Candesartan and glycyrrhizin ameliorate ischemic brain damage through downregulation of the TLR signaling cascade

Eur J Pharmacol. 2014 Feb 5:724:43-50. doi: 10.1016/j.ejphar.2013.12.032. Epub 2013 Dec 27.

Abstract

Stroke is the second leading cause of death in industrialized countries and the most frequent cause of permanent disability in adults worldwide. The final outcome of stroke is determined not only by the volume of the ischemic core, but also by the extent of secondary brain damage inflicted to penumbral tissues by brain swelling, impaired microcirculation, and inflammation. The only drug approved for the treatment ischemic stroke is recombinant tissue plasminogen activator (rt-PA). The current study was designed to investigate the protective effects of candesartan (0.15 mg/kg, orally) and glycyrrhizin (30 mg/kg, orally) experimentally-induced ischemic brain damage in C57BL/6 mice (middle cerebral artery occlusion, MCAO) in comparison to the effects of a standard neuroprotective drug (cerebrolysin, 7.5 mg/kg, IP). All drugs were administered 30 min before and 24h after MCAO. Both candesartan and glycyrrhizin ameliorated the deleterious effects of MCAO as indicated by the improvement in the performance of the animals in behaviour tests, reduction in brain infarction, neuronal degeneration, and leukocyte infiltration. In addition, MCAO induced a significant upregulation in the different elements of the TLR pathway including TLR-2 and TLR-4, Myd88, TRIF and IRF-3 and the downstream effectors TNF-α, IL-1β, IL-6 and NF-kB. All these changes were significantly ameliorated by treatment with candesartan and glycyrrhizin. The results of the current study represent a new indication for both candesartan and glycyrrhizin in the management of ischemic stroke with effects comparable to those of the standard neuroprotective drug cerebrolysin.

Keywords: Candesartan; Glycyrrhizin; MCAO; TLR.

MeSH terms

  • Adaptor Proteins, Vesicular Transport / genetics
  • Animals
  • Behavior, Animal / drug effects
  • Benzimidazoles / pharmacology
  • Benzimidazoles / therapeutic use*
  • Biphenyl Compounds
  • Brain / drug effects
  • Brain / metabolism
  • Brain / pathology
  • Brain Ischemia / drug therapy*
  • Brain Ischemia / metabolism
  • Brain Ischemia / pathology
  • Brain Ischemia / physiopathology
  • Cytokines / metabolism
  • Down-Regulation
  • Glycyrrhizic Acid / pharmacology
  • Glycyrrhizic Acid / therapeutic use*
  • Infarction, Middle Cerebral Artery
  • Interferon Regulatory Factor-3 / genetics
  • Mice
  • Mice, Inbred C57BL
  • Myeloid Differentiation Factor 88 / genetics
  • Neuroprotective Agents / pharmacology
  • Neuroprotective Agents / therapeutic use*
  • Tetrazoles / pharmacology
  • Tetrazoles / therapeutic use*
  • Toll-Like Receptor 2 / genetics
  • Toll-Like Receptor 4 / genetics
  • Transcription Factor RelA / metabolism

Substances

  • Adaptor Proteins, Vesicular Transport
  • Benzimidazoles
  • Biphenyl Compounds
  • Cytokines
  • Interferon Regulatory Factor-3
  • Irf3 protein, mouse
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Neuroprotective Agents
  • TICAM-1 protein, mouse
  • Tetrazoles
  • Tlr2 protein, mouse
  • Tlr4 protein, mouse
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Transcription Factor RelA
  • Glycyrrhizic Acid
  • candesartan