Anti-inflammatory and diuretic effects of the diterpene ent-dihydrotucumanoic acid

Drug Dev Res. 2019 Sep;80(6):800-806. doi: 10.1002/ddr.21561. Epub 2019 Jun 26.

Abstract

Gymnosperma glutinosum (Spreng) Less (Asteraceae) is a shrub used in traditional medicine for the treatment of inflammatory and renal diseases. The ent-dihydrotucumanoic acid (DTA) is a diterpene obtained from G. glutinosum. This study evaluated the antioxidant, genotoxic, and diuretic properties of DTA, as well as its in vitro and in vivo anti-inflammatory actions. The antioxidant actions of DTA were assessed with the 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid) (ABTS), ferric reducing antioxidant power (FRAP), and 2,2'-diphenyl-1-picrylhydrazyl (DPPH) assays, the genotoxic action was assessed with the comet assay, and the diuretic effects of DTA were assessed using metabolic cages. The anti-inflammatory actions were evaluated using primary murine peritoneal macrophages stimulated with LPS and the λ-carrageenan-induced hind paw edema test. DTA lacked antioxidant (IC50 > 25,000 μg/mL) activity in the ABTS, FRAP, and DPPH assays. DTA at 500-1,000 μg/mL showed moderate genotoxicity. In LPS-stimulated macrophages, DTA showed IC50 values of 74.85 μg/mL (TNF-α) and 58.12 μg/mL (NO), whereas the maximum inhibition of IL-6 (24%) and IL-1β (36%) was recorded at 200 μg/mL. DTA induced in vivo anti-inflammatory effects with ED50 = 124.3 mg/kg. The in vitro anti-inflammatory activity of DTA seems to be associated with the decrease in the release of TNF-α and NO. DTA promoted the excretion of urine (ED50 = 86.9 mg/kg), Na+ (ED50 = 66.7 mg/kg), and K+ (ED50 = 8.6 mg/kg). The coadministration of DTA with L-NAME decreased the urinary excretion shown by DTA alone. Therefore, the diuretic activity is probably associated with the participation of nitric oxide synthase. In conclusion, DTA exerted anti-inflammatory and diuretic effects, but lacked antioxidant effects.

Keywords: anti-inflammatory; dihydrotucumanoic acid; diuretic.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / chemistry
  • Anti-Inflammatory Agents / pharmacology*
  • Anti-Inflammatory Agents / therapeutic use
  • Anti-Inflammatory Agents / toxicity
  • Antioxidants / chemistry
  • Antioxidants / pharmacology*
  • Antioxidants / therapeutic use
  • Antioxidants / toxicity
  • Asteraceae
  • Benzothiazoles / chemistry
  • Biphenyl Compounds / chemistry
  • Carrageenan
  • Comet Assay
  • Cytokines / metabolism
  • Diterpenes / chemistry
  • Diterpenes / pharmacology*
  • Diterpenes / therapeutic use
  • Diterpenes / toxicity
  • Diuretics / chemistry
  • Diuretics / pharmacology*
  • Diuretics / therapeutic use
  • Diuretics / toxicity
  • Edema / chemically induced
  • Edema / drug therapy
  • Humans
  • Leukocytes, Mononuclear / drug effects
  • Lipopolysaccharides
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Male
  • Mice, Inbred BALB C
  • Nitric Oxide / metabolism
  • Picrates / chemistry
  • Sulfonic Acids / chemistry

Substances

  • Anti-Inflammatory Agents
  • Antioxidants
  • Benzothiazoles
  • Biphenyl Compounds
  • Cytokines
  • Diterpenes
  • Diuretics
  • Lipopolysaccharides
  • Picrates
  • Sulfonic Acids
  • ent-dihydrotucumanoic acid
  • 2,2'-azino-di-(3-ethylbenzothiazoline)-6-sulfonic acid
  • Nitric Oxide
  • Carrageenan
  • 1,1-diphenyl-2-picrylhydrazyl