Neuroprotective Effect of Daidzein Extracted From Pueraria lobate Radix in a Stroke Model Via the Akt/mTOR/BDNF Channel

Daidzein is a plant isoflavonoid primarily isolated from Pueraria lobate Radix as the dry root of P. lobata (Wild.) Ohwi, have long been used as nutraceutical and medicinal herb in China. Despite the report that daidzein can prevent neuronal damage and improve outcome in experimental stroke, the mechanisms of this neuroprotective action have been not fully elucidated. The aim of this study was to determine whether the daidzein elicits beneficial actions in a stroke model, namely, cerebral ischemia/reperfusion (I/R) injury, and to reveal the underlying neuroprotective mechanisms associated with the regulation of Akt/mTOR/BDNF signal pathway. The results showed that I/R, daidzein treatment significantly improved neurological deficits, infarct volume, and brain edema at 20 and 30 mg/kg, respectively. Meanwhile, it was found out that the pretreatment with daidzein at 20 and 30 mg/kg evidently improved striatal dopamine and its metabolite levels. In addition, daidzein treatment reduced the cleaved Caspase-3 level but enhanced the phosphorylation of Akt, BAD and mTOR. Moreover, daidzein at 30 mg/kg treatment enhanced the expression of BDNF and CREB significantly. This protective effect of daidzein was ameliorated by inhibiting the PI3K/Akt/mTOR signaling pathway using LY294002. To sum up, our results demonstrated that daidzein could protect animals against ischemic damage through the regulation of the Akt/mTOR/BDNF channel, and the present study may facilitate the therapeutic research of stroke.

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Thiamet G mediates neuroprotection in experimental stroke by modulating microglia/macrophage polarization and inhibiting NF-κB p65 signaling

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x16679671 ◽

2016 ◽

Vol 37 (8) ◽

pp. 2938-2951 ◽

Cited By ~ 46

Author(s):

Yating He ◽

Xiaofeng Ma ◽

Daojing Li ◽

Junwei Hao

Keyword(s):

Ischemic Stroke ◽

Inflammatory Responses ◽

Infarct Volume ◽

Neuroprotective Effect ◽

Ischemia Reperfusion ◽

Macrophage Polarization ◽

Neurological Deficits ◽

Experimental Stroke ◽

Bv2 Cells ◽

Anti Inflammatory

Inflammatory responses are accountable for secondary injury induced by acute ischemic stroke (AIS). Previous studies indicated that O-GlcNAc modification (O-GlcNAcylation) is involved in the pathology of AIS, and increase of O-GlcNAcylation by glucosamine attenuated the brain damage after ischemia/reperfusion. Inhibition of β-N-acetylglucosaminidase (OGA) with thiamet G (TMG) is an alternative option for accumulating O-GlcNAcylated proteins. In this study, we investigate the neuroprotective effect of TMG in a mouse model of experimental stroke. Our results indicate that TMG administration either before or after middle cerebral artery occlusion (MCAO) surgery dramatically reduced infarct volume compared with that in untreated controls. TMG treatment ameliorated the neurological deficits and improved clinical outcomes in neurobehavioral tests by modulating the expression of pro-inflammatory and anti-inflammatory cytokines. Additionally, TMG administration reduced the number of Iba1+ cells in MCAO mice, decreased expression of the M1 markers, and increased expression of the M2 markers in vivo. In vitro, M1 polarization of BV2 cells was inhibited by TMG treatment. Moreover, TMG decreased the expression of iNOS and COX2 mainly by suppressing NF-κB p65 signaling. These results suggest that TMG exerts a neuroprotective effect and could be useful as an anti-inflammatory agent for ischemic stroke therapy.

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Neuroprotective Effect of DAHP via Antiapoptosis in Cerebral Ischemia

Behavioural Neurology ◽

10.1155/2018/5050469 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 7

Author(s):

Yanhua Qin ◽

Weiming Hu ◽

Yang Yang ◽

Zhiying Hu ◽

Weiyun Li ◽

...

Keyword(s):

