Antidepressant effect of the translocator protein antagonist ONO-2952 on mouse behaviors under chronic social defeat stress

Autor: Kanako Nozaki, Seishi Katsumata, Takahiro A. Kato, Yosuke Yamawaki, Masahiro Ohgidani, Shigeto Yamawaki, Takashi Kitajima, Ezgi Hatice Sahin, Hidenori Aizawa, Hikaru Ito
Rok vydání: 2020
Předmět:
Cyclopropanes
Lipopolysaccharides
0301 basic medicine
medicine.medical_treatment
Anxiety
Pharmacology
Hippocampus
Nucleus Accumbens
Elevated Plus Maze Test
Social Defeat
Social defeat
Mice
0302 clinical medicine
Medicine
Chronic stress
Behavior
Animal
biology
Microglia
Brain
Amygdala
Antidepressive Agents
medicine.anatomical_structure
Cytokine
Hindlimb Suspension
Cytokines
medicine.symptom
Inflammation
In Vitro Techniques
Nucleus accumbens
Heterocyclic Compounds
4 or More Rings
03 medical and health sciences
Cellular and Molecular Neuroscience
Receptors
GABA
Avoidance Learning
Translocator protein
Animals
GABA-A Receptor Antagonists
Social Behavior
Neuroinflammation
business.industry
Disease Models
Animal
030104 developmental biology
biology.protein
Reactive Oxygen Species
business
Open Field Test
Stress
Psychological
030217 neurology & neurosurgery
Zdroj: Neuropharmacology. 162:107835
ISSN: 0028-3908
Popis: In preclinical models, it has been reported that social defeat stress activates microglial cells in the CNS. Translocator protein 18 kDa (TSPO) is a mitochondrial protein expressed on microglia in the CNS that has been proposed to be a useful biomarker for brain injury and inflammation. We hypothesized that a TSPO antagonist, ONO-2952, would inhibit the neuroinflammation induced by microglial hyperactivation and associated depressive-like behaviors. An in vitro analysis showed that ONO-2952 suppressed the release of pro-inflammatory cytokines and mitochondrial reactive oxygen species in cultured microglia stimulated by lipopolysaccharide. In mice submitted to chronic social defeat stress, microglia predominantly expressed TSPO in limbic areas implicated in depressive-like behaviors, including the amygdala, ventral hippocampus and nucleus accumbens, in which an increase in the production of pro-inflammatory cytokines in vivo were associated. Treating animals with ONO-2952 during chronic social defeat stress ameliorated impairments in social avoidance and anxiety-like behaviors and suppressed pro-inflammatory cytokine production, suggesting that ONO-2952 exerted an anti-stress effect in this animal model of depression. Thus, targeting TSPO as a candidate for the development of antidepressants that reduce susceptibility to chronic stress could pave the way toward therapeutic interventions for relapse prophylaxis in depression.
Databáze: OpenAIRE
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