Scopolamine Prevents Mitochondrial Dysfunction in Depressive Disorder, Potentially via Its Anti-Inflammatory Effects.

Background: Depression imposes a heavy global disease burden accompanied by mitochondrial injury and neuroinflammation predominantly in the prefrontal cortex. Using a chronic unpredictable mild stress (CUMS) rat model, this study aimed to explore the impacts of scopolamine on brain mitochondrial function and its underlying mechanisms. Methods: Twelve male Wistar rats aged 6-8 weeks were randomly assigned to three groups: control, CUMS, and CUMS+scopolamine. Rats received 4 weeks of corresponding treatments, followed by behavioral tests to assess depression-like phenotypes. Transmission electron microscopy (TEM) was used to observe neuronal and mitochondrial morphological alterations in the prefrontal cortex. Quantitative PCR was performed on whole-brain homogenates to detect expression of PGC-1α, Drp1, MFF, mfn2 and GPX4. Western blot and ELISA were further adopted to probe associated inflammatory signaling pathways. Results: Scopolamine alleviated CUMS-induced mitochondrial ultrastructural damage in the prefrontal cortex. PCR results demonstrated that scopolamine reversed stress-triggered upregulation of PGC-1α, Drp1 and MFF as well as downregulation of mfn2, while elevating the level of anti-ferroptotic GPX4. Additionally, Western blot and ELISA data indicated that scopolamine was associated with suppressed NF-κB activation and reduced concentration of pro-inflammatory IL-6. Conclusion: Scopolamine safeguards brain mitochondrial structure and homeostasis in depressive rats, manifested as normalized expression of PGC-1α, Drp1, MFF, mfn2 and GPX4. Such protective effects may be correlated with scopolamine's anti-inflammatory capacity (downregulation of IL-6) via NF-κB pathway suppression. This study bears several important limitations that constrain the robustness of our mechanistic conclusions. Future investigations with larger sample sizes, as well as animal models employing NF‑κB‑specific inhibitor intervention or NF‑κB gene knockout, are therefore warranted.