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Agomelatine (S20098) modulates the expression of cytoskeletal microtubular proteins, synaptic markers and BDNF in the rat hippocampus, amygdala and PFC

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Abstract

Rationale

Agomelatine is described as a novel and clinical effective antidepressant drug with melatonergic (MT1/MT2) agonist and 5-HT2C receptor antagonist properties. Previous studies suggest that modulation of neuronal plasticity and microtubule dynamics may be involved in the treatment of depression.

Objective

The present study investigated the effects of agomelatine on microtubular, synaptic and brain-derived neurotrophic factor (BDNF) proteins in selected rat brain regions.

Methods

Adult male rats received agomelatine (40 mg/kg i.p.) once a day for 22 days. The pro-cognitive effect of agomelatine was tested in the novel object recognition task and antidepressant activity in the forced swimming test. Microtubule dynamics markers, microtubule-associated protein type 2 (MAP-2), phosphorylated MAP-2, synaptic markers [synaptophysin, postsynaptic density-95 (PSD-95) and spinophilin] and BDNF were measured by Western blot in the hippocampus, amygdala and prefrontal cortex (PFC).

Results

Agomelatine exerted pro-cognitive and antidepressant activity and induced molecular changes in the brain areas examined. Agomelatine enhanced microtubule dynamics in the hippocampus and to a higher magnitude in the amygdala. By contrast, in the PFC, a decrease in microtubule dynamics was observed. Spinophilin (dendritic spines marker) was decreased, and BDNF increased in the hippocampus. Synaptophysin (presynaptic) and spinophilin were increased in the PFC and amygdala, while PSD-95 (postsynaptic marker) was increased in the amygdala, consistent with the phenomena of synaptic remodelling.

Conclusions

Agomelatine modulates cytoskeletal microtubule dynamics and synaptic markers. This may play a role in its pharmacological behavioural effects and may result from the melatonergic agonist and 5-HT2C antagonist properties of the compound.

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Acknowledgements

This study was carried out at MAPREG and was sponsored by Servier, Paris, France. The authors CG and EM are employees of Servier and were involved in designing of the study and approval of the report. The authors received income from their primary employer, and no other financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional service, and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest. The authors are grateful to C. Potard, C. Perier and L. Paresys for technical assistance. The authors thank Dr. R. Baeurle for reviewing the very first draft of the manuscript.

Author information

Authors and Affiliations

  1. Institut National de la Santé et de la Recherche Médicale-UMR788, Le Kremlin-Bicêtre, France

    Nataly Ladurelle & Etienne E. Baulieu

  2. Institut de Recherches International Servier, Courbevoie, France

    Cecilia Gabriel & Elisabeth Mocaër

  3. Psychopharmacology Team, MAPREG, Bldg. Gregory PINCUS 80, rue du General Leclerc, 94276, Le Kremlin-Bicetre Cedex, France

    Adela Viggiano, Etienne E. Baulieu & Massimiliano Bianchi

Authors
  1. Nataly Ladurelle
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  2. Cecilia Gabriel
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  3. Adela Viggiano
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  4. Elisabeth Mocaër
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  5. Etienne E. Baulieu
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  6. Massimiliano Bianchi
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Corresponding author

Correspondence to Massimiliano Bianchi.

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Ladurelle, N., Gabriel, C., Viggiano, A. et al. Agomelatine (S20098) modulates the expression of cytoskeletal microtubular proteins, synaptic markers and BDNF in the rat hippocampus, amygdala and PFC. Psychopharmacology 221, 493–509 (2012). https://doi.org/10.1007/s00213-011-2597-5

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  • DOI: https://doi.org/10.1007/s00213-011-2597-5

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