LPS‑induced impairment of neuroregeneration is alleviated by fluoxetine in Dugesia japonica.

Freshwater planarians (Dugesia japonica) are excellent models for neural regeneration due to their neoblast-dependent regenerative capacity. This study explored the regulatory effects of fluoxetine (FLX) on lipopolysaccharide (LPS)-triggered neuroinflammation as well as cyclosporin A (CsA)-mediated mitophagy inhibition during the regeneration of Dugesia japonica. Planarians were exposed to LPS, FLX, and CsA alone or in combination for 10 days, with assessments of regeneration, locomotion, antioxidant function, DNA damage, neoblast proliferation, apoptosis, and PINK1/Parkin pathway activity. Results showed LPS (10 μg/mL) and CsA (0.5 μg/mL) significantly impaired eyespot regeneration and locomotion, disrupted antioxidant enzyme (SOD, CAT, GST, GR) activity/expression, induced DNA damage, suppressed neoblast proliferation, disturbed neurotransmitter-related gene expression, and reduced the level of LC3B, a key protein in the PINK1/Parkin pathway. FLX (2 μg/mL) alleviated these adverse effects by restoring antioxidant balance, mitigating DNA damage, promoting proliferation, potentially associated with the activation of PINK1/Parkin-related mitophagy, and normalizing neurotransmitter synthesis-related genes. Notably, CsA reversed FLX's neuroprotective effects, implying FLX-mediated protection against LPS toxicity may be linked to the PINK1/Parkin-associated mitophagy pathway. This study validates FLX's neuroprotective potential, reinforces D. japonica as a model for mitophagy-related neuroregeneration, and provides preliminary insights for FLX's application in neurological disorders with impaired mitophagy and neuroregeneration.