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Antidepressant-like effect induced by systemic and intra-hippocampal administration of DNA methylation inhibitors

Background. Antidepressant treatment induces histone acetylation ? transcriptional activationStress increases DNA methylation ? transcriptional repressionRepression ? depressive-like behavior. Goal. Examine effects of DNA methyltransferase (DNMT) inhibitors Systemic and Intra-hippocampal admini

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Antidepressant-like effect induced by systemic and intra-hippocampal administration of DNA methylation inhibitors

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    1. Antidepressant-like effect induced by systemic and intra-hippocampal administration of DNA methylation inhibitors Amanda J. Sales ? Caroline Biojone ? Mateus S. Terceti ? Francisco S. Guimaraes ? Marcus V. M. Gomes ? Samia R. L. Joca Presented By Andrew Bubak

    2. Background Antidepressant treatment induces histone acetylation ? transcriptional activation Stress increases DNA methylation ? transcriptional repression Repression ? depressive-like behavior

    3. Goal Examine effects of DNA methyltransferase (DNMT) inhibitors Systemic and Intra-hippocampal administrations Hippocampus – behavioral adaptation to stress Effects: Methylated DNA Hippocampal BDNF levels Antidepressant-like behavioral (immobility time)

    4. Approach (Animals) Male Wistar rats 200-220 grams Male Swiss mice 25-30 grams Submitted to FST, OFT, and TST (for mice) OFT – test for exploratory or motor effects by treatments

    5. Approach (Drugs) Systemic Administration Imipramine (NT reuptake inhibitor) 5-azaD (DNMT inhibitor) 5-azaC (DNMT inhibitor) Intra-hippocampal Administration 5-azaD RG-108 (non-nucleoside DNMT inhibitor)

    6. Experiment 1 Systemic administration of 5-azaD, 5-azaC, and imipramine effects in rats submitted to FST U-shaped results? Toxic effects at high levels due to inhibition of DNA synthesis

    7. Experiment 2 5-azaD and 5-azaC effects on OFT in rats - Shows that results of FST are not related to unspecific motor changes because both drugs showed no significant difference to vehicle

    8. Experiment 3 Effects of single systemic administration of 5-azaD in rats submitted to FST PT (pretest)

    9. Experiment 4 Effects of 5-azaD on methylated DNA and BDNF levels in the hippocampus of rats submitted to the FST

    10. Experiment 5 Effects of intra-hippocampal administration of 5-azaD and RG-108 in rats submitted to the FST

    11. Experiment 6 Effects of 5-azaD systemic administration in mice submitted to the FST (Top), TST (Middle), and OFT (Lower)

    12. Conclusions (Systemic) 5-azaD induced an antidepressant-like effect at 0.4 mg/Kg Higher levels of BDNF in hippocampus suggesting a good target region 5-azaC also induced antidepressant-like effects Strengthens 5-azaD DNMT inhibitory mechanism Overall, DNMT inhibitors may be a strong player in the neurobiology of depression

    13. Hhhmmm… Methylation is known to regulate expressions of other genes in addition to BDNF Other factors responsible…glucocorticoid?

    14. -Thanks

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