Magnolol protects neurons against ischemia injury via the downregulation of p38/MAPK, CHOP and nitrotyrosine
Graphical abstract
Schematic presentation of the signaling pathways involved in magnolol inhibited transient global ischemia brain apoptosis and inflammation in rats. The effect of magnolol on the scavenger of ROS, which inhibits p38 MAPK and CHOP protein inactivation. These results suggest that another role for the iNOS/Akt pathway may be involved in neuronal survival or plasticity by magnolol after ischemic injury.
Introduction
Magnolol, a major active agent isolated from the herb Magnolia officinalis (Chinese herbal name: Hou Pu) is a poly-phenolic compound that exerts its biological properties through a variety of mechanisms (Alonso-Castro et al., 2011, Domínguez et al., 2010). Magnolol has been extensively documented and possesses a range of therapeutic properties such as anxiolytic activity (Kuribara et al., 2000), analgesic activity (Lin et al., 2009), antidepressant activity (Qiang et al., 2009), antimicrobial activity (Kim et al., 2010), antispasmodic activity (Ko et al., 2003), anti-tumorigenic activity (Chen et al., 2009) and an anti-Alzheimer's therapeutic effect (Hoi et al., 2010). Importantly, a recent study has indicated that oral magnolol seems to prevent age-related memory and learning deficits found in senescence-accelerated mice and does this by preserving cholinergic neurons (Lin et al., 2006, Matsui et al., 2009a, Matsui et al., 2009b). However, the mechanism by which the magnolol initiates neuroprotection against ischemic injury to the brain remains poorly understood.
Stroke is the fourth-leading cause of death and the primary cause of long-term disability worldwide (Iadecola and Anrather, 2011). It involves a distinct sequence of events that are not yet fully elucidated. Ischemic insult induces excessive generation of free radicals (reactive oxygen species (ROS) and reactive nitrogen species (RNS)), which then cause endoplasmic reticulum stress, which is signaled by both increased circulating levels of proinflammatory cytokines (TNF, IL-6) and the induction of macrophage infiltration that has been linked to apoptosis by the inducible NOS (iNOS) activation; these events then induce apoptotic cell death in neurons (Towfighi and Saver, 2011). Further ischemic stroke events also occur and these include neurotoxicity mediated by the production of free radicals and a subsequent induction of the p38 MAPK/CHOP pathway that is involved in ER stress-induced apoptosis of neurons; these findings are supported by the fact that ischemic injury is reduced following the induction of endogenous antioxidant pathways and the presence of scavengers targeting nitric oxide (Gotoh and Mori, 2006). As a result of the above findings, a fundamental role as potential neuroprotective agents is recognized for free radical scavengers. This is because ischemic injury is caused by a series of events that involve energy depletion and cell death and these are mediated by various intermediate factors including excess extracellular excitatory free radical formation and the presence of inflammation (Kohno et al., 1997). After arterial occlusion, necrotic cell death occurs predominantly in the ischemic core (Iadecola and Anrather, 2011). Reduced blood flow resulting from arterial occlusion or hypotension leads to tissue hypoxia and hypoglycemia, which then cause protein misfolding and endoplasmic reticulum stress. Ischemia-reperfusion injury of the brain then induces oxidative stress, which leads to production of nitric oxide (NO), a mediator of protein nitrosylation, and other reactive oxygen species (ROS); these alter cellular redox-dependent reactions and have an effect on protein misfolding (Zhu et al., 2003). Despite efforts to develop novel drugs to rescue neurons from delayed neuronal death in the penumbral region of the ischemic core, few currently available drugs are able to effectively treat stroke patients. In the present study we shall explore the biological agent of magnolol and its effect on ischemia reperfusion injury.
Reactive oxygen species derived from ischemia-reperfusion have been shown to be associated with the phosphatidylinositol 3-kinase (PI3K) and Akt signaling pathway that leads to neuronal survival or death (Noshita et al., 2001). PI3K/Akt is a major cell survival pathway that has been extensively studied. The PI3K/Akt pathway promotes cellular survival and cell cycling by phosphorylating and inhibiting death-inducing proteins; this includes phosphorylation of glycogen synthase kinase-3 beta (GSK-3β), and various activation-associated nuclear translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-dependent prosurvival genes (Camandola and Mattson, 2007). Considering the key role of PI3K/Akt and NF-κB in cell survival when studied using a stroke model of ischemia reperfusion brain injury, in the present study we sought to determine whether magnolol is able to effectively improve the neuroprotective effects of PI3K/Akt and NF-κB.
In our current study, a cerebral global ischemic stroke model of temporary ischemia followed by reperfusion onset was used to assess whether magnolol has a neuroprotective effect. We were able to demonstrate that magnolol, a known antioxidant, is able to reduce the oxidative endoplasmic reticulum stress that is generated by global cerebral ischemic injury, thus promoting neuronal cells survival; this involved the p38 mitogen-activated protein kinases (MAPKs), C/EBP homologous protein (CHOP) and the Akt/ NF-κB signal pathway.
Section snippets
Surgery to induce ischemia reperfusion brain injury and drug administration
Adult male Sprague–Dawley rats weighing around 280 ± 20 g were kept individually in a 12-hour light/dark cycle cage and had free access to water and food. Animal care and the general protocols for animal use were approved by the Institutional Animal Care and Use Committee of National Yang-Ming University. All efforts were made to minimize the number of animals used and their suffering. These rats were operated on according to the modified global cerebral ischemia's model, which involves occlusion
Magnolol attenuates brain damage in ischemic rats
A recent investigation has shown that magnolol and its structural analog honokiol are able to promptly cross the blood brain barrier, which then allows them to exert neuroprotective effects on the central nervous systems of ischemic stroke subjects (Lee et al., 2012, Lin et al., 2012). Based on these studies, we tested whether magnolol provides tangible therapeutic benefits by quenching brain impairment in a rat model that resembles ischemic stroke. As shown in Fig. 1A, injection of magnolol
Discussion
This study clearly demonstrates how magnolol suppresses oxidative stress and p38/MAPK and CHOP protein expression after ischemic injury, thus conferring neuroprotection. Magnolol also seems to have another role in that it affects iNOS expression and the Akt/NF-kB pathways, which are involved in neuronal survival/plasticity after ischemia reperfusion injury.
Ischemic damage occurs when the continuity of oxygen and glucose delivery via blood flow in the brain is interrupted (Moskowitz et al., 2010
Conflict of interest
The authors state no conflict of interest.
Acknowledgments
We are grateful to Li-Fu Chen for valuable contributions to the study design and later discussion. This study was supported by grants CGH-MR-9913, RD2011008, CZRPG880253, CMRPF6A0073 and CMRPF6C0032 from Cathay General Hospital, National Yang-Ming University Hospital, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung Memorial Hospital, and Chang Gung University of Science and Technology, Chia-Yi Campus, Taiwan, respectively, and from the National Science Council, Taiwan (
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