Abstract W P235: The Nuclear Receptors FXR and Nur77 Exhibit Neuroprotective Effects in the Ischemic Mouse Brain

Introduction: FXR and Nur77, members of the nuclear hormone superfamily, have been shown to modulate pro- and anti-inflammatory responses by immune cells, such as macrophages or T cells. As ischemic stroke induces an inflammatory response accompanied by activation and recruitment of immune cells, the aim of this study was to investigate the influence of nuclear receptors Nur77, FXR as well as FXR activation by the agonist GW4064 in cerebral ischemia-reperfusion (I/R) injury. Methods: Transient middle cerebral ischemia (MCAO) was induced in adult mice assigned to 4 groups: placebo, Nur77-deficient, FXR-deficient and FXR-ligand GW4064-treated (each n=7-8). A priori survival-time was set to 72 hours. Mice underwent functional tests and histological studies were performed for evaluation of infarct volume, immune cell activation/immigration and neuronal apoptosis. Results: MCAO led to delayed (24-48h after I/R) but severely worsened functional outcome in Nur77 and FXR-ko mice compared to wildtype animals (p<0.001, ANOVA+Bonferroni post-hoc). FXR- and Nur77-ko mice developed increased infarct volumes (Nur77, p<0.05) and had elevated TUNEL+-cell counts within the ischemic lesion (FXR, p<0.05). In contrast, treatment with FXR-agonist GW4064 resulted in improved functional outcome compared to placebo-treated mice. Evaluation of microglia and monocytes/macrophages showed an increased F4/80+-cell count 72h following MCAO in GW4064-treated mice. Conclusion: Deficiency of nuclear receptors Nur77 and FXR significantly worsened functional outcome, increased infarct size and cell apoptosis, whereas treatment with nuclear receptor agonist GW4064 led to improved rotarod performance and altered F4/80+-immune cell response. These results suggest a crucial involvement of the nuclear receptors Nur77 and FXR in pathways relating to post-stroke inflammation and tissue damage development.

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Immune Cells in Ischemic Acute Kidney Injury

Current Protein and Peptide Science ◽

10.2174/1389203720666190507102529 ◽

2019 ◽

Vol 20 (8) ◽

pp. 770-776 ◽

Cited By ~ 8

Author(s):

Long Zheng ◽

Wenjun Gao ◽

Chao Hu ◽

Cheng Yang ◽

Ruiming Rong

Keyword(s):

Acute Kidney Injury ◽

Immune Cells ◽

Immune Cell ◽

Inflammatory Responses ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Systemic Disease ◽

Kidney Injury ◽

Repair Process ◽

Injured Kidney

Acute kidney injury (AKI) is a systemic disease characterized by acute loss of renal function and accumulation of end products of nitrogen metabolism. Ischemic AKI is the most common cause of AKI, and inflammatory responses are inevitablely involved in ischemic AKI. In the process of ischemic AKI, multiple factors are involved in activating and recruitment of immune cell to the injured kidney. These factors include DAMPs and HIFs released from the injured kidney, increased expression of adhesion molecules, the production of chemokines and cytokines, activation of complement system and TLRs as well as the permeability dysfunction of the renal vascular endothelium. Immune cells of both the innate and adaptive immune systems, such as neutrophils, dendritic cells, macrophages and lymphocytes contribute to the pathogenesis of renal injury after ischemia reperfusion injury (IRI), with some of their subpopulations also participating in the repair process. Numerous studies of immune cells involved in the pathogenesis of AKI have enhanced the understanding of their possible mechanisms in AKI which might become the potential targets for the treatment of ischemic AKI. This review describes the function of the immune cells in the pathogenesis and repair of ischemic AKI and emphasizes the treatment of ischemic AKI potentially targeting them.

