Orexin-A Mitigates Traumatic Brain Injury by Inhibiting Neuronal Ferroptosis Through Orexin Receptor 1/Nuclear Factor...

Area of Science:

• Neuroscience
• Cell Biology
• Pathology

Background:

• Traumatic brain injury (TBI) is a leading cause of neurological disability.
• Neuronal ferroptosis is a significant contributor to TBI-induced damage.
• The therapeutic mechanisms of orexin-A (OXA) in TBI are not fully understood.

Purpose of the Study:

• To investigate the neuroprotective mechanisms of OXA in TBI.
• To determine if OXA exerts its effects via the orexin receptor 1 (OX1R)/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway.
• To evaluate the role of OXA in mitigating ferroptosis and oxidative stress post-TBI.

Main Methods:

• Established rat TBI and PC12 cell ferroptosis models.
• Administered OXA and pathway inhibitors (OX1R, Nrf2).
• Assessed neurological function, blood-brain barrier integrity, neuronal damage, oxidative stress, and ferroptosis markers using various assays and molecular techniques.

Main Results:

• OXA administration significantly improved neurological function and reduced neuronal damage in TBI rats.
• OXA suppressed oxidative stress, inhibited ferroptosis markers, and promoted Nrf2 nuclear translocation.
• In vitro studies showed OXA protected PC12 cells from ferroptosis and mitochondrial damage.
• The neuroprotective effects of OXA were dependent on OX1R and Nrf2 activation.

Conclusions:

• OXA mitigates neurological deficits and neuronal ferroptosis following TBI.
• The mechanism involves the activation of the OX1R/Nrf2 signaling pathway.
• Targeting ferroptosis via OXA presents a novel therapeutic strategy for TBI management.