Endogenous histidine peptides are physiological antioxidants that prevent oligodendrocyte cell death and myelin loss in vivo.

Histidine dipeptides (HDs) are synthesized in brain oligodendrocytes by carnosine synthase (carns1), but their role is unknown. Using metabolomics and in vivo experiments with both constitutive and oligodendrocyte-selective carns1-KO mouse models, we found that HDs are critical for oligodendrocyte survival and protect against oxidative stress. Carns1-KO mouse models had lower numbers of mature oligodendrocytes, increased lipid peroxidation, and behavioral changes.