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

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.

Class I histone deacetylases inhibition reverses memory impairment induced by acute stress in mice

“…Finally, we tested the effect of two HDACs inhibitors, 4-phenylbutyrate (PB) and IN14, on acute stress-induced memory blockade. We chose these two drugs for comparative purposes, based on previous studies showing that PB is a reversible inhibitor of classes I and II HDACs with well-known capacity to reverse memory deficiencies, while IN14 appears to be more selective for class I but with similar biochemical and behavioral efficacy [ 29 , 30 ]. Our findings suggest that HDAC2 is involved in extrinsic stress-induced cognitive impairment.…”

Improved HDAC Inhibition, Stronger Cytotoxic Effect and Higher Selectivity against Leukemias and Lymphomas of Novel, Tricyclic Vorinostat Analogues

“…Nevertheless, other applications such as anti-inflammatory [ 14 , 15 , 16 , 17 , 18 , 19 ], antifibriotic [ 20 , 21 , 22 , 23 , 24 ], or neuroprotective effect in Huntington’s disease [ 25 , 26 , 27 ], Alzheimer disease [ 27 , 28 ], spinal muscular atrophy [ 29 ], or Friedreich’s ataxia were studied [ 30 ]. HDAC inhibitors were postulated as possible therapeutic agents in asthma and chronic obstructive pulmonary disease (COPD) [ 31 ], methamphetamine addiction [ 32 ], heart failure [ 33 , 34 , 35 ], diabetes [ 36 , 37 ], depression [ 38 ], or suppression of aging processes [ 39 ]. They were also tested for potential antimicrobial and anti-infective activities as antiviral [ 40 , 41 , 42 ], antibacterial [ 43 ], antifungal [ 44 , 45 ], or antiparasitic [ 46 , 47 , 48 ] agents.…”

Correlations Between SIRT Genetic Polymorphisms and Postpartum Depressive Symptoms in Chinese Parturients Who Had Undergone Cesarean Section

“…11 Meanwhile, in a large and growing body of literature, some HDAC enzymes have been proposed as epigenetic targets involved in the pathophysiology of depression and antidepressant-like action. 12 Sirtuins are HDAC3s. They mediate histone deacetylation in an NAD + -dependent manner and can deacetylate proteins other than histones, which involves a variety of pathophysiological processes.…”

“… 11 Meanwhile, in a large and growing body of literature, some HDAC enzymes have been proposed as epigenetic targets involved in the pathophysiology of depression and antidepressant-like action. 12 …”