have demonstrated that neuron-specific over-expression of HDAC2 impaired memory formation in adult mice, whereas HDAC2 deficiency resulted memory facilitation, similar to that induced by the treatment with nonselective HDAC inhibitors, suggesting that HDAC2 inhibition may be a useful strategy in the treatment of some cognitive impairments associated with psychiatric diseases [22,23]

Methods

Results

Conclusion