RESUMO
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 ß-adrenergic receptors on dexamethasone-induced neurotoxicity in rats focused on changes in ß-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, ß-amyloid and phospho-tau protein levels in addition to histopathological examination of brain tissue using hematoxylin-eosin, Nissl, and Sirius red stains. Moreover, ß-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 ß-arrestin2 but markedly induced degeneration of cortical neurons and significantly increased GFAP, DAG, α-SMA, Smad3, ß-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 ß-arrestin2 levels compared to dexamethasone, propranolol, and doxazosin groups. CONCLUSION: blocking α- and/or ß-adrenergic receptors alleviate dexamethasone-induced neurotoxicity despite their distinct effects on ß-arrestin2 levels in the cerebral cortex.
RESUMO
One of the global alarming prevalent metabolic diseases is Type 2 diabetes mellitus (T2DM) than other diabetes and sustains a substantial burden on public and healthcare systems. This study attempts to endeavor the beneficial effect of chitosan stabilized nanoparticles Ch-SeNPs on combating diabetic nephropathy (DN) after induction of T2DM in rats (DN.STZ-induced T2D). High-fat diet (HFD) and STZ were used for the induction of T2DM in rats, and then they were treated with either metformin alone (MEF) (500 mg/kg b.wt.) or combined with (Ch-SeNPs) (2 mg Se/kg b.wt.) for eight weeks. The microvascular complications in renal tissue of diabetic rats were pronounced by the prevalence of microalbuminuria and elevated levels of urea, creatinine, and BUN. Pronounced oxidative stress with enhanced inflammatory response. In the urine of diabetic rats, a marked increase in Kim 1, ß2-microglobulin, and urinary albumin. Renal morphological alterations were observed in all groups upon induction of T2DM, except for the Ch-SeNPs/MEF group showed noticeable improvements. The expression levels of Aldo-keto reductase AKr1B1, profibrotic protein transforming growth factor-ß1 (TGF-ß1), nestin, desmin, and vimentin, were up-regulated in the diabetic group. Significant down-regulation of their expression and restored antioxidant capacity was observed in the combined-treated group than single treated ones. Ch-SeNPs helped limit the prevalence of TNF-α, IL-6, and IL-1ß while used after T2DM induction by STZ and HFD. Ch-SeNPs/MEF co-therapy could effectively guard the kidneys and reduce the renal tissue injury via inhibiting oxidative stress and restoring glucose hemostasis, which indicates a promising line for treating T2DM nephropathy.