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Parkinson's disease (PD) is a neurodegenerative condition characterized by the progressive loss of dopamine-producing neurons in the substantia nigra pars compacta, which results in severe motor impairments. While the precise cause of PD remains unknown, research indicates that factors such as oxidative stress, mitochondrial dysfunction, and the triggering of apoptotic pathways play key roles in the degeneration of these neurons. Current treatments focus on stabilizing dopamine levels but do not halt disease progression. Therefore, exploring compounds that can mitigate apoptotic neuronal loss is promising for therapy. Chrysoeriol, a 3’-O-methoxy flavone and luteolin derivative, is known for its anti-cancer, anti-diabetic, antioxidant, anti-inflammatory, and neuroprotective properties. Despite extensive research, its effect on PD mouse models is still unclear. This study examines the neuroprotective effects of 5 mg/kg of Chrysoeriol administered intraperitoneally for 14 days in an in vivo sub-acute PD model, established using 20 mg/kg MPTP administered via intraperitoneal injections at two-hour intervals for a total of four doses in one day. Behavioral tests, including the Pole test, Y-maze test, forced swim test, and tail suspension test, showed significant recovery from PD-induced neurological deficits in Chrysoeriol-treated mice. Hematoxylin and Eosin staining confirmed reduced neuronal damage in Chrysoeriol-treated mice in different areas of the brain, including the midbrain, cerebellum, cortex, and hippocampus. qPCR analysis was used to detect the relative expression of α-Synuclein, Bcl-2 (anti-apoptotic) and Bax (pro-apoptotic) proteins. The levels of α-synuclein, a major protein implicated in PD pathology, were significantly downregulated in the treatment group compared to the diseased group, indicating that Chrysoeriol plays a role in the downregulation of α-synuclein. Moreover, in the diseased group, Bax levels were up-regulated, and Bcl-2 levels were downregulated, reducing the Bcl-2/Bax ratio. Chrysoeriol treatment significantly reversed this downregulation. Our results demonstrated that Chrysoeriol treatment significantly reduced MPP+- induced toxicity, downregulated α-synuclein expression levels, and improved Bcl-2/Bax ratio expression levels in in vivo mouse models. Our research indicates that Chrysoeriol offers protection against MPP+-induced apoptosis in mice by activating the PI3K/Akt signaling pathway. This finding suggests that Chrysoeriol could be a promising therapeutic option for PD.