Inhibition of Autophagy Potentiated Hippocampal Cell Death Induced by Endoplasmic Reticulum Stress and its Activation by Trehalose Failed to be Neuroprotective

Abstract

Introduction: Endoplasmic reticulum (ER) stress induced the mobilization of two protein breakdown routes, the proteasomal- and autophagy-associated degradation. During ERassociated degradation, unfolded ER proteins are translocated to the cytosol where they are cleaved by the proteasome. When the accumulation of misfolded or unfolded proteins excels the ER capacity, autophagy can be activated in order to undertake the degradative machinery and to attenuate the ER stress. Autophagy is a mechanism by which macromolecules and defective organelles are included in autophagosomes and delivered to lysosomes for degradation and recycling of bioenergetics substrate. Materials and Methods: Autophagy upon ER stress serves initially as a protective mechanism, however when the stress is more pronounced the autophagic response will trigger cell death. Because autophagy could function as a double edged sword in cell viability, we examined the effects autophagy modulation on ER stress-induced cell death in HT22 murine hippocampal neuronal cells. We investigated the effects of both autophagy-inhibition by 3-methyladenine (3-MA) and autophagy-activation by trehalose on ER-stress induced damage in hippocampal HT22 neurons. We evaluated the expression of ER stress- and autophagy-sensors as well as the neuronal viability. Results and Conclusion: Based on our findings, we conclude that under ER-stress conditions, inhibition of autophagy exacerbates cell damage and induction of autophagy by trehalose failed to be neuroprotective.

Inhibition of Autophagy Prevents Panax Notoginseng Saponins (PNS) Protection on Cardiac Myocytes Against Endoplasmic Reticulum (ER) Stress-Induced Mitochondrial Injury, Ca2+ Homeostasis and Associated Apoptosis

“…Our data indicated that inhibition of autophagy eliminates the protective effects of PNS against ER stress response and associated cell death ( Figure 5 ), which is consistent with the report that under ER stress conditions, autophagy can be activated in order to undertake the degradative machinery to attenuate the ER stress. Inhibition of autophagy by trehalose exacerbates cell damage, and failed to exert neuroprotective function ( Halbe and Rami, 2019 ). Interestingly, we also found that PNS down-regulates the expressions of CHOP and Caspase-12, suggesting that CHOP-mediated ER stress apoptosis pathway may be involved in PNS protection against cardiac myocytes cell apoptosis, which is consistent with the previous report that saponins of Panax notoginseng suppressed the palmitate-induced ROS generation, and the ER stress-associated eIF2α/ATF4/CHOP and Caspase-12 pathways in RGC-5 cells ( Wang et al, 2016 ).…”