Parthenolide Exerts Protection against Hypoxic-Ischemic Brain Damage in Neonatal Rats by Inhibiting Perk-Mediated Endoplasmic Reticulum Stress.

Perinatal hypoxia causes hypoxic-ischemic brain damage (HIBD), which can result in neurological sequelae of varying severity. This syndrome is a major cause of neonatal mortality and pediatric impairment. Although research is ongoing to better understand its origins and develop targeted treatments, endoplasmic reticulum stress (ERS)-mediated apoptosis via the unfolded protein response (UPR) is crucial for the progression of cerebral ischemia injury. Parthenolide (PN), a sesquiterpene lactone derived from the Asteraceae family, exhibits anti-inflammatory, anti-apoptotic, and antioxidant properties that are beneficial in treating central nervous system disorders. To investigate the role of PN in HIBD and its underlying mechanism. In vivo and in vitro experiments were conducted to observe apoptosis and endoplasmic reticulum (ER) hyperactivation in HIBD, followed by a comparison of the neuroprotective effects of PN through modulation of the protein kinase Ribonucleic Acid-like ER kinase (Perk) pathway of ER stress. An in vivo model of HIBD was established using postnatal day 7 rat pups exposed to hypoxia for 2 h after left common carotid artery ligation. The in vitro model involved rat brain astrocyte cells that were depleted of glucose and oxygen for 7 h. Perfusion imaging and 2,3,5-triphenyltetrazolium chloride staining were used to visualize cerebral edema and infarction in HIBD brain tissue. Nissl staining and other histological techniques were used to detect nerve cell loss and destruction in damaged areas. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and CCAAT/enhancer binding protein‌-homologous protein (CHOP) staining were used to localize sites with high expression of apoptosis-positive cells in the liver. Real-time quantitative polymerase chain reaction and Western blotting were used to observe apoptosis and pathway markers at the transcriptional and translational levels, respectively. Behavioral tests were conducted to evaluate the motor and memory abilities of rats over time. In this study, we observed that phosphorylated Perk/Perk (P-Perk/Perk), glucose-regulated protein-78, activating transcription factor 4 (ATF4), phosphorylated eukaryotic translation initiation factor 2α/eukaryotic translation initiation factor 2α (P-eIf2α/eIf2α), CHOP, and various apoptotic factors were significantly elevated in the cortex of rats with HIBD compared to normal rats. PN acts through the Perk pathway, regulating ERS and reducing apoptosis after HIBD in neonatal rat models. Our findings demonstrate that elevated P-Perk expression activates the UPR-mediated pathway and triggers apoptosis, thereby counteracting the protective effects of PN both in vivo and in vitro. Conversely, PN inhibits Perk and the Perk/eIf2α/ATF4/CHOP pathway, leading to reduced apoptosis and astrocyte activation in neonatal rats. This study highlights the preventive role of PN in HIBD by downregulating apoptotic expression, potentially through the modulation of the Perk/eIf2α/ATF4/CHOP pathway within the disease framework.