Cerebral ischemia/reperfusion (I/R) injury is a key reason for the poor prognosis of ischemic stroke. As only a few neuroprotective medications for cerebral I/R injury have been applied in the clinic, it is necessary to design a new therapeutic strategy to treat cerebral I/R injury. The N-salicyloyl tryptamine derivative LZWL02003, synthesized from melatonin and salicylic acid, exhibits a wide range of biological properties. In this study, we assessed the neuroprotective capabilities of LZWL02003 in vivo and in vitro and investigated its possible mechanisms. Oxygen-glucose deprivation/reoxygenation was utilized to create an in vitro model of cerebral I/R damage. Middle cerebral artery occlusion/reperfusion was employed to imitate cerebral I/R injury in vivo. Neuronal apoptosis, oxidative stress, mitochondrial dysfunction, and neuroinflammation are associated with the pathogenesis of cerebral I/R injury. Our findings demonstrated that LZWL02003 upregulated the expression of Bcl-2 and downregulated the expression of Bax, thus maintaining the homeostasis of Bcl-2/Bax proteins and preventing apoptosis. LZWL02003 also reduced oxidative stress by reducing malondialdehyde and reactive oxygen species levels, increasing the superoxide dismutase activity, and resolving mitochondrial malfunction. LZWL02003 can lower interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-6 levels, which in turn suppress neuroinflammation. Activation of the nuclear factor-kappa B (NF-κB) pathway is involved in various pathophysiologies, including cerebral I/R injury. We discovered that LZWL02003 suppressed the phosphorylation activation of NF-κB pathway-related proteins and decreased the nuclear translocation of NF-κB p65 subunits. Taken together, our results suggest that LZWL02003 is a neuroprotective drug with pleiotropic effects and may be a candidate for treating cerebral I/R injury.
Keywords: N-salicyloyl tryptamine; NF-κB; apoptosis; cerebral ischemia and reperfusion; neuroinflammation; oxidative stress.