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Ephedrine attenuates cerebral ischemia/reperfusion injury in rats through NF-κB signaling pathway

Human & Experimental Toxicology ◽

10.1177/0960327120975456 ◽

2020 ◽

pp. 096032712097545

Author(s):

Chanhong Shi ◽

Jianhong Li ◽

Jianwei Li

Keyword(s):

Cerebral Ischemia ◽

Protein Expression ◽

Reperfusion Injury ◽

Rat Model ◽

Inflammatory Responses ◽

Ischemia Reperfusion Injury ◽

Infarct Volume ◽

Ischemia Reperfusion ◽

Cerebral Ischemia Reperfusion ◽

Cerebral Ischemia Reperfusion Injury

The inflammation and immune responses are critical in ischemic stroke and contribute to aggravated brain damage. Ephedrine was reported to play an important role in the control of inflammatory responses. This study was to investigate the repairing effects and potential mechanisms of ephedrine on cerebral ischemic injury in a rat model of focal cerebral ischemia. The rat model of cerebral ischemia/reperfusion injury was established using the middle cerebral artery occlusion (MCAO) method and then rats were treated with ephedrine (5 and 10 mg/kg) for 7 days. The neurobehavioral progression was assessed using the neurological scoring method. The pathology of brain tissue was evaluated by hematoxylin and eosin (H&E) staining. The infarct volume was examined by triphenyltetrazolium chloride (TTC) staining. The apoptosis in ischemic brain tissues was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Inflammatory factors were detected by enzyme-linked immunosorbent assay (ELISA). Gene quantification and protein expression were detected by real-time PCR and western blot, respectively. Ephedrine treatment significantly alleviated the cerebral ischemia/reperfusion injury, evidenced by decreased neurological deficit score, infarct volume and water content. Ephedrine also decreased autophagy and apoptosis in brain tissues. Moreover, ephedrine treatment significantly reduced inflammatory responses, associating with decreasing the protein expression of p-NF-κB. These results demonstrated neuroprotective properties of ephedrine and highlighted it as a new potential anti-inflammatory agent against injury of cerebral ischemia/reperfusion.

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Abstract TP273: Nuclear Receptor NR4A1-deficiency Leads to Worsened Functional Outcome, Increased Inflammation but Inhibited Microglial Activation Following Cerebral Ischemia in Mice

Stroke ◽

10.1161/str.47.suppl_1.tp273 ◽

2016 ◽

Vol 47 (suppl_1) ◽

Author(s):

Jan-Kolja Strecker ◽

Stefanie Hucke ◽

Kai Diederich ◽

Antje Schmidt ◽

Luisa Klotz ◽

...

Keyword(s):

Cerebral Ischemia ◽

Functional Outcome ◽

Nuclear Receptor ◽

Immune Cells ◽

Infarct Volume ◽

Sterile Inflammation ◽

Experimental Stroke ◽

Histological Evaluation ◽

Neutrophil Granulocytes ◽

Deficient Mice

Introduction: The sterile inflammation in consequence of cerebral ischemia is accompanied by the immigration and activation of hematogenous and brain resident immune cells. It has been shown that the nuclear receptor NR4A1 (or Nerve Growth Factor IB) exerts a crucial role within the inflammatory response via regulating macrophage activation. In this study, we aimed to investigate the influence of NR4A1 in a loss-of-function paradigm on the activation and recruitment of both, brain resident and hematogenous immune cells following experimental stroke in mice. Methods: Wildtype (n=19) and NR4A1-deficient (n=18) mice were subjected to ischemia of the MCA (MCAO, 30 min). Animals were tested for functional outcome and were sacrificed on day 1 and 3 after reperfusion. Infarct volume, expression of inflammatory genes and activation/immigration of immune cells were analyzed via RT-PCR, (immuno-)histology and FACS analyses. Results: Lack of NR4A1 led to worsened functional outcome (p<0.001) and increased infarct volume (p<0.01) compared to wildtype mice. NR4A1-deficient mice showed enlarged astroglial scar formation (p<0.01) and increased COX2 expression (p<0.05). Histological evaluation showed increased macrophage counts on day 3 (p<0.05) following MCAO in NR4A1-deficient mice. Flow cytometric quantification of CD11b+/CD45low-cells showed a significantly diminished amount of microglia in NR4A1-deficient mice on day 3 compared to the wildtype group (p<0.001). NR4A1-deficiency resulted in an increased immigration of Ly6G+-granulocytes on day 3 after ischemia (p<0.001). Furthermore, Ly6G+-cells of NR4A1-deficient mice showed an excessively increased expression of MHC-class-II compared to wildtype mice (p<0.001). Conclusion: NR4A1-deficient mice developed enlarged infarcts and aggravated functional outcomes. Lack of NR4A1 led to impaired microglia activation and increased influx of Ly6G+-neutrophil granulocytes. NR4A1-deficient mice showed a strikingly increased number of MHC-II-presenting neutrophils compared to the wildtype group. Taken together, these results reveal a prominent influence of the receptor NR4A1 in regulation and activation of the cellular immune response and development of subsequent brain injury.