Nitric Oxide ◽

Brain Injury ◽

Cerebral Ischemia ◽

Caspase 3 ◽

Focal Cerebral Ischemia ◽

Infarct Volume ◽

Neuroprotective Effect ◽

Ischemia Reperfusion ◽

Tunel Staining ◽

Cox 2

Aberrant production of nitric oxide following inducible nitric oxide synthase (iNOS) expression has been implicated in cell death and contributes to ischemic brain injury. Tetrahydrobiopterin (BH4) is an essential cofactor of NOS activity. Herein, we evaluated antiapoptotic and anti-inflammatory effects of diamino-6-hydroxypyrimidine (DAHP), a guanosine 5′-triphosphate cyclohydrolase 1 (GTPCH1) inhibitor on focal cerebral ischemia-reperfusion injury by middle cerebral artery occlusion and reperfusion (MCAO) and investigated the underlying mechanism. Sprague-Dawley rats were divided into five groups. Experimental groups were subjected to 1.5 h transient MCAO. T2-weighted imaging was performed to evaluate brain edema lesions in the stroke rats. Infarct volume was estimated by 2,3,5-triphenyltetrazolium chloride (TTC) staining after 24 h reperfusion. Western blotting and immunohistochemistry were performed to detect iNOS, caspase-3, Bcl-2, COX-2, and TNF-α protein expressions. Apoptosis was determined by TUNEL staining. T2 hyperintensity changes were observed in primary ischemic region. DAHP pretreatment significantly suppressed iNOS overexpression, caspase-3, and TNF-α. There was also attenuation of neuronal apoptosis with decrement in proteins Bcl-2 and COX-2 expressions. On the basis of our results, we hypothesize DAHP to have a neuroprotective function against focal cerebral ischemia and might attenuate brain injury by decreasing reactive oxygen species (ROS) production, subsequently inhibiting apoptosis.

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Exogenous hydrogen sulfide attenuates cerebral ischemia–reperfusion injury by inhibiting autophagy in mice

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2016-0100 ◽

2016 ◽

Vol 94 (11) ◽

pp. 1187-1192 ◽

Cited By ~ 10

Author(s):

Mengyang Shui ◽

Xiaoyan Liu ◽

Yuanjun Zhu ◽

Yinye Wang

Keyword(s):

Hydrogen Sulfide ◽

Cerebral Ischemia ◽

Ischemia Reperfusion Injury ◽

Infarct Volume ◽

Neuroprotective Effect ◽

Ischemia Reperfusion ◽

Ischemic Injury ◽

Artery Occlusion ◽

Neurological Deficits ◽

Western Blot Assay

Hydrogen sulfide (H2S), the third gas transmitter, has been proven to be neuroprotective in cerebral ischemic injury, but whether its effect is mediated by regulating autophagy is not yet clear. The present study was undertaken to explore the underlying mechanisms of exogenous H2S on autophagy regulation in cerebral ischemia. The effects and its connection with autophagy of NaHS, a H2S donor, were observed through neurological deficits and cerebral infarct volume in middle cerebral artery occlusion (MCAO) mice; autophagy-related proteins and autophagy complex levels in the ischemic hemisphere were detected with Western blot assay. Compared with the model group, NaHS significantly decreased infarct volume and improved neurological deficits; rapamycin, an autophagy activator, abolished the effect of NaHS; NaHS decreased the expression of LC3-II and up-regulated p62 expression in the ischemic cortex 24 h after ischemia. However, NaHS did not significantly influence Beclin-1 expression. H2S has a neuroprotective effect on ischemic injury in MCAO mice; this effect is associated with its influence in down-regulating autophagosome accumulation.

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PPAR-γ Mediates Ta-VNS-Induced Angiogenesis and Subsequent Functional Recovery after Experimental Stroke in Rats

BioMed Research International ◽

10.1155/2020/8163789 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12

Author(s):

Jiani Li ◽

Keming Zhang ◽

Qinbin Zhang ◽

Xueling Zhou ◽

Lan Wen ◽

...

Keyword(s):

Cerebral Ischemia ◽

Molecular Mechanisms ◽

Lentiviral Vector ◽

Neuronal Damage ◽

Infarct Volume ◽

Ischemia Reperfusion ◽

Experimental Stroke ◽

Endothelial Cell Proliferation ◽

Peroxisome Proliferator ◽

Sprague Dawley

Background. Neoangiogenesis after cerebral ischemia in mammals is insufficient to restore neurological function, illustrating the need to design better strategies for improving outcomes. Our previous study has suggested that transcutaneous auricular vagus nerve stimulation (ta-VNS) induced angiogenesis and improved neurological functions in a rat model of cerebral ischemia/reperfusion (I/R) injury. However, the mechanisms involved need further exploration. Peroxisome proliferator-activated receptor-γ (PPAR-γ), well known as a ligand-modulated nuclear transcription factor, plays a crucial role in the regulation of cerebrovascular structure and function. Hence, the present study was designed to explore the role of PPAR-γ in ta-VNS-mediated angiogenesis and uncover the possible molecular mechanisms against ischemic stroke. Methods. Adult male Sprague–Dawley rats were transfected with either PPAR-γ small interfering RNA (siRNA) or lentiviral vector without siRNA prior to surgery and subsequently received ta-VNS treatment. The expression and localization of PPAR-γ in the ischemic boundary after ta-VNS treatment were examined. Subsequently, neurological deficit scores, neuronal damage, and infarct volume were all evaluated. Additionally, microvessel density, endothelial cell proliferation condition, and the expression of angiogenesis-related molecules in the peri-infarct cortex were measured. Results. We found that the expression of PPAR-γ in the peri-infarct cortex increased at 14 d and reached normal levels at 28 d after reperfusion. Ta-VNS treatment further upregulated PPAR-γ expression in the ischemic cortex. PPAR-γ was mainly expressed in neurons and astrocytes. Furthermore, ta-VNS-treated I/R rats showed better neurobehavioral recovery, alleviated neuronal injury, reduced infarct volume, and increased angiogenesis, as indicated by the elevated levels of brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), and phosphorylated endothelial nitric oxide synthase (P-eNOS). Surprisingly, the beneficial effects of ta-VNS were weakened after PPAR-γ silencing. Conclusions. Our results suggest that PPAR-γ is a potential mediator of ta-VNS-induced angiogenesis and neuroprotection against cerebral I/R injury.

