An Innate Neuroprotective Reflex Activates NRF2 via Phosphorylation of p62 at Ser351 to Mitigate Traumatic Brain Injury

In a rat model of severe traumatic brain injury, trigeminal nerve stimulation–evoked diving reflex protects the brain by selectively phosphorylating p62 at Ser351, unlike dimethyl fumarate.

• Why it matters: Direct antioxidant therapies have been therapeutically intractable in TBI, and it is unclear whether NRF2 activation can work when antioxidant reserves are already depleted.
• What they did: Rats with severe TBI were compared across trigeminal nerve stimulation–induced diving reflex, natural diving reflex, exogenous CGRP, and the electrophilic NRF2 activator dimethyl fumarate, with p62 phosphorylation at Ser351 versus Ser403 measured alongside redox status, lesion volume, and functional outcomes.
• The result: The non-electrophilic pathway preserved glutathione reserves, halted lipid peroxidation, and reduced chronic lesion volume with multi-domain recovery, whereas dimethyl fumarate further reduced glutathione and increased lipid peroxidation.

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