Background: Ischemic stroke seriously threatens human health because of high rates of morbidity, mortality and disability. This study compared the effects of nicotinamide adenine dinucleotide (NAD⁺) and butylphthalide (NBP) on in vitro and in vivo ischemic stroke models. Methods: Transient middle cerebral artery occlusion/reperfusion (t-MCAO/R) model was established in mice, and the cultured primary cortical neurons were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R). Cerebral infarct volume, neurobehavioral indices, antioxidant activity, ATP level and lactic acid content were determined. The neuroprotective effects of NAD⁺ or NBP were compared using sirtuin inhibitor niacinamide (NAM). Results: Intraperitoneal injection of NBP within 4 h or intravenous injection of NAD⁺ within 1 h after t-MCAO/R significantly reduced the volume of infarcts, cerebral edema, and neurological deficits. Administration of NAD⁺ and NBP immediately after t-MCAO/R in mice showed similar neuroprotection against acute and long-term ischemic injury. Both NAD⁺ and NBP significantly inhibited the accumulation of MDA and H₂O₂ and reduced oxidative stress. NAD⁺ was superior to NBP in inhibiting lipid oxidation and DNA damage. Furthermore, although both NAD⁺ and NBP improved the morphology of mitochondrial damage induced by ischemia/reperfusion, NAD⁺ more effectively reversed the decrease of ATP and increase of lactic acid after ischemia/reperfusion compared with NBP. NAD⁺ but not NBP treatment significantly upregulated SIRT3 in the brain, but the sirtuin inhibitor NAM could abolish the protective effect of NAD⁺ and NBP by inhibiting SIRT1 or SIRT3. Conclusions: These results confirmed the protective effects of NAD⁺ and NBP on cerebral ischemic injury. NBP and NAD⁺ showed similar antioxidant effects, while NAD⁺ had better ability in restoring energy metabolism, possibly through upregulating the activity of SIRT1 and SIRT3. The protection provided by NBP against cerebral ischemia/reperfusion may be achieved through SIRT1.

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