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Surface-modified engineered exosomes attenuated cerebral ischemia/reperfusion injury by targeting the delivery of quercetin towards impaired neurons

Journal of Nanobiotechnology ◽

10.1186/s12951-021-00879-4 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Lin Guo ◽

Zhixuan Huang ◽

Lijuan Huang ◽

Jia Liang ◽

Peng Wang ◽

...

Keyword(s):

Cerebral Ischemia ◽

Reperfusion Injury ◽

Targeted Delivery ◽

Ischemia Reperfusion Injury ◽

Infarct Volume ◽

Ischemia Reperfusion ◽

Artery Occlusion ◽

Therapeutic Drug ◽

Cerebral Ischemia Reperfusion ◽

Cerebral Ischemia Reperfusion Injury

Abstract Background The incidence of ischemic stroke in the context of vascular disease is high, and the expression of growth-associated protein-43 (GAP43) increases when neurons are damaged or stimulated, especially in a rat model of middle cerebral artery occlusion/reperfusion (MCAO/R). Experimental design We bioengineered neuron-targeting exosomes (Exo) conjugated to a monoclonal antibody against GAP43 (mAb GAP43) to promote the targeted delivery of quercetin (Que) to ischemic neurons with high GAP43 expression and investigated the ability of Exo to treat cerebral ischemia by scavenging reactive oxygen species (ROS). Results Our results suggested that Que loaded mAb GAP43 conjugated exosomes (Que/mAb GAP43-Exo) can specifically target damaged neurons through the interaction between Exo-delivered mAb GAP43 and GAP43 expressed in damaged neurons and improve survival of neurons by inhibiting ROS production through the activation of the Nrf2/HO-1 pathway. The brain infarct volume is smaller, and neurological recovery is more markedly improved following Que/mAb GAP43-Exo treatment than following free Que or Que-carrying exosome (Que-Exo) treatment in a rat induced by MCAO/R. Conclusions Que/mAb GAP43-Exo may serve a promising dual targeting and therapeutic drug delivery system for alleviating cerebral ischemia/reperfusion injury.

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Abstract WP77: Final Infarct Volume May Predict Functional Outcome After Mild, Nondisabling Ischemic Stroke: Results From the PRISMS Trial

Stroke ◽

10.1161/str.51.suppl_1.wp77 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Shyam Prabhakaran ◽

Achala Vagal ◽

Heidi Sucharew ◽

Thomas Tomsick ◽

Janice Carrozzella ◽

...

Keyword(s):

