title: Candesartan and glycyrrhizin ameliorate ischemic brain damage through downregulation of the TLR signaling cascade.
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.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, 44519 Zagazig, Egypt. Electronic address: waled055@yahoo.com.
authors.forename: Waleed
authors.initials: W
authors.lastname: Barakat
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, 44519 Zagazig, Egypt.
authors.forename: Nancy
authors.initials: N
authors.lastname: Safwet
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, 44519 Zagazig, Egypt.
authors.forename: Nabila N
authors.initials: NN
authors.lastname: El-Maraghy
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, 44519 Zagazig, Egypt.
authors.forename: Mohamed N M
authors.initials: MN
authors.lastname: Zakaria
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001562:Benzimidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D001713:Biphenyl Compounds; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation; D019695:Glycyrrhizic Acid / Q000494:pharmacology / Q000627:therapeutic use*; D020244:Infarction, Middle Cerebral Artery; D050838:Interferon Regulatory Factor-3 / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D051195:Toll-Like Receptor 2 / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000235:genetics; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D016207:Cytokines; D019695:Glycyrrhizic Acid; D050838:Interferon Regulatory Factor-3; D053594:Myeloid Differentiation Factor 88; D018696:Neuroprotective Agents; D013777:Tetrazoles; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051996:Transcription Factor RelA; C494233:Irf3 protein, mouse; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; C081643:candesartan
keywords: Candesartan; Glycyrrhizin; MCAO; TLR