Dapagliflozin mitigates lipopolysaccharide-induced neuroinflammation through potential involvement of the IL-17A/GSK3β signaling pathway and modulation of inflammatory cytokines.

BACKGROUND

Neuroinflammation drives neuronal degeneration and cognitive decline through various mechanisms. Interleukin (IL)-17A, secreted by Th17 cells, activates glycogen synthase kinase 3 beta (GSK3β), worsening neuroinflammation via the nuclear factor kappa B (NF-κB) pathway. Dapagliflozin (DPG), a sodium/glucose cotransporter 2 inhibitor with neuroprotective effects, reduces oxidative stress, apoptosis, and inflammation. This study examines DPG's molecular impact on neuroinflammation in an LPS-induced rat model.

METHODS

The experiment was designed with four groups as control, lipopolysaccharide (LPS) (5 mg/kg, intraperitoneal), LPS + DPG (10 mg/kg via oral gavage), and DPG, with a total of thirty-two female Wistar Albino rats. After five days of treatment, the rats were euthanized. Brain and cerebellum tissues were gathered for biochemical analysis to examine oxidative stress parameters spectrophotometrically; histological and immunostaining analysis focusing on caspase-9 (Cas-9), NF-κB, and IL-10 immunoexpressions, and genetic analysis as IL-17A, GSK3β, IL-6, and cyclooxygenase 2 gene expressions by qRT-PCR.

RESULTS

Histopathological evaluation revealed hyperemia, edema, mild degeneration, neuronal death, and modest gliosis in the LPS group. Increment of Cas-9 and NF-κB immunoexpressions, oxidative stress parameters, and the mRNA expressions of all four genes, in addition to the decrement of IL-10 and total antioxidant status, have been observed. DPG treatment significantly reversed all these findings and protected the neuronal tissues against LPS-induced substantial neuronal damage.

CONCLUSION

In conclusion, DPG may exert neuroprotective effects through the involvement of the IL-17A/GSK3β pathway and reduction of oxidative stress; however, further studies are needed to clarify causal mechanisms and broader anti-inflammatory actions.