Parkinson's disease (PD) is a neurodegenerative disease characterized by motor and non-motor symptoms, often associated with the accumulation of α-synuclein, neuroinflammation and oxidative stress in the central and peripheral systems. Considering that patients with Parkinson's disease often have gastrointestinal symptoms, this study aimed to investigate whether a rotenone-induced rat model of PD can induce intestinal changes and the neuroprotective effects of a cannabidiol (CBDne) nanoemulsion formulation, focusing on the striatum and intestine. Wistar rats were divided into six groups: control, rotenone (2.75 mg/kg), CBDne (1.25 mg/kg) and rotenone, CBDne (2.5 mg/kg) and rotenone, CBDne (5.0 mg/kg) and rotenone and CBDne alone (1.25 mg/kg). Behavioral assessments, including open field, Y maze and novel object recognition tests, were performed to evaluate motor and cognitive functions. Biochemical, histological and immunohistochemical analyses were performed to assess markers of neuroinflammation, oxidative stress (iNOS, nNOS, nitrite levels, lipid peroxidation, glutathione content, GFAP, IBA1) and α-synuclein aggregation in the striatum and duodenum. The results showed that rotenone treatment significantly increased α-synuclein accumulation in both the striatum and duodenum, along with elevated levels of GFAP and IBA1, indicating elevated glial activation. In addition, rotenone significantly increased oxidative stress markers, including nitrite levels and lipid peroxidation in the prefrontal cortex, hippocampus and striatum. CBDne normalized these markers, returning them to control levels. In addition, rotenone caused a 38-47 % reduction in glutathione (GSH) content, with the most significant decrease in the striatum. CBDne effectively restored GSH levels to those of the control group. Behavioral improvements were observed in the CBDne-treated groups, along with attenuation of rotenone-induced weight loss. These findings suggest that CBDne exerts broad neuroprotective, anti-inflammatory and antioxidant effects, targeting central and peripheral α-synucleinopathies and oxidative damage. Its ability to modulate inflammation, oxidative stress and protein aggregation highlights its therapeutic potential for controlling the motor and non-motor symptoms of PD.
