BACKGROUND: Hesperidin (HPD) is a bioflavonoid found in citrus fruits. This study aimed to investigate the effects of HPD on cerebral morphology and cognitive behavior in sevoflurane anesthetized neonatal rats and the molecular mechanisms involved.

MATERIAL AND METHODS: Sixty neonatal Sprague–Dawley rats were divided into five groups, including the untreated control group, and the sevoflurane anesthesia groups untreated and treated with 25 mg/kg/day of HPD (HPD25), 50 mg/kg/day of HPD (HPD50), and 100 mg/kg/day of HPD (HPD100). The rat model was created by the administration of sevoflurane on the sixth postnatal day (P6) and for a further three days. Neonatal rats pre-treated with HPD for 19 days were given sevoflurane 30 minutes beforehand (P3 to P21). Rat hippocampal tissue specimens were investigated using the TUNEL assay for apoptosis. Hippocampal tissue homogenates underwent Western blot for the quantification of markers of neuroinflammation and oxidative stress. The neonatal rats were also investigated for behavior, learning, and memory.

RESULTS: HPD significantly reduced sevoflurane-induced neuronal apoptosis and protein expression of cleaved caspase-3, BAD, BAX, NF-κB, TNF-α, IL-6, and IL-1β (p<0.05). HPD significantly increased the expression of Bcl-xL and Bcl-2 (p<0.05), and activated the PI3/Akt pathway. Learning and memory were significantly improved following HPD treatment (p<0.05). HPD treatment modulated the PI3/Akt/PTEN and NF-κB signaling pathways, and reduced oxidative stress (p<0.05).

CONCLUSIONS: In the sevoflurane anesthetized neonatal rat model, treatment with HPD reduced neuronal degeneration, hippocampal inflammation, and improvised memory, learning, and cognitive responses by modulating the PI3/Akt/PTEN and NF-κB signaling pathways.

Keywords: Anesthesia, Cognition Disorders, Hesperidin, neurogenic inflammation, Anesthetics, Inhalation, Brain, cognitive dysfunction, Neurons, PTEN Phosphohydrolase, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, sevoflurane