Although multiple mechanisms have been studied, there is still a lack of effective treatment on non-motor symptoms in Parkinson's disease (PD) patients. Therapeutic effects of 5-(4-hydroxy-3-dimethoxybenzylidene)-thiazolidinone (RD-1), one of rhodamine derivatives, on motor recovery have been previously demonstrated, but its effects on non-motor symptoms remain unclear. Herein, we explored the beneficial effects of RD-1 on PD-related non-motor symptoms and changes in synaptic plasticity in the mesencephalon. To investigate its therapeutic effects in the non-motor symptoms of Parkinsonian model, we employed male C57BL/6N mice and double injection with noradrenergic specific neurotoxin N-2-Chloroethyl-N-ethyl-2-bromobenzylamine hydrochloride, followed 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Next, we performed behavioral tests, histological analyses and immunoblotting. Our findings showed that RD-1 significantly alleviated locomotor abnormality, motor disturbance, anxiety/depression-like behavior and memory deficit. It rescued the levels of tyrosine hydroxylase in substantia nigra, and striatum. Moreover, RD-1 upregulated expression levels of α-synuclein, synapsin II, postsynaptic density 95 and vesicle-associated membrane protein 2. The restoration of synaptic function may underlie the neuroprotective effects of RD-1 in double lesioned mice, confirming its protective effect for dopaminergic neurodegeneration.Copyright © 2023. Published by Elsevier B.V.