The Impact of Salubrinal in Preventing Fetal Brain Damage in a Model of Chorioamnionitis Induced by LPS

Abstract

Objective: Chorioamnionitis (CRY), with membrane rupture, preterm labor, prolonged labor, smoking, and bacterial or viral infection origin; is a condition that presents a risk for both maternal and neonatal sequelae. Our study aimed to investigate the effect of Salubrinal (SLB), an endoplasmic reticulum (ER) stress inhibitor, against damage to placental tissue and fetal brain in the Lipopolysaccharide (LPS) induced CRY model. Material and Method: In this study, 24 Wistar Albino rats on the 17th gestational day; were divided into 4 groups; control, LPS (1 mg/kg intraperitoneal (ip)), LPS + SLB (1 mg/kg LPS ip and 1 mg/kg SLB ip) and SLB (1 mg/kg ip). After an experimental hysterectomy, the placenta and fetal brain tissues were taken into formaldehyde solution for histopathological analysis. Results: According to the findings obtained; widespread congestion in the basal zone, degeneration of trophoblastic cells in the labyrinth zone, and inflammatory cell infiltrations in both basal and labyrinth zones were observed in the placental tissues of the LPS group. No pathology was detected in only the SLB group. While edema and congestion were detected in the ventricular and intermediate zones in the fetal brain tissues of the LPS group, a significant improvement was observed in these findings with SLB treatment. Conclusion: As a result; ER stress is one of the mechanisms that play a role in placental tissue and fetal brain damage due to CRY, and SLB therapy might prevent this damage.

Keywords

• Chorioamnionitis
• Endoplasmic reticulum stress
• Lipopolysaccharide
• Salubrinal

References

1. 1. Dicanio D, Spoto G, Alibrandi A, Minutoli R, Nicotera AG, Di Rosa G. Long-Term Predictivity of Early Neurological Assessment and Developmental Trajectories in Low-Risk Preterm Infants. Front Neurol 2022;13. doi: 10.3389/fneur.2022.958682.
2. 2. Ophelders DRMG, Gussenhoven R, Klein L, Jellema RK, Westerlaken RJJ, Hütten MC, Vermeulen J, Wassink G, Gunn AJ, Wolfs TGAM. Preterm Brain Injury, Antenatal Triggers, and Therapeutics: Timing Is Key. Cells 2020.
3. 3. Christiaens I, Zaragoza DB, Guilbert L, Robertson SA, Mitchell BF, Olson DM. Inflammatory Processes in Preterm and Term Parturition. J Reprod Immunol 2008.
4. 4. Elliott CL, Loudon JAZ, Brown N, Slater DM, Bennett PR, Sullivan MHF. IL-1β and IL-8 in Human Fetal Membranes: Changes with Gestational Age, Labor, and Culture Conditions. American Journal of Reproductive Immunology 2001;46. doi: 10.1034/j.1600-0897.2001.d01-11.x.
5. 5. Shi Z, Ma L, Luo K, Bajaj M, Chawla S, Natarajan G, Hagberg H, Tan S. Chorioamnionitis in the Development of Cerebral Palsy: A Meta-Analysis and Systematic Review. Pediatrics 2017.
6. 6. Bo Hyun Yoon, Jong Kwan Jun, Romero R, Kyo Hoon Park, Gomez R, Choi H, Kim IO. Amniotic Fluid Inflammatory Cytokines (interleukin-6, interleukin-1β, and tumor necrosis factor-α), Neonatal Brain White Matter Lesions, and Cerebral Palsy. Am J Obstet Gynecol 1997;177. doi: 10.1016/S0002-9378(97)70432-0.
7. 7. Wang X, Rousset CI, Hagberg H, Mallard C. Lipopolysaccharide-Induced Inflammation and Perinatal Brain Injury. Semin Fetal Neonatal Med 2006;11. doi: 10.1016/j.siny.2006.04.002.
8. 8. Lemberg MK, Strisovsky K. Maintenance of Organellar Protein Homeostasis by ER-Associated Degradation and Related Mechanisms. Mol Cell 2021.

