Endothelin Confers Protection against High Glucose-Induced Neurotoxicity via Alleviation of Oxidative Stress

Abstract

Recent findings linked the inhibition in the neuromodulator peptide endothelin-1 (ET-1) level to the high glucose-evoked neurotoxicity. However, definitive neuroprotective role for ET-1 and the major neuronal ET (ET-3) against high glucose-evoked toxicity and the implicated neurochemical responses triggered by their ET-A and ET-B receptors remain unknown. Here, we tested the hypothesis that ET-B activation alleviates high glucose-evoked oxidative stress and cell death. High glucose (100 mM for 48 hours)-evoked cell death was associated with elevation in reactive oxygen species, inhibition of catalase activity, and a paradoxical upregulation of hemeoxygenase-1 expression along with ET-A and ET-B receptors were downregulated and upregulated, respectively. ET-1 or ET-3, in concentrations that had no effect on PC12 cell viability in normal glucose medium, alleviated all high glucose-evoked neurochemical responses, except for the reduction in ET-A receptor expression. Prior (4 hours) incubation with a selective ET-A (BQ123) or ET-B (BQ788) receptor blocker abrogated the neuroprotection conferred by ET-1 or ET-3. However, the ET-B receptor played a greater role because BQ788 abrogated the favorable ET-1- or ET-3-mediated reversal of the ERK1/2 phosphorylation and the inhibition in catalase activity caused by high glucose. These findings suggest that endothelin exerts ET-B receptor-dependent favorable redox and neuroprotective effects against high glucose-evoked oxidative damage and neurotoxicity.

Restoration of Rostral Ventrolateral Medulla Cystathionine-γ Lyase Activity Underlies Moxonidine-Evoked Neuroprotection and Sympathoinhibition in Diabetic Rats

“…We focused on neuronal oxidative stress as an underlying mechanism for the diabetes-evoked neuronal injury and sympathoexcitation based on current evidence in different model systems (Wang et al, 2014;Fouda and Abdel-Rahman, 2017;Oshima et al, 2017). In accordance with current guidelines Fig.…”

“…ROS Measurement. Oxidative stress was measured using 29,79-dichlorofluorescein diacetate (DCFH-DA), a general detector of oxidative species (Rezq and Abdel-Rahman, 2016;Fouda and Abdel-Rahman, 2017). Briefly, a stock solution of DCFH-DA (20 mM; Molecular Probes, Grand Island, NY) was prepared in methanol and kept at 220°C protected from light.…”

“…We studied the role of HO-1 in our model system because it is expressed in the RVLM neurons (Mazza et al, 2001), exerts neuronal antioxidant and antiapoptotic effects (Spitz et al, 1987;Fouda and Abdel-Rahman, 2017;Kim et al, 2017), and mediates sympathoinhibition (Nassar et al, 2011). Our findings suggest H 2 S-dependent regulation of HO-1 in the RVLM contributes to the diabetes-evoked neurotoxicity and its alleviation by moxonidine for the following reasons.…”

“…Diabetes mellitus, a metabolic disorder, is associated with oxidative stress (Yan et al, 2014) as a result of reactive oxygen species (ROS) overproduction and reduction in antioxidant defense mechanisms (Ceretta et al, 2012;Fouda and Abdel-Rahman, 2017). The brain is more sensitive to oxidative stress, which affects gene expression and multiple cell functions (Giacco and Brownlee, 2010), due to its high oxygen consumption rate, plentiful lipid content, and relatively limited antioxidant mechanisms (Abdel Moneim, 2015).…”

Cannabidiol protects against high glucose‐induced oxidative stress and cytotoxicity in cardiac voltage‐gated sodium channels

“…High glucose concentrations (up to 100 mM of d ‐glucose) have also been previously used to mimic human hyperglycaemia in cell line studies (Viskupicova et al, 2015). 100 mM of glucose was used in many studies and in different cell lines, including human erythrocytes (incubation for 72 hr; Viskupicova et al, 2015), human SH‐SY5Y neuroblastoma cell line (Liu et al, 2019) and neuronal PC 12 cells (Chen et al, 2016; Fouda & Abdel‐Rahman, 2017). We used the MTS cell viability assay to check the viability of CHO cells at different glucose concentrations.…”