Minocycline alleviates NLRP3 inflammasome-dependent pyroptosis in monosodium glutamate-induced depressive rats

Biochem Biophys Res Commun. 2020 Jun 4;526(3):553-559. doi: 10.1016/j.bbrc.2020.02.149. Epub 2020 Apr 1.

Abstract

Background: Inflammasome activation and followed by the release of proinflammatory cytokines play a pivotal role in the development and progression of depression. However, the involvement of gasdermin D (GSDMD)-mediated pyroptosis in inflammasome-associated depression has not been studied. The present study aimed to determine the involvement of pyroptosis in the development of depression.

Methods: The rat depressive model was established by the administration of monosodium glutamate (MSG) in postnatal rats. Minocycline (an anti-inflammatory agent) and VX-765 (a specific inhibitor of caspase-1) were given as intervention treatments when rats were two-month-old. Rat depressive behaviors were evaluated by behavioral tests, including open field test, sucrose preference test, and forced swim test. Rat hippocampi were collected for western blotting and immunofluorescence examination.

Results: MSG administration induced depressive-like behavior in rats. MSG upregulated protein presences of caspase-1, GSDMD, interleukin-1β (IL-1β), interleukin-18 (IL-18), NLR pyrin domain-containing 3 (NLRP3), apoptosis-associated speck-like protein (ASC), high mobility group box 1 protein (HMGB1), and the receptor for advanced glycation end products (RAGE) in the hippocampus. Protein presences of HMGB1, NLRP3 and GSDMD were upregulated in Olig2+ oligodendrocytes in the hippocampus. The data suggest that both HMGB1/RAGE/NLRP3 signalings and GSDMD-dependent pyroptosis were activated. Both minocycline and VX-765 treatments improved depressive-like behaviors. Minocycline treatment significantly reduced both HMGB1/RAGE/NLRP3 inflammasome signalings and GSDMD-dependent pyroptosis. VX-765 downregulated GSDMD-dependent pyroptosis, but not HMGB1/RAGE signalings, indicating that GSDMD-dependent pyroptosis is a key player in the progress of depression.

Conclusion: In rats hippocampus, NLRP3 inflammasome activates GSDMD mediated-pyroptosis in the hippocampus of MSG-induced depressive rats.

Keywords: Depression; GSDMD; Minocycline; NLRP3 inflammasome; Pyroptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / therapeutic use
  • Anti-Inflammatory Agents / therapeutic use
  • Antidepressive Agents / therapeutic use*
  • Depressive Disorder / chemically induced
  • Depressive Disorder / drug therapy*
  • Depressive Disorder / metabolism
  • Disease Models, Animal
  • Inflammasomes / metabolism*
  • Male
  • Minocycline / therapeutic use*
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • Pyroptosis / drug effects*
  • Rats
  • Rats, Sprague-Dawley
  • Sodium Glutamate

Substances

  • Anti-Bacterial Agents
  • Anti-Inflammatory Agents
  • Antidepressive Agents
  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, rat
  • Minocycline
  • Sodium Glutamate