GHK Peptide Outperforms Carnosine in Neutralizing Toxic HNE Aldehyde

Alpha,beta-4-hydroxy-trans-2-nonenal (HNE) is a highly reactive and toxic aldehyde produced during lipid peroxidation, implicated in various oxidative stress-related diseases like neurodegeneration, cardiovascular disease, and inflammation. Its accumulation contributes significantly to cellular damage and disease progression. While antioxidants are known to mitigate HNE toxicity, the specific mechanisms and efficacy of natural peptides like Glycyl-histidyl-lysine (GHK) in directly neutralizing HNE, especially compared to other known quenchers like carnosine, remained underexplored at a molecular level.

Both GHK and carnosine reacted with HNE, forming stable adducts primarily through Michael addition and Schiff base formation, effectively neutralizing the toxic aldehyde. ESI-MS and 1H NMR data confirmed that GHK reacted with HNE at multiple sites, specifically the amino group of lysine and the imidazole nitrogen of histidine, forming stable covalent bonds. Carnosine primarily reacted via its amino group and imidazole nitrogen, similar to GHK, but with different stoichiometry. The study revealed that GHK demonstrated a significantly higher quenching capacity for HNE compared to carnosine, forming 2:1 and 3:1 (GHK:HNE) adducts, whereas carnosine mainly formed 1:1 adducts. This indicates GHK can neutralize more HNE molecules per peptide molecule than carnosine, suggesting superior efficiency in mitigating HNE-induced toxicity.