Parkinson’s disease (PD) is the second most common neurodegenerative disorder presenting with motor deficits such as tremors, rigidity and postural instability. The majority of PD cases are idiopathic, and epidemiological evidence implicates environmental toxins in PD onset and progression as well as highlighting the occurrence of non-motor symptoms such as gastrointestinal (GI) deficits preceding the motor symptoms by decades. Previous work from our lab has described a novel environmental model of parkinsonism in rats that results from oral administration of subthreshold doses of paraquat (P) and lectin (L). This “bottom-up” (i.e., gut-brain) model results in synucleinopathy that is transported from the gut to the brainstem via the efferent vagus nerve, and then to the SNpc where it induces neuronal loss and motor deficits. Many of the core pathophysiological processes of PD overlap with those implicated in type 2 diabetes (T2DM), which is associated with increased PD risk and more severe symptoms. GLP-1 receptor agonists (GLP-1RAs), FDA-approved for treating T2DM, act as multi-system neuroprotective drugs, targeting common pathways of oxidative stress, inflammation, and metabolic dysfunction in neurodegeneration. In toxin-based and genetic preclinical PD models, GLP-1RAs were shown to preserve dopaminergic neurons in the SNpc and motor function, as well as improving autophagy and preserving mitochondrial function. This study aimed to assess the efficacy of chronic semaglutide treatment in our body-first environmental model of parkinsonism and test the hypothesis that it delays the progression of motor deficits and preserves dopaminergic neurons in the SNpc.Male Sprague-Dawley rats were orally gavaged with P+L (1.5mg/kg and 0.75mg/kg, respectively, in 10% sucrose; N=7) for 7 days. At 4 weeks post-gavage, rats received daily intraperitoneal (i.p.) semaglutide (0.3ug/kg; N=2) or saline (N=1) daily for 4 weeks with further 4 rats (N=2 for semaglutide, N=2 for vehicle) kept receiving the treatment for 8 weeks. Progression of motor deficits was tested weekly with stepping and vibrissae tests. While P+L rats that received semaglutide did not show physiologically significant reductions in their food intake and bodyweight they showed significantly fewer motor deficits compared to P+L saline injected rats (unpaired t test, p=0.0012; N=4 for semaglutide, N=3 for saline; p< 0.05). At 4 or 8 weeks post-treatment, rats were perfused fixed and 50µm midbrain sections containing the SNpc were processed for immunohistochemical localization of tyrosine hydroxylase (TH) and phosphorylated α-synuclein aggregates. Unbiased stereological counting of SNpc dopaminergic neurons in the SNpc showed a trend towards neuronal loss in control vs semaglutide treated rats after 4 weeks of treatment (mean = 1834.11 vs 2063.19 neurons). Similarly, after 8 weeks of treatment, the number of SNpc dopaminergic neurons was lower in control vs semaglutide treated rats (mean = 1371.74 vs 1901.63 neurons).This data suggests that in our body-first environmental model of parkinsonism, semaglutide slows the progression of motor deficits associated with preservation of dopaminergic SNpc neurons. As our preliminary data also has shown that GLP-1 receptors are expressed on astrocytes as well as dopaminergic neurons in the SNpc, further research is needed to elaborate the mechanism through which semaglutide exerts its beneficial effects. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
YALÇIN et al. (Fri,) studied this question.