Nobiletin alleviates brain injury in uremic mice and inhibits indoxyl sulfate-induced neurotoxicity in HT22 cells through the phosphatidylinositol 3-kinase/protein kinase B signaling pathway.

OBJECTIVE

Uremic encephalopathy presents as central nervous system symptoms in acute and chronic renal failure. Nobiletin (NOB), an extract from chenpi, has demonstrated anti-inflammatory bioactivity and potential neuroprotective effects without remarkable toxicity. This study aims to evaluate the pharmacological effects of NOB on treating uremic brain injury and elucidate its underlying mechanisms.

MATERIAL AND METHODS

A uremic encephalopathy mouse model was established by inducing renal failure with cisplatin (DDP). The therapeutic effects of NOB were investigated by assessing its effect on brain damage and neuronal viability. HT22 murine hippocampal neurons were also treated with DDP to induce neurotoxicity, and the effects of NOB on cell viability, apoptosis, and the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway were examined. The PI3K inhibitor LY294002 was used to further investigate the involvement of the PI3K/Akt pathway in the neuroprotective effects of NOB.

RESULTS

NOB alleviated uremia-induced brain damage in mice, and this function was associated with the activation of the PI3K/Akt signaling pathway. , NOB improved the DPP-suppressed cell viability in HT22 neurons and restored apoptosis. NOB treatment also restored the phosphorylation levels of PI3K, Akt, and Pyruvate dehydrogenase kinase 1. These effects were partially blocked by the PI3K inhibitor LY294002.

CONCLUSION

NOB exerts potent neuroprotective effects by activating the PI3K/Akt pathway, mitigating uremia-induced brain injury and preventing DDP-induced neurotoxicity. These findings support the potential therapeutic application of NOB for uremic encephalopathy and provide insights into its underlying mechanisms.