The Effects of HDAC Inhibitor in the Control Mechanism of Stress Responses

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  • Miyagawa Kazuya
    Department of Pharmacology, School of Pharmacy, International University of Health and Welfare
  • Saito Atsumi
    Department of Pharmacology, School of Pharmacy, International University of Health and Welfare
  • Miyagishi Hiroko
    Department of Pharmacology, School of Pharmacy, International University of Health and Welfare
  • Takeda Kotaro
    Department of Pharmacology, School of Pharmacy, International University of Health and Welfare
  • Tsuji Minoru
    Department of Pharmacology, School of Pharmacy, International University of Health and Welfare
  • Takeda Hiroshi
    Department of Pharmacology, School of Pharmacy, International University of Health and Welfare

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  • HDAC阻害薬とストレス反応の調節機構
  • HDAC ソガイヤク ト ストレス ハンノウ ノ チョウセツ キコウ

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Abstract

The term epigenetic refers to long-lasting changes in gene expression that are beyond the DNA base sequence. Mounting evidences suggest that epigenetic regulation of brain functions is important in the aetiology of psychiatric disorders. We previously reported that pretreatment of mice with 5-HT1A receptor agonists 24 hr before testing suppressed the decrease in emotional behaviors induced by exposure to acute restraint stress. In addition, DNA microarray analysis showed that such a pretreatment with 5-HT1A receptor agonist produces changes in several gene transcriptions including the reduction of histone deacetylase 10 (HDAC10). These findings have led us to investigate epigenetic mechanisms in stress resistance. The aim of this review was to summarize our recent findings on the association between the development of stress resistance or stress adaptation and histone acetylation. We found that acetylated histone H3 increased in the hippocampus of mice that had developed resistance to emotional stress by pretreatment with 5-HT1A receptor agonists 24 hr before testing. On the other hand, pretreatment with benzodiazepine anxiolytic diazepam did not have similar effects. Interestingly, similar to 5-HT1A receptor agonists, the histone deacetylase inhibitor trichostatin A also protected against the emotional changes induced by acute restraint stress, as well as histone H3 acetylation. In addition, an increase of histone H3 acetylation was observed in the hippocampus of mice that has been developed stress adaptation. The present findings suggest that the epigenetic mechanisms of gene regulation may play an important role in the development of stress resistance or stress adaptation.

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