Endoplasmic Reticulum Stress Instigates the Rotenone Induced Oxidative Apoptotic Neuronal Death: a Study in Rat Brain

Abstract

The present study was conducted to evaluate the involvement of endoplasmic reticulum stress in rotenone-induced oxidative neuronal death in rat brain. Rotenone (6 μg/3 μl) was administered intranigrally, unilaterally (right side) in SD rat brain. Neuronal morphology, expression level of tyrosine hydroxylase (TH) and endoplasmic reticulum (ER) stress markers like glucose-regulated protein 78 (GRP78), growth arrest and DNA damage-inducible gene 153 (GADD153), eukaryotic translation initiation factor 2α (p-eIF2α/eIF2α) and cleaved caspase-12 were estimated in the rat brain. Levels of reactive oxygen species (ROS), reduced glutathione (GSH) and enzymatic activities of glutathione peroxidase (GPx) and glutathione reductase (GRd) were estimated to assess the rotenone induced oxidative stress. Apoptotic death of neurons was assessed by estimating the mRNA level of caspase-3. Rotenone administration caused altered neuronal morphology, decreased expression of TH, augmented ROS level, decreased level of GSH and decreased activities of GPx and GRd enzymes which were significantly attenuated with the pretreatment of ER stress inhibitor, salubrinal (1 mg/kg, intraperitoneal). Significantly increased levels of GRP78, GADD, dephosphorylated eIF2α and cleaved caspase-12 was also observed after rotenone administration, which was inhibited with the pretreatment of salubrinal. Rotenone-induced increased mRNA level of caspase-3 was also attenuated by pretreatment of salubrinal. Findings suggested that salubrinal treatment significantly inhibited the rotenone-induced neurotoxicity implicating that ER stress initiates the rotenone-induced oxidative stress and neuronal death.

Downregulation of miR-384-5p attenuates rotenone-induced neurotoxicity in dopaminergic SH-SY5Y cells through inhibiting endoplasmic reticulum stress

“…More recently, Salganik et al (40) found that GRP78 protein overexpression protected aging nigral dopamine neurons in the ␣-synuclein-induced rat model of PD. Rotenone has been reported to induce ER stress both in cell models and animal models of PD (10,11,49). Here, we showed that downregulating miR-384-5p increased the expression of GRP78 and reduced ER stress signaling induced by rotenone.…”

Cytoprotective effects of myristicin against hypoxia-induced apoptosis and endoplasmic reticulum stress in rat dorsal root ganglion neurons

“…Protein folding in the endoplasmic reticulum (ER) is impaired under various physical and pathological conditions, termed endoplasmic reticulum stress (ERS) (9). ERS, induced by the activation of the unfolded protein response (UPR), is characterized by the upregulation of molecular chaperone glucose-related protein 78 (GRP78) and the activation of apoptosis (9,10). GRP78 associates with various critical transmembrane ER signaling proteins (9,11).…”

Epigallocatechin Gallate Reduces Amyloid β‐Induced Neurotoxicity via Inhibiting Endoplasmic Reticulum Stress‐Mediated Apoptosis

“…Aβ 1-42 treatment decreased cell viability, increased the expression of cleaved-caspase3 as well as ER stress-associated proteins GRP78, CHOP and cleaved-caspase12 (Figure 2). Salubrinal (Sal), a specific inhibitor of ER stress, [23,24] reversed these effects ( Figure 2). These findings suggested that Aβ 1-42 induced apoptosis in SH-SY5Y cells via ER stress.…”