In an MPTP mouse model of Parkinson's disease, intranasal balenine (a methylated, carnosine-resistant analog) improved object-location memory, preserved tyrosine hydroxylase-positive neurons, reduced GFAP-driven inflammation, and proteomics pointed to modulation of KEAP1–NFE2L2 (Nrf2), neddylation,…

The study presents a brain-targetable, degradation-resistant antioxidant/anti-inflammatory compound with translational potential (intranasal delivery and Nrf2-related mechanism) that could be advanced for neuroprotective PD strategies, though validation in alpha-synuclein models and…

Carnosine, an imidazole dipeptide, has potential for treating neurodegenerative diseases, including Parkinson's disease. However, carnosine-degrading enzymes limit its bioavailability. In this study, we established a mouse model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-induced Parkinson's disease and intranasally administered balenine, a carnosine analog featuring a methylated imidazole that is resistant to degradation enzymes, to target the brain via the olfactory epithelium. MPTP + balenine-treated mice demonstrated improved recognition scores in the object location test. They also exhibited a significantly increased tyrosine hydroxylase-positive cells and reduced expression of glial fibrillary acidic protein, an inflammatory marker, indicating that balenine mitigated neurodegenerative damage and inflammation in mice with MPTP-induced Parkinson's disease. Proteomic analysis revealed that activation of the KEAP1-NFE2L2 pathway, neddylation, and GSK3B and BTRC:CUL1-mediated degradation of NFE2L2. Collectively, these results highlight the efficacy of intranasal drops of balenine in Parkinson's disease and their potential to improve neurodegenerative disease prognosis.