NAD+ vs PE-22-28

Metabolic

Cognitive

Research Only

Research Only

NAD+ functions as a primary electron carrier in glycolysis, the TCA cycle, and oxidative phosphorylation. Beyond its redox role, NAD+ serves as a consumable substrate for sirtuin deacetylases (SIRT1-7), poly(ADP-ribose) polymerases (PARPs), and CD38/CD157 ectoenzymes. Sirtuin activation is linked to mitochondrial biogenesis, autophagy, and stress-response gene expression, and PARP activity is central to DNA-damage repair. Oral bioavailability of intact NAD+ is poor, which is why clinics market IV infusion; the best human data for raising tissue NAD+ involve oral precursors NR (nicotinamide riboside) and NMN (nicotinamide mononucleotide) rather than NAD+ itself.

PE-22-28 is a highly selective antagonist of the TREK-1 (KCNK2) two-pore-domain potassium channel, with reported in vitro IC50 near 0.12 nM — roughly 300–500× more potent than the parent spadin peptide (IC50 ~40–60 nM). TREK-1 is enriched in serotonergic neurons of the dorsal raphe nucleus; blocking it depolarizes these neurons and enhances 5-HT transmission to limbic targets. In rodents, TREK-1 blockade also increases hippocampal neurogenesis and synaptic markers (PSD-95, BDNF), which is hypothesized to underlie its rapid-onset antidepressant signature.

Short in rodents; modified G/A-PE 22-28 analog extended to ~21–23 hours