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Targeting the BH3-interacting domain death agonist to develop mechanistically unique antidepressants

Molecular Psychiatry volume 17, pages 770–780 (2012)Cite this article

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Abstract

The BH3-interacting domain death agonist (Bid) is a pro-apoptotic member of the B-cell lymphoma-2 (Bcl-2) protein family. Previous studies have shown that stress reduces levels of Bcl-2 in brain regions implicated in the pathophysiology of mood disorders, whereas antidepressants and mood stabilizers increase Bcl-2 levels. The Bcl-2 protein family has an essential role in cellular resilience as well as synaptic and neuronal plasticity and may influence mood and affective behaviors. This study inhibited Bid in mice using two pharmacological antagonists (BI-11A7 and BI-2A7); the selective serotonin reuptake inhibitor citalopram was used as a positive control. These agents were studied in several well-known rodent models of depression—the forced swim test (FST), the tail suspension test (TST), and the learned helplessness (LH) paradigm—as well as in the female urine sniffing test (FUST), a measure of sex-related reward-seeking behavior. Citalopram and BI-11A7 both significantly reduced immobility time in the FST and TST and attenuated escape latencies in mice that underwent the LH paradigm. In the FUST, both agents significantly improved duration of female urine sniffing in mice that had developed helplessness. LH induction increased the activation of apoptosis-inducing factor (AIF), a caspase-independent cell death constituent activated by Bid, and mitochondrial AIF expression was attenuated by chronic BI-11A7 infusion. Taken together, the results suggest that functional perturbation of apoptotic proteins such as Bid and, alternatively, enhancement of Bcl-2 function, is a putative strategy for developing novel therapeutics for mood disorders.

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Acknowledgements

We would like to acknowledge the support of the Intramural Research Program of the National Institute of Mental Health (NIMH: OM, TT, DRA, IDH, GC and HKM) and NIH Grant (R01 HL082574) to JCR. Adithya Simha provided invaluable technical assistance.

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Authors and Affiliations

  1. Laboratory of Molecular Pathophysiology, National Institute of Mental Health, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA

    O Malkesman, D R Austin, T Tragon, G Chen & H K Manji

  2. Mood and Anxiety Disorders Research Program, National Institute of Mental Health, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA

    O Malkesman, D R Austin, T Tragon, I D Henter, G Chen & H K Manji

  3. Sanford-Burnham Medical Research Institute, La Jolla, CA, USA

    J C Reed & M Pellecchia

  4. Johnson & Johnson Pharmaceutical Research and Development, Titusville, NJ, USA

    G Chen & H K Manji

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Correspondence to H K Manji.

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There are no personal financial holdings that could be perceived as constituting a potential conflict of interest. Drs Chen and Manji are now at Johnson & Johnson Pharmaceutical Research and Development; this work was initiated and largely undertaken while they were employees of the NIMH.

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Malkesman, O., Austin, D., Tragon, T. et al. Targeting the BH3-interacting domain death agonist to develop mechanistically unique antidepressants. Mol Psychiatry 17, 770–780 (2012). https://doi.org/10.1038/mp.2011.77

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