Punicalagin Activates AMPK/PGC‐1α/Nrf2 Cascade in Mice: The Potential Protective Effect against Prenatal Stress

• Published in: Molecular nutrition & food research 2020-07, Vol.64 (14), p.e2000312-n/a
• Main Authors: Cao, Ke, Lv, Weiqiang, Hu, Shaoqin, Gao, Jing, Liu, Jiankang, Feng, Zhihui
• Format: Article
• Language: English
• Subjects: Activation; Adipose tissue; AMP; AMP‐activated protein kinase; Antioxidants; Biosynthesis; Cell viability; Deactivation; Glucocorticoids; Hippocampus; Kinases; Membrane potential; Mitochondria; mitochondrial biogenesis; Nrf2 pathway; Offspring; Prenatal experience; prenatal stress; Protein kinase; Proteins; punicalagin; Spatial discrimination learning; Spatial memory; Stress
• ISSN: 1613-4125; 1613-4133
• DOI: 10.1002/mnfr.202000312

Scope Prenatal stress is closely associated with poor health outcomes for offspring, yet the specific mechanisms and effective interventions remain limited. Methods and Results In the present study, both male and female rat offspring exposed to prenatal restraint stress (PRS) are confirmed to have impaired spatial learning and memory, accompanied by reduced AMP‐activated protein kinase (AMPK) activity and decreased protein expression of mitochondrial biogenesis and antioxidant pathways in the hippocampus. Interestingly, a deficiency in the AMPK cascade also occurs in liver, heart, and adipose tissues, suggesting that the systemic deactivation of AMPK in the offspring is potentially attributed to increased maternal glucocorticoid levels under PRS. Punicalagin (PU), a major ellagitannin in pomegranate, is found to effectively induce mitochondrial biogenesis and phase II enzymes through activation of AMPK in both HT22 and primary hippocampal neurons, thereby inhibiting glutamate‐induced cell viability and mitochondrial membrane potential loss. Meanwhile, the activation of AMPK cascade is also confirmed in mice administrated with PU for three days. Conclusions Altogether, these results indicate that the systemic deficiency of the AMPK cascade can be the key factor that contributes to poor outcomes of PRS, and PU may be used as an effective maternal nutritional intervention. Punicalagin can induce PGC‐1α mediated mitochondrial biogenesis and Nrf2‐mediated phase II enzymes expression in hippocampal neurons through activating the AMPK signal, which is found to be significantly suppressed in multiple tissues of the prenatal stressed offspring. The study indicates that punicalagin can be an effective nutrient preventing prenatal‐stress‐induced offspring development disorders, including cognitive dysfunction.