Gua Lou Gui Zhi decoction exerts neuroprotective effects on post-stroke spasticity via the modulation of glutamate levels and AMPA receptor expression

Tao, Jing; Xue, Xiehua; Yang, Shanli; Han, Ping; Lin, Zhicheng; Xu, Wei; Lin, Jiumao; Peng, Jun; Chen, Lidian

doi:10.3892/ijmm.2013.1262

Cited by 33 publications

(31 citation statements)

References 23 publications

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“…The recognition that cerebral stroke is a manifestation of chronic progressive inflammation has had great influence on the development of therapeutic and preventative strategies (13,14) and as such, the Chinese formula may be a promising therapeutic strategy for ameliorating strokeinduced inflammatory pathological events. GLGZD has been reported to be an effective treatment for stroke in clinical practice and in animal experiments (15)(16)(17). In our previous study in vitro, we demonstrated that GLGZD water extract exerts anti-inflammatory effects in LPS-induced microglial cells mediated by the nuclear factor-κB (NF-κB) sinaling pathway (9); however, the precise molecular mechanisms responsible for its neuroprotective effects have not yet been elucidated.…”

Section: Discussionmentioning

confidence: 99%

GuaLou GuiZhi decoction inhibits LPS-induced microglial cell motility through the MAPK signaling pathway

Zhu

et al. 2013

International Journal of Molecular Medicine

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Abstract.Microglial activation plays an important role in neroinflammation following ischemic stroke. Activated microglial cells can then migrate to the site of injury to proliferate and release substances which induce secondary brain damage. It has been shown that microglial migration is associated with the activation of the mitogen-activated protein kinase (MAPK) signaling pathways. The Chinese formula, GuaLou GuiZhi decoction (GLGZD), has long been administered in clinical practice for the treatment of post-stroke disabilities, such as muscular spasticity. In a previous study, we demonstrated that the anti-inflammtory effects of GLGZD were mediated by the TLR4/NF-κB pathway in lipopolysaccharide (LPS)-stimulated microglial cells. Therefore, in this study, we evaluated the role of GLGZD in microglial migration by performing scratch wound assays and migration assays. We wished to elucidate the cellular and molecular mechanisms elicited by this TCM formula in microglial-induced inflammation by evaluating the release and expression of chemotactic cytokines [monocyte chemo attractant protein-1 (MCP-1), macrophage inflammatory protein-1α (MIP-1α) and interleukin (IL)-8] by ELISA and quantitative PCR. Our results revealed that the migration of microglial cells was enhanced in the presence of LPS (100 ng/ml); however, GLGZD (100 µg/ml) significantly inhibited cell motility and the production of chemokines through the inhibition of the activation of the p38 and c-Jun N-terminal protein kinase (JNK) signaling pathway. We demonstrate the potential of GLGZD in the modulation of microglial motility by investigating the effects of GLGZD on microglial migration induced by LPS. Taken together, our data suggest that GLGZD per se cannot trigger microglial motility, whereas GLGZD impedes LPS-induced microglial migration through the activation of the MAPK signaling pathway. These results provide further evidence of the anti-inflammatory effects of GLGZD and its potential for use in the treatment of ischemic stroke. IntroductionStroke is a leading cause of mortality and disability worldwide and 70-80% of all cases are ischemic stroke (1). Post-ischemic inflammation is an essential step in the progression of ischemic stroke (2). Microglial cells constitute the resident immune cell population of the mammalian central nervous system (CNS), which play a pivotal role in neuroinflammation by avidly surveying the brain parenchyma (3,4). In this sense, microglial cells become activated and migrate to the injury site in order to fully develop a concerted immune response, involving the release of both trophic and pro-inflammatory factors, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-6 and IL-1β and nitric oxide (NO), which are believed to lead to severe neuronal death and brain injury (5,6). Chemokines [monocyte chemo attractant protein-1 (MCP-1), IL-8 and macrophage inflammatory protein-1α (MIP-1α)] produced by microglial cells are also important enhancers of post-ischemic inflammation (7,8). Gua Lou Gui Zhi decoction (GLGZD)...

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Section: Discussionmentioning

confidence: 99%

GuaLou GuiZhi decoction inhibits LPS-induced microglial cell motility through the MAPK signaling pathway

Zhu

et al. 2013

International Journal of Molecular Medicine

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“…A previous study has demonstrated that GLGZD treatment may inhibit spasticity resulting from ischemia by modulating glutamate levels in an experimental rat model (16). Furthermore, previous studies have suggested that GLGZD may exhibit anti-neuroinflammatory effects by suppressing microglial activation in a lipopolysaccharide (LPS)-induced microglial cell culture experimental model (17,18).…”

Section: Introductionmentioning

confidence: 99%

“…The aim of the present study was to investigate whether GLGZD exerted an anti-inflammatory and protective effect via the NF-κB signaling pathway, following cerebral ischemic injury. (16,17).…”

Section: Anti-inflammatory Effects Of Gualou Guizhi Decoction In Tranmentioning

confidence: 99%

“…The MCAO rat model was established according to the methods of a previous study (16). Briefly, the rats were anesthetized using 10% chloral hydrate (Sinopharm Chemical Reagent Co., Ltd., Shanghai, China), subsequently the left common carotid artery (CCA), the left external carotid artery and the internal carotid artery (ICA) were isolated and exposed.…”

Section: Animalsmentioning

confidence: 99%

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Anti-inflammatory effects of Guolou Guizhi decoction in transient focal cerebral ischemic brains

