Abstract
AimsLeonurine has been shown to trigger antioxidant responses during ischemic stroke, and nuclear factor erythroid 2‐related factor 2 (Nrf‐2) imparts protective effects against oxidative injury. The present study has determined that leonurine prevents ischemic injury of brain tissues via Nrf‐2 pathway activation.MethodsMale ICR mice and Nrf‐2−/− mice were subjected to permanent middle cerebral artery occlusion (pMCAO) and received leonurine treatment at 2 hours after pMCAO by intraperitoneal injection. Neurological deficit scores as well as infarct volume were assessed to determine the neuroprotective role of leonurine. Nrf‐2 was investigated using Western blotting and real‐time polymerase chain reaction (RT‐PCR) analysis to elucidate the neuroprotective mechanism of leonurine. Commercial kits were employed to determine reactive oxygen species (ROS), superoxide (SOD), catalase (CAT), glutathione peroxidase (GSH‐Px), malonaldehyde (MDA), and glutathione (GSH). Vascular endothelial growth factor (VEGF) was evaluated by Western blotting and RT‐PCR analysis, and VEGF was localized using immunofluorescence.ResultsThe application of leonurine on ICR mice resulted in an improvement in neurological deficit scores and a reduction in infarct volume. Leonurine upregulated nuclear Nrf‐2 protein and increased total Nrf‐2 protein expression and mRNA levels. Leonurine regulated SOD, MDA, CAT, GSH, and GSH‐Px, and it significantly inhibited ROS production in ICR mice. Leonurine improved VEGF expression and increased VEGF expression in neurons, astrocytes, and endothelial cells. However, leonurine had no obvious beneficial effects on Nrf‐2−/− mice.ConclusionsLeonurine exerted neuroprotective effects, promoted antioxidant responses, and upregulated VEGF expression by activating the Nrf‐2 pathway.
Highlights
Leonurine (C14H21N3O5) is one of the effective components of Herba leonuri
One major finding of the present study is that leonurine decreases neurological deficit scores as well as infarct volume postischemic
Leonurine plays an antineuroinflammatory role by inhibiting microglial overactivation in Alzheimer's disease Sprague Dawley (SD) rats.[24]. These findings suggest that leonurine has multiple biological effects on nervous system diseases and may be poten‐ tially used in therapeutic regimens.[25,26,27,28]
Summary
Prior evaluations have shown that leonurine exerted neuroprotective effects by suppressing mitochondrial reactive ox‐ ygen species (ROS) production and adenosine triphosphate biosyn‐ thesis after ischemic stroke.[1,2] When oxidative stress occurs after ischemic stroke, ROS react with the macromolecular substances, such as cellular proteins, nucleic acids, and lipids, leading to cell injury and death.[3,4,5,6] It has been proven that ROS could be scavenged by anti‐ oxidant enzymes, which are downstream molecules of nuclear factor erythroid 2‐related factor 2 (Nrf‐2), including superoxide (SOD), cata‐ lase (CAT), glutathione peroxidase (GSH‐Px), and glutathione (GSH).[7]. We initially described the impact of leonurine on Nrf‐2 expres‐ sion and showed that the protective role of leonurine in a mouse model for permanent middle cerebral artery occlusion (pMCAO) was correlated to the upregulation of Nrf‐2, induction of antioxidant stress, and VEGF upregulation
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