Related Experiment Video
Updated: May 31, 2026
Method for Identifying Small Molecule Inhibitors of the Protein-protein Interaction Between HCN1 and TRIP8b
Published on: November 11, 2016
Targeting the BH3-interacting domain death agonist to develop mechanistically unique antidepressants
O Malkesman1, D R Austin, T Tragon
1Laboratory of Molecular Pathophysiology, National Institute of Mental Health, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA.
Insights
Inhibiting the BH3-interacting domain death agonist (Bid) shows promise for treating mood disorders. This study found Bid inhibition and enhanced Bcl-2 function may offer novel therapeutic strategies for depression.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- The B-cell lymphoma-2 (Bcl-2) protein family, including BH3-interacting domain death agonist (Bid), plays a crucial role in cellular resilience and neuronal plasticity.
- Reduced Bcl-2 levels in specific brain regions are linked to mood disorder pathophysiology, while antidepressants can increase these levels.
- Bid is a pro-apoptotic protein implicated in cellular stress responses relevant to mood disorders.
Purpose of the Study:
- To investigate the therapeutic potential of inhibiting Bid in rodent models of depression.
- To evaluate the effects of Bid antagonists (BI-11A7, BI-2A7) and a selective serotonin reuptake inhibitor (citalopram) on depression-related behaviors.
- To explore the impact of Bid inhibition on apoptosis-inducing factor (AIF) activation in the context of learned helplessness.
Main Methods:
- Pharmacological inhibition of Bid using antagonists BI-11A7 and BI-2A7 in mice.
- Utilized established depression models: forced swim test (FST), tail suspension test (TST), and learned helplessness (LH) paradigm.
- Assessed reward-seeking behavior using the female urine sniffing test (FUST) and measured AIF activation.
Main Results:
- Both citalopram and the Bid antagonist BI-11A7 significantly reduced immobility in the FST and TST.
- These agents also attenuated escape latencies in the LH paradigm and improved sniffing behavior in the FUST.
- Learned helplessness induction increased AIF activation, which was attenuated by chronic BI-11A7 treatment.
Conclusions:
- Functional perturbation of apoptotic proteins like Bid represents a potential therapeutic strategy for mood disorders.
- Enhancing Bcl-2 function offers an alternative avenue for developing novel depression therapeutics.
- Targeting apoptotic pathways provides a promising direction for future mood disorder treatments.
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.
More Related Videos
11:44Cellular Membrane Affinity Chromatography Columns to Identify Specialized Plant Metabolites Interacting with Immobilized Tropomyosin Kinase Receptor B
Published on: January 19, 2022
05:33High-Throughput Cellular Profiling of Targeted Protein Degradation Compounds Using HiBiT CRISPR Cell Lines
Published on: November 9, 2020
Related Concept Videos
01:23Antidepressant Drugs: MAOIs and Other Agents
01:25Antidepressant Drugs: Overview
01:26Targets for Drug Action: Overview
Receptors are either membrane-spanning or intracellular proteins, which upon binding a ligand, get activated and transmit the signal downstream to elicit a response. Drugs bind receptors, either mimicking the action of endogenous ligands or blocking the receptor activity to bring about a modified response. Nearly 35% of approved drugs target the G...
01:24Principles of Drug Action
Drugs can be agonists or antagonists. Like the endogenous ligands, agonists always bind and activate the target to produce a cellular response. Agonist binding induces a conformational change which in turn...
01:29Pharmacogenomics: Identification of New Drug Targets
01:28Structure-Activity Relationships and Drug Design
SAR studies the intricate relationship between a drug's chemical structure and biological activity. It focuses on understanding how modifications to a drug's structure can influence its...