The enhanced Wnt/β-catenin pathway upregulation by sacubitril/valsartan via neprilysin inhibition compared to valsartan in the rotenone induced Parkinson's disease rat model.

Parkinson's disease (PD), the second most common neurodegenerative disorder, is characterized by the progressive loss of dopaminergic neurons in the basal ganglia, particularly in the substantia nigra, and the accumulation of α-synuclein into Lewy bodies. Recently, the WNT/β-catenin signaling pathway has emerged as a potential neuroprotective mechanism in PD, activated by natriuretic peptides (NPs) such as ANP, BNP, and CNP. Sacubitril/valsartan (SAC/VAL) is an FDA-approved medication for chronic heart failure. SAC contains neprilysin inhibition, while VAL is an angiotensin receptor blocker used to treat hypertension. This study aimed to determine whether SAC/VAL could activate the WNT/β-catenin pathway by increasing NP levels. To isolate the effect of SAC, VAL was administered separately. Male Wistar rats were injected with 2 mg/kg rotenone subcutaneously (S.C.) for 35 days to induce a PD-like model. VAL and SAC/VAL were administered orally at 20 mg/kg/day and 40 mg/kg/day, respectively, one week before rotenone treatment for six weeks. SAC/VAL was more effective than VAL in reducing rotenone-induced behavioral deficits, mitigating dopaminergic injury, normalizing dopamine (DA), tyrosine hydroxylase (TH), and NP levels, and activating the WNT/β-catenin pathway. SAC/VAL also suppressed oxidative stress and neuroinflammation. In conclusion, SAC/VAL exhibited greater neuroprotection against PD-induced neurodegeneration than VAL, likely due to neprilysin inhibition by the SAC component, which activates the WNT/β-catenin pathway.