The protective effects of β-caryophyllene on LPS-induced primary microglia M 1/M 2 imbalance: A mechanistic evaluation

Life Sci. 2019 Feb 15;219:40-73. doi: 10.1016/j.lfs.2018.12.059. Epub 2019 Jan 5.

Abstract

Aims: Neuroinflammation is observed as a routine characterization of neurodegenerative disorders such as dementia, multiple sclerosis (MS) and Alzheimer's diseases (AD). Scientific evidence propounds both of the neuromodulatory and immunomodulatory effects of CB2 in the immune system. β-Caryophyllene (BCP) is a dietary selective CB2 agonist, which deserves the anti-inflammatory and antioxidant effects at both low and high doses through activation of the CB2 receptor.

Methods: In this study, we investigated the protective effects of a broad range concentration of BCP against LPS-induced primary microglia cells inflammation and M1/M2 imbalance and identifying the portion of the involvement of related signaling pathways on BCP effects using pharmacological antagonists of CB2, PPAR-γ, and sphingomyelinase (SMase).

Key findings: The protective effects of BCP on LPS-induced microglia imbalance is provided by the M2 healing phenotype of microglia, releasing the anti-inflammatory (IL-10, Arg-1, and urea) and anti-oxidant (GSH) parameters and reducing the inflammatory (IL-1β, TNF-α, PGE2, iNOS and NO) and oxidative (ROS) biomarkers. Moreover, we showed that BCP exerts its effects through CB2 receptors which overproduction of ceramides by SMase at middle to higher concentrations of BCP reduce the protective activity of BCP and results in the activation of the PPAR-γ pathway.

Significance: In conclusion, the low concentration of BCP has higher selective anti-inflammatory effects rather than high levels. On this occasion, BCP by modulating the microglia is able to have potential therapeutic effects in neuro-inflammation conditions and microglia cells such as MS and AD.

Keywords: Cannabinoid; Caryophyllene; Inflammation; Microglia; PPAR-γ; Sphingomyelinase.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Anti-Inflammatory Agents / therapeutic use*
  • Antioxidants / metabolism
  • Arginase / metabolism
  • Cells, Cultured
  • Cytokines / metabolism
  • Inflammation / chemically induced
  • Inflammation / drug therapy*
  • Lipopolysaccharides / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Microglia / drug effects*
  • Neuroprotective Agents / pharmacology
  • Neuroprotective Agents / therapeutic use*
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase Type II / metabolism
  • Polycyclic Sesquiterpenes
  • Reactive Oxygen Species / metabolism
  • Sesquiterpenes / pharmacology
  • Sesquiterpenes / therapeutic use*
  • Urea / metabolism

Substances

  • Anti-Inflammatory Agents
  • Antioxidants
  • Cytokines
  • Lipopolysaccharides
  • Neuroprotective Agents
  • Polycyclic Sesquiterpenes
  • Reactive Oxygen Species
  • Sesquiterpenes
  • Nitric Oxide
  • Urea
  • caryophyllene
  • Nitric Oxide Synthase Type II
  • Arg1 protein, mouse
  • Arginase