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Punicalagin Activates AMPK/PGC-1α/Nrf2 Cascade in Mice: The Potential Protective Effect against Prenatal Stress
Ke Cao1, Weiqiang Lv1, Shaoqin Hu1
1Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, 710049, China.
Insights
Prenatal stress impairs offspring learning and memory by reducing AMP-activated protein kinase (AMPK) activity. Pomegranate extract (Punicalagin) may counteract these effects, offering a potential maternal nutritional intervention.
Area of Science:
- Neuroscience
- Developmental Biology
- Biochemistry
Background:
- Prenatal stress is linked to adverse offspring health outcomes.
- Mechanisms and interventions for prenatal stress effects are not well-established.
Purpose of the Study:
- To investigate the impact of prenatal restraint stress (PRS) on offspring health.
- To explore the role of AMP-activated protein kinase (AMPK) in PRS-induced deficits.
- To evaluate Punicalagin (PU) as a potential intervention.
Main Methods:
- Rat offspring exposed to PRS were assessed for spatial learning and memory.
- AMPK activity, mitochondrial biogenesis, and antioxidant pathways were analyzed in hippocampus and other tissues.
- In vitro studies used HT22 and primary hippocampal neurons to assess PU effects on AMPK and cell viability.
- In vivo studies administered PU to mice.
Main Results:
- Prenatal stress led to impaired spatial learning and memory in offspring.
- PRS reduced AMPK activity and mitochondrial/antioxidant pathway proteins in the hippocampus and systemically.
- Increased maternal glucocorticoids may contribute to systemic AMPK deficiency.
- Punicalagin activated AMPK, induced mitochondrial biogenesis, and protected neurons from glutamate toxicity.
- PU administration activated AMPK in mice.
Conclusions:
- Systemic AMPK deficiency is a key factor in poor outcomes associated with prenatal stress.
- Punicalagin shows potential as an effective maternal nutritional intervention to mitigate PRS effects.
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.
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