Arctigenin Treatment Protects against Brain Damage through an Anti-Inflammatory and Anti-Apoptotic Mechanism after Needle Insertion

Abstract

Convection enhanced delivery (CED) infuses drugs directly into brain tissue. Needle insertion is required and results in a stab wound injury (SWI). Subsequent secondary injury involves the release of inflammatory and apoptotic cytokines, which have dramatic consequences on the integrity of damaged tissue, leading to the evolution of a pericontusional-damaged area minutes to days after in the initial injury. The present study investigated the capacity for arctigenin (ARC) to prevent secondary brain injury and the determination of the underlying mechanism of action in a mouse model of SWI that mimics the process of CED. After CED, mice received a gavage of ARC from 30 min to 14 days. Neurological severity scores (NSS) and wound closure degree were assessed after the injury. Histological analysis and immunocytochemistry were used to evaluated the extent of brain damage and neuroinflammation. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) was used to detect universal apoptosis. Enzyme-linked immunosorbent assays (ELISA) was used to test the inflammatory cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-10) and lactate dehydrogenase (LDH) content. Gene levels of inflammation (TNF-α, IL-6, and IL-10) and apoptosis (Caspase-3, Bax and Bcl-2) were detected by reverse transcription-polymerase chain reaction (RT-PCR). Using these, we analyzed ARC’s efficacy and mechanism of action. Results: ARC treatment improved neurological function by reducing brain water content and hematoma and accelerating wound closure relative to untreated mice. ARC treatment reduced the levels of TNF-α and IL-6 and the number of allograft inflammatory factor (IBA)- and myeloperoxidase (MPO)-positive cells and increased the levels of IL-10. ARC-treated mice had fewer TUNEL+ apoptotic neurons and activated caspase-3-positive neurons surrounding the lesion than controls, indicating increased neuronal survival. Conclusions: ARC treatment confers neuroprotection of brain tissue through anti-inflammatory and anti-apoptotic effects in a mouse model of SWI. These results suggest a new strategy for promoting neuronal survival and function after CED to improve long-term patient outcome.

Arctigenin prevents the progression of osteoarthritis by targeting PI3K/Akt/NF‐κB axis: In vitro and in vivo studies

“…Mice in the DMM group received a gavage of vehicle (0.5% CMC‐Na, a dietary cosolvent), while mice in the DMM + ATG group received oral administration of ATG (30 mg/kg, dissolved in CMC‐Na) daily for 8 weeks. This dose of ATG was prepared by adapting the procedure used in the previous study and our preliminary experiments. The mice were maintained in a temperature‐controlled room (20 ± 2°C) on a 12:12‐h light‐dark cycle and given free access to water and food.…”

Overview of the anti-inflammatory effects, pharmacokinetic properties and clinical efficacies of arctigenin and arctiin from Arctium lappa L

“…This was observed in various colitis mouse models by the decreased activity of myeloperoxidase (MPO), eosinophil peroxidase (EPO), and cluster of differentiation 68 (CD68), indicators of neutrophils, eosinophils and macrophages, respectively [2,26,28] . In addition, AR reduced brain water content and hematoma and accelerated wound closure in convection-enhanced delivery induced brain injury in mice through regulation of various inflammatory factors and numbers of MPO-positive cells [28] . The anti-inflammatory effect of AR was first shown to be mediated through the suppression of NO production via inhibition of inducible nitric oxide synthase (iNOS) at both the expression and activity levels.…”

“…Cytokine-mediated feed-forward loops can amplify and coordinate this inflammatory response [15] . The anti-inflammatory effect of AR has been attributed to its potent in vitro and in vivo modulating effects on several important cytokines, such as tumor necrosis factor-α (TNF-α) [2,22,26,28,31,36,37] , interleukin-6 (IL-6) [2,26,28,29,31,37] , interleukin-1β (IL-1β) [2,29,37] , and interleukin-10 (IL-10) [2,28] . Inhibitory effects of AR on the expression levels of other cytokines, such as interleukin-2 and interferon-γ (IFNγ), were also found in vitro [3] .…”

Arctigenin Attenuates Ischemia/Reperfusion Induced Ventricular Arrhythmias by Decreasing Oxidative Stress in Rats

“…Previous studies reported that ATG can inhibit intracellular ROS production by increasing hemeoxygenase-1 gene expression in rat primary astrocytes [12], and inducing endothelial nitric oxide synthase and attenuating subarachnoid hemorrhage-induced vasospasm through PI3K/Akt pathway in a rat model [13]. Arctigenin even has been shown to have a neuroprotective effect by mechanisms of anti-neuroinflammation and anti-oxidative stress [14]. It is unknown if ATG has a biological effect on myocardial ischemia/reperfusion-induced ventricular arrhythmias and if it exerts anti oxidative effects.…”