9. 9. Wodrich APK, Scott AW, Shukla AK, Harris BT, Giniger E. The Unfolded Protein Responses in Health, Aging, and Neurodegeneration: Recent Advances and Future Considerations. Front Mol Neurosci 2022.
10. 10. Lu W, Ni K, Li Z, Xiao L, Li Y, Jiang Y, Zhang J, Shi H. Salubrinal Protects Against Cisplatin-Induced Cochlear Hair Cell Endoplasmic Reticulum Stress by Regulating Eukaryotic Translation Initiation Factor 2α Signalling. Front Mol Neurosci 2022;15. doi: 10.3389/fnmol.2022.916458.
11. 11. Matsuoka M, Komoike Y. Experimental Evidence Shows Salubrinal, an eIF2α Dephosphorylation Inhibitor, Reduces Xenotoxicant-Induced Cellular Damage. Int J Mol Sci 2015.
12. 12. Yavuz A, Sezik M, Ozmen O, Asci H. Fingolimod Against Endotoxin-Induced Fetal Brain Injury in a Rat Model. Journal of Obstetrics and Gynaecology Research 2017;43. doi: 10.1111/jog.13444.
13. 13. Wang Z feng, Gao C, Chen W, Gao Y, Wang H chen, Meng Y, Luo C liang, Zhang M yang, Chen G, Chen X ping, et al. Salubrinal Offers Neuroprotection Through Suppressing Endoplasmic Reticulum Stress, Autophagy, and Apoptosis in a Mouse Traumatic Brain Injury Model. Neurobiol Learn Mem 2019;161. doi: 10.1016/j.nlm.2019.03.002.
14. 14. Song IG. Neurodevelopmental Outcomes of Preterm Infants. Clin Exp Pediatr 2023. 15. Karakuyu NF, Özmen Ö. Dekspantenol, Sıçanlarda LPS’nin Neden Olduğu Akut Akciğer Hasarında Artan VCAM-1 ve Kaspaz-3 Ekspresyonlarını Azaltarak İnflamasyonu ve Apoptozu İnhibe Eder. Kocatepe Veterinary Journal 2022; doi: 10.30607/kvj.1101065.
15. 16. Bao J, Liu Y, Yang J, Gao Q, Shi SQ, Garfield RE, Liu H. Nicotine Inhibits LPS-Induced Cytokine Production and Leukocyte Infiltration in rat Placenta. Placenta 2016;39. doi: 10.1016/j.placenta.2016.01.015.
16. 17. Yavuz A, Sezik M, Eris Yalcin S, Asci H, Ozmen O. Immunohistochemical Analysis of Protective Effects of Maternal Fingolimod on the Placenta and Fetal Lung and Brain in Chorioamnionitis-Induced Preterm Birth Rat Model. Immunopharmacol Immunotoxicol 2020;42. doi: 10.1080/08923973.2020.1818771.
17. 18. Moradi Vastegani S, Hajipour S, Sarkaki A, Basir Z, Parisa Navabi S, Farbood Y, Khoshnam SE. Curcumin Mitigates Lipopolysaccharide-Induced Anxiety/Depression-Like Behaviors, Blood–Brain Barrier Dysfunction, and Brain Edema by Decreasing Cerebral Oxidative Stress in Male Rats. Neurosci Lett 2022;782. doi: 10.1016/j.neulet.2022.136697.
18. 19. Ohri SS, Hetman M, Whittemore SR. Restoring Endoplasmic Reticulum Homeostasis Improves Functional Recovery After Spinal Cord Injury. Neurobiol Dis 2013;58. doi: 10.1016/j.nbd.2013.04.021.
19. 20. Rubovitch V, Barak S, Rachmany L, Goldstein RB, Zilberstein Y, Pick CG. The Neuroprotective Effect of Salubrinal in a Mouse Model of Traumatic Brain Injury. Neuromolecular Med 2015;17. doi: 10.1007/s12017-015-8340-3.
20. 21. Anuncibay-Soto B, Pérez-Rodríguez D, Santos-Galdiano M, Font E, Regueiro-Purriños M, Fernández-López A. Post-Ischemic Salubrinal Treatment Results in a Neuroprotective Role in Global Cerebral Ischemia. J Neurochem 2016; doi: 10.1111/jnc.13651.