Cerebral Ischemia ◽

Functional Outcome ◽

Infarct Volume ◽

Final Diagnosis ◽

White Matter Hyperintensity ◽

Secondary Outcome ◽

Acute Infarction ◽

Acute Cerebral Ischemia ◽

Acute Infarct ◽

Mri Scans

Introduction: In patients with acute cerebral ischemia (ACI) within 3h of onset with mild deficit judged as nondisabling at presentation, up to 20% experience poor functional outcome at 90 days. We tested the hypothesis that the presence of infarction at 24h would independently predict worse outcome at 3 months, and also explored the role of final infarct volume (FIV) on outcomes. Methods: The phase 3b, randomized PRISMS trial compared intravenous alteplase to aspirin for mild (NIHSS 0-5), nondisabling stroke at <3 h from onset. In a prespecified analysis, we included patients with 24h MRI performed and excluded acute cerebral ischemia mimics. Central readers assessed Day 24h MRIs for acute infarct, chronic infarcts, and white matter hyperintensity (WMH) burden; FIV and WMH volumes were measured quantitatively using semi-automated software. The primary outcome was 3-month EQ5D scores, a measure of QOL, and the secondary outcome was modified Rankin Scale (mRS) scores, a measure of disability. Multivariable linear regression and proportional odds cumulative logit models were used to evaluate the association between (1) acute infarction presence and (2) FIV on the primary and secondary outcomes, respectively, adjusting for relevant covariates (Table 1). Results: Of 313 patients enrolled, 273 had a final diagnosis of ACI and 212/273 (77%) had 24h MRI scans. Acute infarcts were present In 109 (51%), and median FIV was 1.20 mL (IQR 0.57-2.50). No association between presence of acute infarcts and 3-month EQ5D (p=0.84) or mRS (p=0.17) scores was observed (Table 1A). No association between FIV and EQ5D scores (p=0.31) was observed as well, but FIV was strongly associated with mRS scores (OR 1.11, 95% CI 1.04-1.18, p<0.001), in adjusted models (Table 1B). Conclusions: Among patients presenting with mild, nondisabling ACI, FIV appears to be associated with worse functional outcome. Since this was a post-hoc analysis, this hypothesis requires further prospective study.

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Abstract 496: Genetic Neutrophil Deficiency Ameliorates Cerebral Ischemia-Reperfusion Injury

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.37.suppl_1.496 ◽

2017 ◽

Vol 37 (suppl_1) ◽

Author(s):

Ryan A Frieler ◽

Yutein Chung ◽

Jianrui Song ◽

Thomas M Vigil ◽

Richard M Mortensen

Keyword(s):

Cerebral Ischemia ◽

Infarct Size ◽

Knockout Mice ◽

Neutralizing Antibodies ◽

Immune Cell ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Cell Types ◽

Artery Occlusion ◽

Cross Reactivity

Background: Neutrophils respond rapidly to cerebral ischemia and are thought to contribute to inflammation-mediated injury during stroke. Neutralizing antibodies and inhibition of neutrophil chemotactic molecules can be protective during models of stroke, but many of these techniques have the potential to result in cross-reactivity and non-specificity with other immune cell types. Using myeloid Mcl1 knockout mice as a model of genetic neutrophil deficiency, we investigated the contribution of neutrophils to stroke pathophysiology. Methods: Myeloid Mcl1 knockout mice were subjected to transient 90-min middle cerebral artery occlusion and infarct size was assessed by MRI after 24 hours reperfusion. Immune cell mobilization and infiltration was assessed by flow cytometry after 24 hours reperfusion. Results: We found that myeloid Mcl1 knockout mice had significantly reduced infarct size when compared to heterozygous and wild type control mice (MyMcl1 +/+ : 78.0 mm 3 ; MyMcl1 +/- : 83.4 mm 3 ; MyMcl1 -/- : 55.1 mm 3 ). This was accompanied by a nearly complete absence of neutrophils in the ischemic hemisphere of myeloid Mcl1 knockout mice. Although myeloid Mcl1 knockout mice were protected from cerebral infarction, no significant differences in the expression of inflammatory genes were detected. Inhibition of neutrophil chemotaxis using CXCR2 pepducin treatment partially reduced neutrophil mobilization and recruitment to the brain after stroke, but did not reduce infarct size 24 hours after transient MCA occlusion. Conclusions: These data confirm that neutrophils have an important role in infarct development during stroke pathophysiology and suggest that complete deficiency, but not partial inhibition, is necessary to prevent neutrophil-mediated injury during stroke.

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Poly(I:C) preconditioning ameliorates cognitive dysfunction after cerebral I/R injury by inhibiting TRAF6 signaling

10.21203/rs.3.rs-19235/v1 ◽

2020 ◽

Author(s):

Peng-Fei Wang ◽

Wei-Bin Zhong ◽

Xiao-Hua Ju ◽

Zhen-Guang LI ◽

Fa-Xiang Wang

Keyword(s):

