Resveratrol protects against cadmium chloride‐induced hippocampal neurotoxicity by inhibiting ER stress and GAAD 153 and activating sirtuin 1/AMPK/Akt

Abstract

This study investigated whether the apoptotic effect induced by cadmium chloride (CdCl2) in rat's hippocampi and neuroprotection afforded by resveratrol (RES) are mediated by modulation of ER stress and involve sirtuin 1 (SIRT1)/AMPK/Akt axis. Adult male Wistar rats were divided into four groups (n = 24/group) as control, control + RES (300 mg/kg), CdCl2 (5 mg/kg), and CdCl2 + RES. All treatments were conducted orally for 45 days. Also, cultured hippocampal cells were treated with CdCl2 in the presence or absence of RES and with or without preincubation with SIRT1, AMPK, or PI3K inhibitors. CdCl2 impaired retention and spatial memories of rats and reduced levels and activities of SIRT1 and inhibited AMPK/Akt axis in their hippocamapi where SIRT1 was the upstream regulator. It also enahnced hippocampal levels of reactive oxygen species (ROS) and expression of caspase‐12 and caspase‐3, depleted glutathione (GSH) levels, and activated GRP78, activating transcription factor‐6, GAAD 153, X‐box binding protein‐1 arms of ER stress. On the contrary, RES coadminsitration completley abolished all these events. Interstingly and in control rats, RES not only increased levels of GSH, but also enhenced protein levels of B‐cell lymphoma 2 (Bcl‐2) and dwonregulated GAAD 153. In both control and CdCl2‐treated rats, pharmacological inhibtion of SIRT1, AMPK, and Akt compleltely abolished all effects afforded by RES. In conclusion, CdCl2‐induced hippocampal apopotis is associated with reduction of SIRT1/AMPK/Akt activity levels, ROS generation, downregulation of Bcl‐2, and activities, activation of ER stress, and GAAD 153, whereas RES is able to reverse these effects through activation of SIRT1/AMPK/Akt.

Resveratrol Alleviates the Inhibitory Effect of Tunicamycin-Induced Endoplasmic Reticulum Stress on Expression of Genes Involved in Thyroid Hormone Synthesis in FRTL-5 Thyrocytes

“…This was evident from an attenuated induction of ER stress-sensitive genes (HSPA5, DDIT3) and reduced splicing of XBP-1 in thyrocytes co-treated with RSV and TM as compared to thyrocytes treated with ER stress-inducer TM alone. The observed attenuation of TM-induced ER stress by RSV in the non-transformed FRTL-5 cell line is in line with a large number of published studies reporting an inhibitory effect of RSV on ER stress in different cell lines and tissues [ 19 , 20 , 21 , 22 , 23 , 24 ]. Second, the strong impairment of expression of genes involved in thyroid hormone synthesis and some of their transcriptional regulators (TTF-1, PAX-8) in FRTL-5 thyrocytes exposed to TM-induced ER stress is attenuated, but not completely abolished by RSV.…”

“…Amongst these compounds, the polyphenol resveratrol (RSV; IUPAC name: 5-[(E)-2-(4-hydroxyphenyl)ethenyl] benzene-1,3-diol), which is naturally found at high concentrations in red grapes and different berries, like blueberries, mulberries and raspberries, is a potential candidate for the treatment of ER stress-associated thyroid disorders. RSV was shown to inhibit ER stress in different cell types and tissues [ 19 , 20 , 21 , 22 , 23 , 24 ] and to induce the expression of NIS and key regulators of genes involved in thyroid hormone synthesis, such as TTF-1, TTF-2 and PAX-8, in non-transformed FRTL-5 thyrocytes and thyroid carcinoma cells [ 25 , 26 ]. In view of this, the present study tested the hypothesis that RSV alleviates the inhibitory effect of TM-induced ER stress on expression of genes involved in thyroid hormone synthesis and their transcriptional regulators in FRTL-5 thyrocytes.…”

Di-2-ethylhexyl phthalate (DEHP) induces apoptosis of mouse HT22 hippocampal neuronal cells via oxidative stress

“…Apoptosis is an ordered and orchestrated cellular process of programmed cell death that occurs in physiological and pathological conditions, and it plays an important role in the pathogenesis of many diseases such as degenerative neurological diseases. The apoptosis of the hippocampus can be induced by many chemicals such as bisphenol A (Lee et al, 2008), perfluorooctane sulfonate (Li et al, 2017), and cadmium (Shati, 2019). However, there is no study showing that DEHP can induce apoptosis of the hippocampus.…”

Norcantharidin combined with paclitaxel induces endoplasmic reticulum stress mediated apoptotic effect in prostate cancer cells by targeting SIRT7 expression

“…Many reports suggested that the SIRT family may be associated with the regulation of ER stress and cell apoptosis 28,29 . To clarify the role of SIRT proteins in NCTD combined with PTX in PCa cells.…”