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Neuroprotective Effect of Sodium Butyrate against Cerebral Ischemia/Reperfusion Injury in Mice

BioMed Research International ◽

10.1155/2015/395895 ◽

2015 ◽

Vol 2015 ◽

pp. 1-8 ◽

Cited By ~ 28

Author(s):

Jing Sun ◽

Fangyan Wang ◽

Haixiao Li ◽

Huiqing Zhang ◽

Jiangtao Jin ◽

...

Keyword(s):

Cerebral Ischemia ◽

Sodium Butyrate ◽

Caspase 3 ◽

Ischemia Reperfusion Injury ◽

Neuroprotective Effect ◽

Ischemia Reperfusion ◽

Neurological Deficits ◽

Morphological Examination ◽

Neuroprotective Effects ◽

Cerebral Ischemia Reperfusion

Sodium butyrate (NaB) is a dietary microbial fermentation product of fiber and serves as an important neuromodulator in the central nervous system. In this study, we further investigated that NaB attenuated cerebral ischemia/reperfusion (I/R) injury in vivo and its possible mechanisms. NaB (5, 10 mg/kg) was administered intragastrically 3 h after the onset of reperfusion in bilateral common carotid artery occlusion (BCCAO) mice. After 24 h of reperfusion, neurological deficits scores were estimated. Morphological examination was performed by electron microscopy and hematoxylin-eosin (H&E) staining. The levels of oxidative stress and inflammatory cytokines were assessed. Apoptotic neurons were measured by TUNEL; apoptosis-related protein caspase-3, Bcl-2, Bax, the phosphorylation Akt (p-Akt), and BDNF were assayed by western blot and immunohistochemistry. The results showed that 10 mg/kg NaB treatment significantly ameliorated neurological deficit and histopathology changes in cerebral I/R injury. Moreover, 10 mg/kg NaB treatment markedly restored the levels of MDA, SOD, IL-1β, TNF-α, and IL-8. 10 mg/kg NaB treatment also remarkably inhibited the apoptosis, decreasing the levels of caspase-3 and Bax and increasing the levels of Bcl-2, p-Akt, and BDNF. This study suggested that NaB exerts neuroprotective effects on cerebral I/R injury by antioxidant, anti-inflammatory, and antiapoptotic properties and BDNF-PI3K/Akt pathway is involved in antiapoptotic effect.

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The Antiapoptosis Effect of Geum japonicum Thunb. var. chinense Extracts on Cerebral Ischemia Reperfusion Injury via PI3K/Akt Pathway

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2018/7290170 ◽

2018 ◽

Vol 2018 ◽

pp. 1-13 ◽

Cited By ~ 2

Author(s):

Bingjin Ou ◽

Wei Tao ◽

Songbai Yang ◽

Jiateng Feng ◽

Jinfeng Wang ◽

...

Keyword(s):

Cerebral Ischemia ◽

Ischemia Reperfusion Injury ◽

Infarct Volume ◽

Neuroprotective Effect ◽

Ischemia Reperfusion ◽

Activity Level ◽

Neurological Deficits ◽

High Dose ◽

Dependent Manner ◽

Cerebral Ischemia Reperfusion

Geum japonicum Thunb. var. chinense (GJ) is a type of wild vegetable found in China and other Asian countries; it has been reported that its extracts possess a neuroprotective effect against cerebral ischemia reperfusion (CIR) injury. The aim of this study is to explore the effect GJ extracts on transient focal CIR injury and neurons apoptosis and to clarify its possible underlying mechanisms in vivo. Our results indicated that pretreatment with GJ extracts significantly ameliorated the infarct volume, decreased neurological deficits, lessened neural cells apoptosis, downregulated GFAP activity level, and increased surviving neurons. Moreover, GJ extracts preadministration increased Bcl-2 levels and attenuated the increase in the expressions of Bax and it also lowered the cleaved caspase-3 activity in ischemic cortex tissues which was caused by CIR and increased the expression of PI3K and p-Akt. The above effects of high dose of GJ (GJ-H) group were much better than those of low dose of GJ (GJ-L), which indicated that GJ extracts may be helpful in the suppression of CIR injury with a dose-dependent manner.