Cerebral Ischemia ◽

Cognitive Dysfunction ◽

Sham Group ◽

Infarct Volume ◽

Ischemia Reperfusion ◽

Poly I:C ◽

Model Group ◽

Vector Group ◽

Aav Vector ◽

Cerebral Ischemia Reperfusion

Abstract Objective: Toll-like receptor (TLR) activation plays an important role in cerebral ischemia-reperfusion injury. In addition, increasing evidence suggests that TLRs may affect cognitive behavior through TLR-mediated signaling. Here, we explored the protective effects of TLR3 on cognitive dysfunction after ischemia in the context of poly(I:C) preconditioning.Materials and Methods : Mice (n=84) were randomly divided into the sham group, AAV (vector) group, middle cerebral artery occlusion (MCAO) model group, poly(I:C) (pre) + MCAO model group, and AAV (TRAF6) + poly(I:C) (pre) + MCAO model group. The mice were injected i.p. with poly(I:C) (1.25 mg/g) 24 h prior to cerebral ischemia. Then, neurological scores were assessed, and the infarct volume was measured after cerebral ischemia-reperfusion. We evaluated the poly(I:C) preconditioning-induced attenuation of neuronal damage using Nissl and TUNEL staining. We assessed the poly(I:C) preconditioning-mediated inhibition of I/R-induced glial activation, inflammatory factor levels and TRAF6 expression. We also assessed whether TRAF6 affects poly(I:C) preconditioning to improve cognitive dysfunction and neuroprotection.Results: The results showed that compared with those of the sham group and AAV (vector) group, the functional neurological scores and focal infarct volume of the MCAO group and poly(I:C) preconditioning group were significantly increased. The results also showed that compared with those of the MCAO group, the functional neurological scores and focal infarct volume of the poly(I:C) preconditioning group were significantly reduced. Our results indicated that poly(I:C) preconditioning significantly attenuated neuronal apoptosis and cell loss. Poly(I:C) preconditioning also inhibited I/R-induced glial cell activation and reduced NF-κB, TNF-α and IL-β levels. Our findings showed that poly(I:C) preconditioning affected cognitive dysfunction following cerebral I/R. Here, we observed that poly(I:C) preconditioning affected the expression and distribution of TRAF6 following cerebral I/R. TRAF6 overexpression abolished poly(I:C)-induced neuroprotection and worsened cognitive dysfunction in cerebral I/R injury.Significance: Our findings suggested that poly(I:C) preconditioning ameliorates cognitive dysfunction after cerebral I/R injury by inhibiting TRAF6 signaling, which is a potential therapeutic target for the treatment of cognitive dysfunction after stroke.

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NLRC5 alleviated OGD/R-induced PC12-cell injury by inhibiting activation of the TLR4/MyD88/NF-κB pathway

Journal of International Medical Research ◽

10.1177/0300060520940455 ◽

2020 ◽

Vol 48 (8) ◽

pp. 030006052094045

Author(s):

Zhen Zhang ◽

Yuhan Sun ◽

Xin Chen

Keyword(s):

Cerebral Ischemia ◽

Oxidative Damage ◽

Pc12 Cells ◽

Pc12 Cell ◽

Cell Injury ◽

Inflammatory Responses ◽

Ischemia Reperfusion ◽

Terminal Deoxynucleotidyl Transferase ◽

Enzyme Linked Immunosorbent Assay ◽

Apoptosis Rate

Objective To assess the role of NOD-like receptor C5 (NLRC5; a major NLRC family protein that regulates immunity, inflammation and tissue fibrosis), in cerebral ischemia-reperfusion injury, characterized by inflammation and oxidative damage. Methods Blood NLRC5 levels were assessed in neonates with cerebral ischemia and in healthy controls. A stable PC12 cell line was established that overexpressed or knocked down NLRC5. Inflammatory responses, apoptosis rate and oxidative damage in PC12 cells under oxygen-glucose deprivation/reperfusion (OGD/R) conditions were evaluated using enzyme-linked immunosorbent assay (ELISA), terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) and reactive oxygen species (ROS) assay. Results Blood NLRC5 levels were suppressed in neonates with cerebral ischemia. ELISAs showed that NLRC5 suppressed levels of tumour necrosis factor-α, interleukin (IL)-6, IL-1β, ROS and superoxide dismutase in OGD/R-treated PC12 cells. Furthermore, NLRC5 overexpression was associated with reduced apoptosis rate in PC12 cells treated by OGD/R. Overexpression of NLRC5 also inhibited levels of toll-like receptor (TLR)4, myeloid differentiation primary response protein MyD88 (MyD88) and phosphorylated nuclear factor kappa B-transcription factor p65 (NF-κB p-p65) in PC12 cells, and decreased nuclear levels of NF-κB p-p65. Conclusion NLRC5 alleviated inflammatory responses, oxidative damage and apoptosis in PC12 cells under OGD/R conditions by suppressing activation of the TLR4/MyD88/NF-κB pathway.

