Sephin1 Protects Neurons against Excitotoxicity Independently of the Integrated Stress Response

Abstract

Sephin1 is a derivative of guanabenz that inhibits the dephosphorylation of the eukaryotic initiation factor 2 alpha (eIF2α) and therefore may enhance the integrated stress response (ISR), an adaptive mechanism against different cellular stresses, such as accumulation of misfolded proteins. Unlike guanabenz, Sephin1 provides neuroprotection without adverse effects on the α2-adrenergic system and therefore it is considered a promising pharmacological therapeutic tool. Here, we have studied the effects of Sephin1 on N-methyl-D-aspartic acid (NMDA) receptor signaling which may modulate the ISR and contribute to excitotoxic neuronal loss in several neurodegenerative conditions. Time-course analysis of peIF2α levels after NMDA receptor overactivation showed a delayed dephosphorylation that occurred in the absence of activating transcription factor 4 (ATF4) and therefore independently of the ISR, in contrast to that observed during endoplasmic reticulum (ER) stress induced by tunicamycin and thapsigargin. Similar to guanabenz, Sephin1 completely blocked NMDA-induced neuronal death and was ineffective against AMPA-induced excitotoxicity, whereas it did not protect from experimental ER stress. Interestingly, both guanabenz and Sephin1 partially but significantly reduced NMDA-induced cytosolic Ca2+ increase, leading to a complete inhibition of subsequent calpain activation. We conclude that Sephin1 and guanabenz share common strong anti-excitotoxic properties with therapeutic potential unrelated to the ISR.

PERK modulation, with GSK2606414, Sephin1 or salubrinal, failed to produce therapeutic benefits in the SOD1G93A mouse model of ALS

“…However, since Sephin1 did not affect the expression of ATF4, our findings challenge the thesis that Sephin1’s neuroprotective properties are mediated through the prolongation of the phosphorylation of eIF2α. Instead, our results align better with the conclusions of an increasing number of recent studies indicating that Sephin1 confers neuroprotection by attenuating the IRE1α branch of the UPR 36,37 , or by blocking the NMDA-induced neuronal death 53 .…”

Single-cell RNA sequencing reveals the suppressive effect of PPP1R15A inhibitor Sephin1 in antitumor immunity

“… 16 , 57 , 58 Usage of Sephin1 in mammals can lead to a promotion of ISR activity; thus, it is used as a potential treatment in neuron motor-, and proteostasis-related diseases. 48 , 49 , 50 In our study, we found that the usage of Sephin1 in mice can lead to antitumor immunity suppression, which is most likely to be achieved by ISR process by single-cell expression analysis. In the C56BL/6 mice injected subcutaneously with B16F1 cells, the tumor growth rate in the Sephin1 group was significantly higher than that in the normal group, which indicated a possible relationship between the ISR process and antitumor immune activities.…”

“… 48 Because of its effect to PPP1R15A and ISR, Sephin1 is now used as a potential treatment in neuron-, motor-, and proteostasis-related diseases. 48 , 49 , 50 In this study, we used Sephin1 as an inhibitor of PPP1R15A to explore the effect of Sephin1 on the TIME, especially the impact on antitumor immune cells. We performed both in vivo and in vitro experiments and studied two different cell lines, B16F1 and 4T1.…”

Secondary Mechanisms of Neurotrauma: A Closer Look at the Evidence

“…Similarly, Guanabenz and its derivatives (e.g., sephin1) have been shown to increase eIF2α phosphorylation [ 8 , 85 ]. Recent studies examining the therapeutic effect of Guanabenz and sephin1 have shown reductions in unfolded protein production, ER stress, and TBI neural deficits [ 86 , 87 , 88 , 89 , 90 ]. Additionally, Tauroursodeoxycholic acid (TUDCA), an endogenous bile acid, is another potential treatment targeting ER stress.…”