In conclusion, the behavioral, histological, cellular, and neurochemical findings of the current study support for the first time the role of MasR/PI3K/Akt/CREB/BDNF/TrKB pathway activation and iNOS inhibition in the neuroprotective effect of DAHP against neurotoxicity and mitochondrial dysfunction induced by 3-NP, thus, offering a new prospect for the possible role of BH4 inhibitors in HD. Here, NOS2 is linked to Huntington disease.