Adrenergic receptors blockade alleviates dexamethasone-induced neurotoxicity in adult male Wistar rats: Distinct effects on β-arrestin2 expression and molecular markers of neural injury

Rasha M S M Mohamed; Enssaf Ahmad Ahmad; Dalia M Amin; Samar Ahmed Abdo; Islam A A E-H Ibrahim; Mona F Mahmoud; Shimaa Abdelaal

doi:10.1007/s40199-023-00490-y

Adrenergic receptors blockade alleviates dexamethasone-induced neurotoxicity in adult male Wistar rats: Distinct effects on β-arrestin2 expression and molecular markers of neural injury

Daru. 2023 Nov 15. doi: 10.1007/s40199-023-00490-y. Online ahead of print.

Authors

Rasha M S M Mohamed¹, Enssaf Ahmad Ahmad², Dalia M Amin³, Samar Ahmed Abdo⁴, Islam A A E-H Ibrahim⁵, Mona F Mahmoud⁶, Shimaa Abdelaal⁶

Affiliations

¹ Department of Clinical Pharmacology, Faculty of Medicine, Zagazig University, Zagazig, 44519, Egypt.
² Department of Human Anatomy and Embryology, Faculty of Medicine, Zagazig University, Zagazig, 44519, Egypt.
³ Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Zagazig University, Zagazig, 44519, Egypt.
⁴ Department of Biochemistry, Faculty of Veterinary Medicine, Zagazig University, Zagazig, 44519, Egypt.
⁵ Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt. eaebrahiem@pharmacy.zu.edu.eg.
⁶ Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt.

PMID: 37966585
DOI: 10.1007/s40199-023-00490-y

Abstract

Background: Dexamethasone-induced neurotoxicity has been previously reported. However, the molecular mechanisms are still not completely understood.

Objectives: The current work aimed to investigate the modulatory effects of α- and β-adrenergic receptors on dexamethasone-induced neurotoxicity in rats focused on changes in β-arrestin2 and molecular markers of neural injury in cerebral cortex.

Methods: Male Wistar rats were subcutaneously injected with dexamethasone (10 mg/kg/day) for 7 days to induce neural injury in the cerebral cortex. The experiment involved 5 groups: control, dexamethasone, carvedilol, propranolol, and doxazosin. In the last 3 groups, drugs were given 2 hours before dexamethasone injection. At the end of experiment, brain samples were collected for measurement of brain derived neurotrophic factor (BDNF), glial fibrillary acidic protein (GFAP), kinase activity of protein kinase B (Akt), diacylglycerol (DAG), α-smooth muscle actin (α-SMA), Smad3, β-amyloid and phospho-tau protein levels in addition to histopathological examination of brain tissue using hematoxylin-eosin, Nissl, and Sirius red stains. Moreover, β-arrestin2 levels in the cerebral cortex were measured using immunohistochemical examination.

Results: Dexamethasone slightly reduced brain weight and significantly decreased BDNF, Akt kinase activity and β-arrestin2 but markedly induced degeneration of cortical neurons and significantly increased GFAP, DAG, α-SMA, Smad3, β-amyloid and phospho-tau protein levels compared to controls. Carvedilol, propranolol, and doxazosin reversed all dexamethasone-induced molecular changes and slightly ameliorated the histopathological changes. Carvedilol significantly increased brain weight and β-arrestin2 levels compared to dexamethasone, propranolol, and doxazosin groups.

Conclusion: blocking α- and/or β-adrenergic receptors alleviate dexamethasone-induced neurotoxicity despite their distinct effects on β-arrestin2 levels in the cerebral cortex.

Keywords: Carvedilol; Dexamethasone; Doxazosin; Neurotoxicity; Propranolol; β-Arrestin2.