The diving reflex elicits potent, non-electrophilic Nrf2 activation via trigeminal CGRP signaling.

Activation of nuclear factor erythroid 2-related factor 2 (Nrf2) is a powerful neuroprotective strategy, yet clinical translation to conditions of high stress remains limited by the paradoxical depletion of glutathione and increase of reactive oxygen species observed with conventional electrophilic activation. Here, we identify the diving reflex (DR) as a potent, non-electrophilic physiological activator of Nrf2 in the brain that circumvents this potential liability. Using a validated voluntary diving model in rats with acute (single session) and chronic (4-week) paradigms, we show that DR triggers calcitonin gene-related peptide (CGRP) release from trigeminal afferents, which engages parallel KEAP1-dependent (p62/Ser351-mediated autophagic degradation) and KEAP1-independent (AMPK/SIRT1/PI3K) signaling cascades to drive Nrf2 nuclear translocation and phosphorylation across multiple brain regions. Anti-CGRP antibody blockade abolished these effects, establishing CGRP as the essential upstream mediator. Unbiased proteomic profiling of 2388 brain proteins confirmed upregulation of Nrf2-regulated antioxidant enzymes with concurrent downregulation of oxidative stress markers. Critically, DR preserved cellular glutathione pools, elevated the GSH/GSSG ratio, and suppressed lipid peroxidation and protein nitration, a redox-sparing profile divergent from electrophilic activation. DR also exhibited a unique biphasic response: acute exposure produced rapid transcriptional upregulation of antioxidant genes, while chronic exposure generated a sustained extranuclear reserve of phosphorylated Nrf2, conferring long-term resilience. In a vascular dementia model of chronic cerebral hypoperfusion, chronic DR rescued hippocampal Nrf2 depletion, restored glutathione homeostasis, and preserved working memory. These findings establish the DR-CGRP-Nrf2 axis as a druggable, non-electrophilic pathway for neuroprotection that achieves pharmacological-level potency without redox compromise.