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Succinate Is an Inflammation-Induced Immunoregulatory Metabolite in Macrophages

Metabolites ◽

10.3390/metabo10090372 ◽

2020 ◽

Vol 10 (9) ◽

pp. 372 ◽

Cited By ~ 2

Author(s):

Karl J. Harber ◽

Kyra E. de Goede ◽

Sanne G. S. Verberk ◽

Elisa Meinster ◽

Helga E. de Vries ◽

...

Keyword(s):

Immune Responses ◽

Immune Cells ◽

Immune Cell ◽

Inflammatory Responses ◽

Inflammatory Diseases ◽

Cell Phenotype ◽

Independent Manner ◽

Inflammatory Macrophages ◽

Necrosis Factor

Immunometabolism revealed the crucial role of cellular metabolism in controlling immune cell phenotype and functions. Macrophages, key immune cells that support progression of numerous inflammatory diseases, have been well described as undergoing vast metabolic rewiring upon activation. The immunometabolite succinate particularly gained a lot of attention and emerged as a crucial regulator of macrophage responses and inflammation. Succinate was originally described as a metabolite that supports inflammation via distinct routes. Recently, studies have indicated that succinate and its receptor SUCNR1 can suppress immune responses as well. These apparent contradictory effects might be due to specific experimental settings and particularly the use of distinct succinate forms. We therefore compared the phenotypic and functional effects of distinct succinate forms and receptor mouse models that were previously used for studying succinate immunomodulation. Here, we show that succinate can suppress secretion of inflammatory mediators IL-6, tumor necrosis factor (TNF) and nitric oxide (NO), as well as inhibit Il1b mRNA expression of inflammatory macrophages in a SUCNR1-independent manner. We also observed that macrophage SUCNR1 deficiency led to an enhanced inflammatory response without addition of exogenous succinate. While our study does not reveal new mechanistic insights into how succinate elicits different inflammatory responses, it does indicate that the inflammatory effects of succinate and its receptor SUCNR1 in macrophages are clearly context dependent.

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Protective effect of extract of the Camellia japonica L. on cerebral ischemia-reperfusion injury in rats

Arquivos de Neuro-Psiquiatria ◽

10.1590/0004-282x20180146 ◽

2019 ◽

Vol 77 (1) ◽

pp. 39-46 ◽

Cited By ~ 5

Author(s):

Weizhuo Lu ◽

Ling Xv ◽

Jiyue Wen

Keyword(s):

Cerebral Ischemia ◽

Protective Effect ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Infarct Volume ◽

Ischemia Reperfusion ◽

Camellia Japonica ◽

Lactate Dehydrogenase Activity ◽

Cerebral Ischemia Reperfusion ◽

Cerebral Ischemia Reperfusion Injury

ABSTRACT Objective: We investigated the protective effect of the extract of the Camellia japonica L. flower on cerebral ischemia-reperfusion injury in rats. Methods: The rat ischemia-reperfusion injury was induced by middle cerebral artery occlusion for 90 minutes and reperfusion for 48 hours. The animals received an intravenous injection once a day of 20, 40, 80 mg/kg extract of C. japonica for three consecutive days before the ischemia reperfusion. The learning and memory function, the infarct volume, serum malondialdehyde (MDA) level and lactate dehydrogenase activity, and extravasation of immunoglobulin G (IgG) into cerebral parenchyma were assessed as the cell damage index. Results: Pretreatment with extract of C. japonica markedly reduced the infarct volume, serum malondialdehyde level and lactate dehydrogenase activity, and markedly inhibited the extravasation of IgG. Moreover, pretreatment with extract of C. japonica may also inhibit the learning and memory deficits induced by an ischemia-reperfusion injury. Conclusion: It was concluded that pretreatment with extract of C. japonica has a protective effect on cerebral ischemia-reperfusion injury in rats.

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