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Published on: March 15, 2024
PFGA12 ameliorates Hypoxic-Ischemic brain injury by directly regulating PRDX1 and inhibiting ferroptosis
Haocong Chen1, Jing Zhao2, Yu Kang1
1Department of Anesthesiology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 1111 XianXia Road, Shanghai 200336, China.
Insights
PFGA12 peptide protects against hypoxic-ischemic brain damage (HIBD) by targeting PRDX1. This peptide enhances neuronal survival, reduces brain injury, and improves cognitive function in HIBD models.
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Hypoxic-ischemic brain damage (HIBD) causes significant neuronal loss and functional deficits, posing a major challenge in neonatal care.
- Fibrinogen alpha chain (FGA)-derived peptide PFGA12 is downregulated in infants with hypoxic-ischemic encephalopathy (HIE).
Purpose of the Study:
- To investigate the neuroprotective potential of PFGA12 in HIBD.
- To elucidate the molecular mechanisms underlying PFGA12's therapeutic effects.
Main Methods:
- In vitro studies using oxygen-glucose deprivation/reperfusion (OGD/R) models on neuronal cells.
- In vivo studies using a rat model of HIBD.
- Y-maze tests for cognitive assessment.
- Western blotting and co-immunoprecipitation to analyze protein interactions and modifications.
Main Results:
- PFGA12 treatment significantly enhanced neuronal viability and reduced OGD/R-induced cell death.
- In HIBD rats, PFGA12 alleviated cerebral edema, reduced infarct volume, and attenuated neuronal damage.
- PFGA12 inhibited microglial and astrocyte activation, reducing neuroinflammation and improving spatial learning and memory.
- PFGA12 directly binds to peroxiredoxin-1 (PRDX1), inhibiting its phosphorylation and enhancing its antioxidant activity, thereby reducing ferroptosis.
Conclusions:
- PFGA12 demonstrates significant neuroprotective effects against HIBD.
- PFGA12 acts by targeting PRDX1, enhancing its antioxidant function and inhibiting ferroptosis.
- PFGA12 holds promise as a novel therapeutic agent for HIBD.
Abstract:
Hypoxic-ischemic brain damage (HIBD) is a severe condition leading to extensive neuronal loss and functional impairments, representing a significant challenge in neonatal care. PFGA12, a peptide derived from fibrinogen alpha chain (FGA), which is notably downregulated in the umbilical cord blood of hypoxic-ischemic encephalopathy (HIE) infants. We demonstrate that PFGA12 significantly enhances cell viability and mitigates oxygen-glucose deprivation/reperfusion (OGD/R)-induced neuronal cell death. PFGA12 treatment significantly alleviated cerebral edema, reduced infarct volume, and attenuated neuronal damage in HIBD rats, attributable to its stable presence within neurons. Additionally, PFGA12 attenuated neuroinflammation by inhibiting the activation of microglia and astrocytes. Moreover, Y-maze test demonstrated that PFGA12 effectively improved the spatial learning and memory abilities. Mechanistically, PFGA12 exerts potent neuroprotective effects by specifically targeting peroxiredoxin-1 (PRDX1). PFGA12 directly binds to PRDX1, effectively inhibiting phosphorylation at Tyr194 (p-PRDX1), thereby enhancing its peroxidase activity. This PRDX1-mediated antioxidant mechanism substantially reduces lipid reactive oxygen species (ROS) accumulation and provides protection against OGD/R-induced neuronal ferroptosis, as demonstrated by the upregulation of Glutathione peroxidase 4 (GPX4) and suppression of Acyl-CoA synthetase long-chain family member 4 (ACSL4). Notably, overexpression of PRDX1 mitigates ferroptotic damage induced by OGD/R, while knockdown of PRDX1 completely abolishes the protective effects of PFGA12 in OGD/R-treated HT22 cells, confirming PRDX1 as the critical molecular target through which PFGA12 inhibits ferroptosis. These results demonstrate that PFGA12, an active peptide, exhibits potential as a novel treatment option for HIBD.
