Targeting inflammasome complexes as a novel therapeutic strategy for mood disorders

ABSTRACT

Introduction

Inflammasome complexes, especially NLRP3, have gained great attention as a potential therapeutic target in mood disorders. NLRP3 triggers a caspase 1-dependent release of the inflammatory cytokines IL-1β and IL-18, and seems to interact with purinergic and kynurenine pathways, all of which are implicated in mood disorders development and progression.

Areas covered

Emerging evidence supports NLRP3 inflammasome as a promising pharmacological target for mood disorders. We discussed the available evidence from animal models and human studies and provided a reflection on drawbacks and perspectives for this novel target.

Expert opinion

Several studies have supported the involvement of NLRP3 inflammasome in MDD. However, most of the evidence comes from animal models. The role of NLRP3 inflammasome in BD as well as its anti-manic properties is not very clear and requires further exploration. There is evidence of anti-manic effects of P2×R7 antagonists associated with reduction in the brain levels of IL-1β and TNF-α in a murine model of mania. The involvement of other NLRP3 inflammasome expressing cells besides microglia, like astrocytes, and of other inflammasome complexes in mood disorders also deserves further investigation. Preclinical and clinical characterization of NLRP3 and other inflammasomes in mood disorders is needed before considering translational approaches, including clinical trials.

KEYWORDS:

• Mood disorders
• inflammasome
• NLRP3
• P2XR7
• depression
• bipolar disorder
• cytokines

Article highlights

• Inflammasomes, especially the NLRP3, and their downstream inflammatory signaling seem to play a role in the neurobiological processes implicated in mood disorders.

• Growing evidence has supports NLRP3 inflammasome as promising pharmacological targets for depression.

• NLRP3 inflammasome seems to interact with purinergic and/or kynurenine pathways to induce depressive-like behaviors.

• The involvement of NLRP3 inflammasome and its potential as a therapeutic target in BD requires further exploration.

• Preclinical and clinical characterization of NLRP3 inflammasome in mood disorders is needed before considering translational approaches, including clinical trials.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers in this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The authors have received financial support from the Brazilian government funding agencies: FAPEMIG (Fundação de Amparo à Pesquisa do Estado de Minas Gerais, Brazil), CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brazil) and CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior). ALT is partly funded by the Pat Orme Endowed Chair in Alzheimer’s and Neurodegenerative Disease Research. AS Miranda is a CNPq fellowship recipient. JCO is supported by funding from NIH R01 and VA Merit Award.