Implication of Let7b/AhR/ARNT/HMGB1/RAGE cascade in neuroplasticity disturbances induced by glucocorticoids and the promising reversible effect of 3,3 diindolymethane: Bidirectional crosstalk of Aryl hydrocarbon receptors
Mai A. Abd-Elmawla , Asmaa A. ElMonier , Enas S. Gad , Haneen Y. Khidr , May A. Azzam
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引用次数: 0
Abstract
Prolonged exposure to glucocorticoids (GC) disrupts neuronal architecture, hinders neuroplasticity, and triggers neuroinflammation. However, the precise underlying mechanisms have not been studied yet. The current study aimed to investigate the mechanisms of GC-induced neuroinflammatory effects by stimulating the miRNA let7b, aryl hydrocarbon receptor (AhR)/ARNT, HMGB1/RAGE, and other downstream targets. Rats were divided into 4 groups; control, GC (20 mg/kg, S.C.), 3,3′-diindolylmethane (DIM) 50 mg/kg/day, and donepezil (DNZ) 4 mg/kg/day for 21 days. Behavioral tests and histopathological investigations of cerebral cortex were done. Let7b, AhR, ARNT, and cytochrome A1A were estimated using qRT-PCR. HMGB1, RAGE, NQO1and NRF2 were estimated using ELISA, whereas GFAP and TNF-α by immunohistochemical analysis. Keap1 was estimated using Western technique. GSH and TBARS were assessed by colorimetric assay. In the current study, GC elevates the gene expressions of let7b, AhR, ARNT, and cytochrome A1A, along with the protein contents of HMGB1, RAGE, NQO1and NRF2. In addition, GC showed increased GFAP, TNF-α, and TBARS, together with decreased Keap1 and GSH. On the other side, DIM and DNZ reversed all the above-mentioned findings. Collectively, the study documents for the first time the effect of GC in upregulating let7b and activating the AhR/ARNT loop which subsequently stimulates RAGE/HMGB1 and NRF2/Keap1 cascade leading to stimulating further inflammatory and oxidative signaling pathways. Certainly, these effects are responsible for the behavioral fluctuations, the brain’s histological disruption, altered neuroplasticity, and neuroinflammation induced by GC. Moreover, DIM conquers GC-induced neuroinflammation due to its characteristic role in modulating AhR and its downstream targets.
期刊介绍:
Biochemical Pharmacology publishes original research findings, Commentaries and review articles related to the elucidation of cellular and tissue function(s) at the biochemical and molecular levels, the modification of cellular phenotype(s) by genetic, transcriptional/translational or drug/compound-induced modifications, as well as the pharmacodynamics and pharmacokinetics of xenobiotics and drugs, the latter including both small molecules and biologics.
The journal''s target audience includes scientists engaged in the identification and study of the mechanisms of action of xenobiotics, biologics and drugs and in the drug discovery and development process.
All areas of cellular biology and cellular, tissue/organ and whole animal pharmacology fall within the scope of the journal. Drug classes covered include anti-infectives, anti-inflammatory agents, chemotherapeutics, cardiovascular, endocrinological, immunological, metabolic, neurological and psychiatric drugs, as well as research on drug metabolism and kinetics. While medicinal chemistry is a topic of complimentary interest, manuscripts in this area must contain sufficient biological data to characterize pharmacologically the compounds reported. Submissions describing work focused predominately on chemical synthesis and molecular modeling will not be considered for review.
While particular emphasis is placed on reporting the results of molecular and biochemical studies, research involving the use of tissue and animal models of human pathophysiology and toxicology is of interest to the extent that it helps define drug mechanisms of action, safety and efficacy.