Mitochondrion-Mediated Apoptosis Induced by Acrylamide is Regulated by a Balance Between Nrf2 Antioxidant and MAPK Signaling Pathways in PC12 Cells

Abstract

Acrylamide (ACR) is a potent toxin that affects the human nervous system. However, the underlying mechanism of ACR neurotoxicity remains poorly understood. In the present study, we investigated whether ACR induces mitochondrion-dependent apoptosis and the involved signaling pathways in PC12 cells. ACR exposure activated the mitochondrial apoptotic pathway in PC12 cells and triggered the up-regulation of Bax/Bcl-2 ratio, excessive release of cytochrome c, cleavage of capase-9 and caspase-3, depolarization of the mitochondrial membrane, structural damages to the mitochondria, and compaction of nuclear heterochromatin. ACR-induced oxidative stress was also observed based on distinct increase in cellular reactive oxygen species (ROS) and malondialdehyde (MDA), and significant decrease in glutathione (GSH). Mitogen-activated protein kinases (MAPK) signaling including extracellular signal-regulated protein kinases (ERK), c-Jun N-terminal kinases (JNK), and p38 were phosphorylated by ROS overproduction in PC12 cells in a time-and dose-dependent manner. ACR promoted the translocation of nuclear factor E2-related factor 2 (Nrf2) from the cytosol to the nucleus, thereby enhancing the expression of downstream γ-glutamyl-cysteine synthetase (γ-GCS). The regulation of Nrf2 activation by MAPK pathways was confirmed by the blockade of MAPK pathways. The suppression of JNK and p38 pathways showed a protective effect on ACR-induced mitochondrial dysfunction and apoptosis. Nrf2 knockdown further enhanced MDA production and reduced GSH generation induced by ACR. These results suggest that MAPK and Nrf2 signaling pathways contribute to mitochondrion-mediated apoptosis induced by ACR in PC12 cells.

Therapeutic effect of curcumin on acrylamide‐induced apoptosis mediated by MAPK signaling pathway in Leydig cells

“…These results are in agreement with the previous report that CUR prevented apoptosis and testicular damage against cisplatin toxicity . AA exposure leading to apoptosis through increased the phosphorylation of JNK and p38 and causes an increase in ERK phosphorylation in PC12 cells . Furthermore, AA at low concentrations (<1 mM) caused senecence at macrophages through activating JNK, p38, and ERK1/2 .…”

“…Previous reports indicated that AA triggered apoptosis through the mitochondrial pathway . AA increased apoptosis in the testes, induced early apoptosis in R2C Leydig cells and changed the expression levels of apoptotic genes in TM3 Leydig cells .…”

“…In this study AA, increased the OH˙ levels concentration‐dependently, however, H 2 O 2 levels increased only at 1000 μM AA concentration (Figure D and E). Several reports indicated that oxidative stress‐related AA toxicity results in overproduction of intracellular ROS, lipid peroxidation and mitochondrial dysfunction . MDA, which is a biomarker of the degraded oxidant status and final product of lipid peroxidation in cells, has increased depending on the concentration of AA (Figure C).…”

Metformin Protects against Experimental Acrylamide Neuropathy in Rats

“…ACR‐treated rats also showed increased caspase3 positive cells area% in cerebrum, cerebellum, spinal cord and sciatic nerve together with an increase in caspase3 OD of positive cells in cerebrum, cerebellum and spinal cord. Parallel to these results, Pan et al, [] reported that ACR triggered the mitochondrial apoptotic pathway in PC12cells and increased up regulation of the Bax/Bcl2 ratio, liberation of cytochrome c, activation of capase‐9 and caspase‐3 and mitochondrial dysfunction. It is noteworthy that apoptosis can be controlled by down regulating caspase3 activation [Ye et al, ] and increasing Bcl‐2 expression [Abdel Shakor et al, ].…”

TBHQ Alleviated Endoplasmic Reticulum Stress‐Apoptosis and Oxidative Stress by PERK‐Nrf2 Crosstalk in Methamphetamine‐Induced Chronic Pulmonary Toxicity

“…Nrf2 can enhance the transcription of cytoprotective genes during oxidative stress [12]. In addition, it has been reported that Nrf2 is involved in increasing the levels of endogenous antioxidants, attenuating apoptosis, and increasing mitochondrial biogenesis [13–15]. According to the above, it is prompted that there are some interactions between oxidative stress and ERS and that oxidative stress can cause ERS; meanwhile, ERS can also cause or aggravate oxidative stress [16, 17].…”