Post‐ischemic salubrinal treatment results in a neuroprotective role in global cerebral ischemia

Abstract

This study describes the neuroprotective effect of treatment with salubrinal 1 and 24 h following 15 min of ischemia in a twovessel occlusion model of global cerebral ischemia. The purpose of this study was to determine if salubrinal, an enhancer of the unfolded protein response, reduces the neural damage modulating the inflammatory response. The study was performed in CA1 and CA3 hippocampal areas as well as in the cerebral cortex whose different vulnerability to ischemic damage is widely described. Characterization of proteins was made by western blot, immunofluorescence, and ELISA, whereas mRNA levels were measured by Quantitative PCR. The salubrinal treatment decreased the cell demise in CA1 at 7 days as well as the levels of matrix metalloprotease 9 (MMP-9) in CA1 and cerebral cortex at 48 h and ICAM-1 and VCAM-1 cell adhesion molecules. However, increases in tumor necrosis factor a and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-jB) inflammatory markers were observed at 24 h. Glial fibrillary acidic protein levels were not modified by salubrinal treatment in CA1 and cerebral cortex. We describe a neuroprotective effect of the post-ischemic treatment with salubrinal, measured as a decrease both in CA1 cell demise and in the blood-brain barrier impairment. We hypothesize that the ability of salubrinal to counteract the CA1 cell demise is because of a reduced ability of this structure to elicit unfolded protein response which would account for its greater ischemic vulnerability. Data of both treated and non-treated animals suggest that the neurovascular unit present a structuredependent response to ischemia and a different course time for CA1/cerebral cortex compared with CA3. Finally, our study reveals a high responsiveness of endothelial cells to salubrinal in contrast to the limited responsiveness of astrocytes.

Unfolded protein response in brain ischemia: A timely update

“…68 And salubrinal, a highly selective small molecule inhibitor of eIF2a dephosphorylation, 48 is neuroprotective in experimental forebrain ischemia and stroke. 47,69 Collectively, these reports support a role for ER stress in brain ischemia/stroke, but they do not provide information on the cells involved because global approaches were used in each case to analyze or manipulate ER pathways.…”

Post‐ischemic salubrinal administration reduces necroptosis in a rat model of global cerebral ischemia

“…Previous studies allow us to estimate that we could detect changes at p ≤ 0.05 level with a statistical power of ≥ 80% with n ≥ 5 rats/ group (Llorerente et al ; Llorerente et al ; Anuncibay‐Soto et al ; Ugidos et al ; Anuncibay‐Soto et al ). Thus, prior to experimental procedure, the number of animals to be used in each group was established in five.…”

“…Salubrinal is a small chemical molecule which inhibits the dephosphorylation of the eukaryotic translation initiation factor 2 subunit α (eIF2α), thus inhibiting general protein translation and enhancing the UPR, therefore decreasing ER stress (Boyce et al ). The administration of salubrinal pre‐ischemically (Nakka et al ) and post‐ischemically (Anuncibay‐Soto et al ,) has been proved to have a neuroprotective role.…”

Integrated Stress Response as a Therapeutic Target for CNS Injuries

“…Salubrinal has neuroprotective effects in animal models of CNS injury, such as a rat brain excitotoxicity [43], cerebral ischemia/reperfusion [44, 45], and chronic intermittent hypoxia [46]. It is neuroprotective also in mouse models of sleep apnea [47], traumatic brain injury [48, 49], and cortical stab injury [50].…”

“…Moreover, salubrinal protects oligodendrocytes, reducing demyelination and improving functional recovery after spinal cord injury [51]. The prosurvival effects of salubrinal after CNS injury are mediated by decreasing the ER stress response [43, 45, 48–50]. Limiting energy consumption is achieved under pathological conditions by diminishing ER protein overload [52].…”