Lin

Zhu

et al. 2012

Molecular Medicine Reports

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Abstract. The aim of the present study was to explore the neuroprotective effects of Gualou Guizhi decoction (GLGZD) in a rat model of middle cerebral artery occlusion (MCAO). Sprague-Dawley rats were divided into three groups: Sham (no MCAO), MCAO (MCAO with no GLGZD treatment) and GLGZD (MCAO with GLGZD treatment). Rats in the MCAO and GLGZD groups were subjected to permanent occlusion of the left middle cerebral artery. Neurological function and infarct volume were measured. Microglial activation and inflammatory cell accumulation were measured using immunohistochemistry. mRNA and protein expression of inflammatory mediators were examined using reverse transcription-quantitative polymerase chain reaction and an enzyme-linked immunosorbent assay. The expression of proteins associated with the nuclear factor κ-B (NF-κB) inflammation signaling pathway was analyzed using western blotting. The results of the present study suggested that infarct size was significantly reduced and neurological behavior function was improved in rats with MCAO treated with GLGZD compared with rats in the MCAO group. Amoeboid microglial expansion and inflammatory cell migration were observed in the infarcted areas of rats in the GLGZD group and were not identified in those of the MCAO group. Target mRNA and protein levels, and inflammatory cell infiltration were significantly reduced in the GLGZD group compared with the MCAO model group. Notably, GLGZD treatment induced neuroprotective effects, reducing inflammation and inhibiting NF-κB signaling compared with the MCAO group. Therefore, GLGZD may exhibit anti-inflammatory effects against ischemia-reperfusion brain injury and may be a therapeutic target for ischemic stroke. IntroductionStroke is the one of leading causes of morbidity and mortality worldwide (1,2). Ischemic stroke is a sudden interruption of blood supply to the brain caused by the blockage of an artery, which may result in brain damage and neurologic dysfunction (3). The suppression of brain damage resulting from ischemic stroke is essential in order to prevent a decrease in the quality of life for patients. However, a therapeutic strategy for cerebral ischemia/reperfusion injury has yet to be established (4-6). Neuroinflammation following ischemia is characterized by the rapid activation of resident microglia and the infiltration of inflammatory cells. Neuroinflammation causes an increase in the expression of proinflammatory cytokines and reactive oxygen species, and may lead to blood-brain barrier disruption, brain edema, and cell necrosis and apoptosis. Recent studies have demonstrated that reactive microglia express inflammatory mediators that may increase the risk of stroke in patients with permanent middle cerebral artery occlusion (MCAO) and transient ischemia (7-9). The maintenance of microglial function during focal stroke may be more important than that of neurons. The mechanisms of microglial activation involve nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPK) signaling pathways. The infla...

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“…This relationship appeared to predominantly occur after exposure to both foot shock plus low temperature (Yuen et al 2009) and repeated immobilization, thereby emphasizing the importance of gene expression events on increased neuronal excitability and vulnerability (Schewendt and Jezová 2000). Moreover, the reduction of GluR1 mRNA expression capacities by CNQX concomitantly to the few neurodegenerative signals tends to s u p p o r t a n e u r o p r o t e c t i v e r o l e p l a y e d b y t h i s AMPAergic antagonist very likely as a consequence of reduced Ca 2+ influx, which constitutes a major factor responsible for the consolidation of synaptic silencing (Tanaka et al 2002;Huang et al 2013). In particular, the notable decrease of GluR1 mRNA levels with respect to those of GluR2 reported for HIP and COR might comprise a probable cause of diminished excitotoxic effects on GluR2-lacking Ca 2+ -permeable AMPARs in global ischemia (Higuchi et al 2000;Liu and Zukin 2007;Mele et al 2014).…”

Section: Discussionmentioning

confidence: 99%

Distinct Amygdalar AMPAergic/GABAergic Mechanisms Promote Anxiolitic-Like Effects in an Unpredictable Stress Model of the Hamster

et al. 2014

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Studies have pointed to both α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) antagonists and GABA(A) receptor (GABA(A)R) agonists as potent antistress agents. In this work, separate subchronic injections of the AMPAR antagonist, 6-ciano-7-nitroquinoxaline-2,3-dione (CNQX), and α1 GABA(A)R subunit agonist (Zol) within the central amygdala nucleus modified the elevated plus maze performances of hamsters exposed randomly to one of the following stressful conditions: food/water deprivation, forced swimming test, and permanence in cold room. Indeed, stressed hamsters treated with CNQX or Zol displayed a very great (p < 0.001) increase of entrance plus a moderate (p < 0.05) time spent into open arms, respectively. At the cellular level, Zol-treated animals supplied a moderately evident argyrophilic reaction (indicative of neurodegeneration) in the hippocampus while it was absent in the hypothalamus. Interestingly, this reaction was significantly reduced by CNQX supporting its preferential protective role. Furthermore, both agents were responsible for a mixed expression pattern of GluR1 and GluR2 mRNA levels in which Zol overall upregulated GluR1 mRNAs, while they were downregulated by CNQX in the hippocampal oriens-pyramidalis layer and in layer III of the cerebral cortex. These findings support the amygdalar AMPAergic protective response against anxiety states in chronically stressed hamsters, which may constitute useful therapeutic strategies for panic-related mood disorders.

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Gua Lou Gui Zhi decoction exerts neuroprotective effects on post-stroke spasticity via the modulation of glutamate levels and AMPA receptor expression

Cited by 33 publications

References 23 publications

GuaLou GuiZhi decoction inhibits LPS-induced microglial cell motility through the MAPK signaling pathway

GuaLou GuiZhi decoction inhibits LPS-induced microglial cell motility through the MAPK signaling pathway

Anti-inflammatory effects of Guolou Guizhi decoction in transient focal cerebral ischemic brains

Distinct Amygdalar AMPAergic/GABAergic Mechanisms Promote Anxiolitic-Like Effects in an Unpredictable Stress Model of the Hamster

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