Sephin1 Protects Neurons against Excitotoxicity Independently of the Integrated Stress Response

International Journal of Molecular Sciences

Carolina Ortiz-Sanz¹  Carlos Matute¹  Jone Zuazo¹  Celia Luchena¹  Asier Ruiz¹  Elena Alberdi¹ 

[1] Departamento de Neurociencias, Universidad del País Vasco (UPV/EHU), Achucarro Basque Center for Neuroscience and Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), 48940 Leioa, Spain;

关键词: excitotoxicity;    integrated stress response;    calpain;    Sephin1;    guanabenz;    calcium;   

DOI  :  10.3390/ijms21176088

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown