Neuroprotective Effects Of Sotagliflozin In A Rotenone-Induced Zebrafish Model Of Parkinson’s Disease

Abstract

Background and Objectives: In this study, we investigated the neuroprotective potential of sotagliflozin, a dual SGLT1/2 inhibitor (SGLT1/2i), in a rotenone-induced zebrafish model of Parkinson’s disease (PD). Rotenone, a mitochondrial complex I inhibitor, induces dopaminergic neuronal loss and replicates pathological features related to PD, including oxidative stress and neuroinflammation. As SGLT2 inhibitors have been reported to provide neuroprotection by reducing oxidative stress and inflammation, this study aimed to assess the efficacy of sotagliflozin in mitigating neurodegenerative changes and behavioral impairments related to PD in zebrafish.

Materials and Methods: Zebrafish embryos were initially subjected to acute toxicity tests using various concentrations of sotagliflozin to determine the safe and effective dose range. Adult wild zebrafish were subjected to 5 µg/L ROT to induce PD-like symptoms and subsequently treated with sotagliflozin at 4, 8, and 16 mg/L. A positive control group received levodopa (25 mg/L) and carbidopa (2.5 mg/L). Behavioural assessments, markers of oxidative stress, antioxidant enzyme levels, peroxidation of lipid, acetylcholinesterase (AChE) levels, apoptosis- related gene expression (BAX and BCL2), and brain histopathology were evaluated in the study.

Results: Toxicity assessments revealed that higher concentrations of sotagliflozin 32mg/L led to significant developmental impairments, including delayed hatching and morphological abnormalities in zebrafish embryos. In contrast, in adult zebrafish with rotenone-induced PD, sotagliflozin, particularly at 16 mg/L exerted pronounced neuroprotective effects. This high dose also significantly reduced oxidative stress, enhanced catalase and superoxide dismutase activity, restored glutathione levels, and lowered lipid peroxidation. AChE activity was improved, indicating better neurotransmitter function. Histological analysis showed reduced inflammation, edema, and cellular damage in the brain. Furthermore, sotagliflozin modulated the expression of apoptosis-related genes by reducing BAX and increasing BCL2 expression.

Conclusion: Sotagliflozin (16 mg/L) exhibited neuroprotective effects in a zebrafish model of PD by improving motor function, reducing oxidative stress, and modulating apoptotic pathways. These findings highlight the therapeutic potential of SGLT2 inhibitors in neurodegenerative conditions such as Parkinson’s disease, supporting their role beyond glycemic control.