Semaglutide is Neuroprotective and Reduces α-Synuclein Levels in the Chronic MPTP Mouse Model of Parkinson's Disease

Parkinson's disease (PD) is a progressive neurological motor control disorder. A key feature is the loss of midbrain dopaminergic neurons and the accumulation of aggregated alpha-synuclein (alpha-syn). No current treatment is on the market that slows or halts disease progression. Previous studies have shown that glucagon-like peptide-1 (GLP-1) receptor agonists have neuroprotective effects in animal models of PD. In addition, in a phase II clinical trial, the GLP-1 receptor agonist exendin-4 has shown good protective effects in PD patients. In the present study, we have investigated the neuroprotective effects of the GLP-1 analogues semaglutide (25 nmol/kg ip. once every two days for 30 days) and liraglutide (25 nmol/kg ip. once daily for 30 days) in the chronic MPTP mouse model of PD. Both drugs are currently on the market as a treatment for Type II diabetes. Our results show that both semaglutide and liraglutide improved MPTP-induced motor impairments. In addition, both drugs rescued the decrease of tyrosine hydroxylase (TH) levels, reduced the accumulation of alpha-syn, alleviated the chronic inflammation response in the brain, reduced lipid peroxidation, and inhibited the mitochondrial mitophagy signaling pathway, and furthermore increased expression of the key growth factor GDNF that protects dopaminergic neurons in the substantia nigra (SN) and striatum. Moreover, the long-acting GLP-1 analogue semaglutide was more potent compared with once daily liraglutide in most parameters measured in this study. Our results demonstrate that semaglutide may be a promising treatment for PD. A clinical trial testing semaglutide in PD patients will start shortly.