Targeting Oxidative Stress Reduction and Inhibition of HDAC1, MECP2, and NF-kB Pathways in Rats With Experimentally Induced Hyperglycemia by Administration of Thymus marshallianus Willd. Extracts

Alexandra C Sevastre-Berghian; Irina Ielciu; Andrei Otto Mitre; Gabriela A Filip; Ilioara Oniga; Laurian Vlase; Daniela Benedec; Ana-Maria Gheldiu; Vlad A Toma; Bianca Mihart; Andra Mihuţ; Ioana Bâldea; Diana Olteanu; Irina C Chis; Simona V Clichici; Daniela Hanganu

doi:10.3389/fphar.2020.581470

Targeting Oxidative Stress Reduction and Inhibition of HDAC1, MECP2, and NF-kB Pathways in Rats With Experimentally Induced Hyperglycemia by Administration of Thymus marshallianus Willd. Extracts

Front Pharmacol. 2020 Sep 23:11:581470. doi: 10.3389/fphar.2020.581470. eCollection 2020.

Authors

Alexandra C Sevastre-Berghian¹, Irina Ielciu², Andrei Otto Mitre¹, Gabriela A Filip¹, Ilioara Oniga³, Laurian Vlase⁴, Daniela Benedec³, Ana-Maria Gheldiu², Vlad A Toma^{5

6

7}, Bianca Mihart¹, Andra Mihuţ¹, Ioana Bâldea¹, Diana Olteanu¹, Irina C Chis¹, Simona V Clichici¹, Daniela Hanganu³

Affiliations

¹ Department of Physiology, Faculty of Medicine, "Iuliu Haţieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.
² Department of Pharmaceutical Botany, Faculty of Pharmacy, "Iuliu Haţieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.
³ Department of Pharmacognosy, Faculty of Pharmacy, "Iuliu Haţieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.
⁴ Department of Pharmaceutical Technology and Biopharmacy, "Iuliu Haţieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.
⁵ Department of Molecular Biology and Biotechnology, Faculty of Biology and Geology, Babeş-Bolyai University, Cluj-Napoca, Romania.
⁶ Department of Biochemistry and Experimental Biology, Institute of Biological Research, Cluj-Napoca, Romania.
⁷ Department of Molecular and Biomolecular Physics, NIRD for Isotopic and Molecular Technologies, Cluj-Napoca, Romania.

Abstract

The effects of two lyophilized extracts obtained from the aerial parts of Thymus marschallianus Willd. and harvested from wild flora (TMW) and obtained from culture (TMC) were evaluated in Wistar rats with experimentally induced hyperglycemia. The hyperglycemia was induced by streptozotocin (STZ) administration and the obtained results were evaluated in comparison for TMW and TMC. The polyphenolic composition of extracts was evaluated by spectrophotometrical and LC-MS methods. In vitro antioxidant capacity assays (DPPH, FRAP, EPR) were performed in order to preliminary establish the ability of tested samples to protect against free radical induced damage. Afterwards, the effects of these extracts were assessed in vivo on rats with experimental-induced hyperglycemia. Oxidative stress biomarkers (e.g. malondialdehyde-MDA), phosphorylated transcription factor subunit of nuclear kappaB (NF-kB) p65, methyl CpG binding protein (MECP) 2 and histone deacetylase 1 (HDAC1) expressions in hippocampus and frontal lobe were assessed. Open Field Test (OFT) and Elevated Plus Maze (EPM) were conducted on tested animals. Malondialdehyde (MDA) levels and HDAC1and MeCP2 expressions increased significantly in hippocampus (p<0.05) and frontal lobe (p<0.001) of diabetes group compared to the control group in parallel with decreasing of GSH/GSSG ratio. TMW and TMC administration reduced blood glucose levels and diminished lipid peroxidation, HDAC1 expression and enhanced antioxidant capacity in frontal lobe. TMW improved central locomotion of rats, increased phospho-NFkB p65 and diminished MECP2 expressions in hippocampus. Both tested samples exerted a beneficial effect by increasing the antioxidant defense. Our findings indicate that the administration of these extracts might represent a good option in the treatment of diabetes and its complications.

Keywords: HDAC1; MECP2; NF-kB; Thymus marschallianus; antioxidant; experimentally induced hyperglycemia; oxidative stress; polyphenols.