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A20-Binding Inhibitor of NF-κB 1 Ameliorates Neuroinflammation and Mediates Antineuroinflammatory Effect of Electroacupuncture in Cerebral Ischemia/Reperfusion Rats

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2020/6980398 ◽

2020 ◽

Vol 2020 ◽

pp. 1-14

Author(s):

Xueling Zhou ◽

Wenhao Lu ◽

You Wang ◽

Jiani Li ◽

Yong Luo

Keyword(s):

Cerebral Ischemia ◽

Infarct Volume ◽

Neuroprotective Effect ◽

Ischemia Reperfusion ◽

Artery Occlusion ◽

Neurological Deficits ◽

Sprague Dawley ◽

Cerebral Ischemia Reperfusion ◽

Neuroprotective Strategy

A20-binding inhibitor of NF-κB 1 (ABIN1) is an inhibitor of NF-κB and exerts anti-inflammatory effect. Electroacupuncture (EA) is considered as a neuroprotective strategy by inhibiting neuroinflammatory damage after cerebral ischemia. This study was performed to explore the role of ABIN1 and investigate whether the ABIN1 is involved in the mechanism of EA in cerebral ischemia/reperfusion (I/R) rats. Male Sprague-Dawley (SD) rats were subjected to middle cerebral artery occlusion/reperfusion (MCAO/R) and received EA after reperfusion once a day. Lentivirus-mediated ABIN1 gene knockdown was used to detect the role of ABIN1 in neuroinflammation after I/R. ABIN1 expression, proinflammatory cytokine levels, microglial activation, neurological function, infarct volumes, and NF-κB activation were assessed. ABIN1 expression was elevated in the peri-infarct cortex and was further upregulated by EA. ABIN1 knockdown increased the levels of proinflammatory cytokines and activation of microglia, worsened neurological deficits, and enlarged the infarct volume. Moreover, ABIN1 was blocked to partially reverse the neuroprotective effect of EA, and this treatment weakened the ability of EA to suppress NF-κB activity. Based on these findings, ABIN1 is a potential suppressor of neuroinflammation and ABIN1 mediates the antineuroinflammatory effect of EA in cerebral I/R rats.

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Curcumin Protects Neuron against Cerebral Ischemia-Induced Inflammation through Improving PPAR-Gamma Function

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2013/470975 ◽

2013 ◽

Vol 2013 ◽

pp. 1-10 ◽

Cited By ~ 14

Author(s):

Zun-Jing Liu ◽

Wei Liu ◽

Lei Liu ◽

Cheng Xiao ◽

Yu Wang ◽

...

Keyword(s):

Cerebral Ischemia ◽

Neuronal Damage ◽

Infarct Volume ◽

Critical Role ◽

Ischemic Injury ◽

Ppar Gamma ◽

Neurological Deficits ◽

Protective Effects ◽

Cerebral Ischemic Injury ◽

Cerebral Ischemic

Cerebral ischemia is the most common cerebrovascular disease worldwide. Recent studies have demonstrated that curcumin had beneficial effect to attenuate cerebral ischemic injury. However, it is unclear how curcumin protects against cerebral ischemic injury. In the present study, using rat middle cerebral artery occlusion model, we found that curcumin was a potent PPARγagonist in that it upregulated PPARγexpression and PPARγ-PPRE binding activity. Administration of curcumin markedly decreased the infarct volume, improved neurological deficits, and reduced neuronal damage of rats. In addition, curcumin suppressed neuroinflammatory response by decreasing inflammatory mediators, such as IL-1β, TNF-α, PGE2, NO, COX-2, and iNOS induced by cerebral ischemia of rats. Furthermore, curcumin suppressed IκB degradation that was caused by cerebral ischemia. The present data also showed that PPARγinteracted with NF-κB-p65 and thus inhibited NF-κB activation. All the above protective effects of curcumin on cerebral ischemic injury were markedly attenuated by GW9662, an inhibitor of PPARγ. Our results as described above suggested that PPARγinduced by curcumin may play a critical role in protecting against brain injury through suppression of inflammatory response. It also highlights the potential of curcumin as a therapeutic agent against cerebral ischemia.

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MitoKATP opener, diazoxide, reduces neuronal damage after middle cerebral artery occlusion in the rat

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00054.2002 ◽

2002 ◽

Vol 283 (3) ◽

pp. H1005-H1011 ◽

Cited By ~ 74

Author(s):

Katsuyoshi Shimizu ◽

Zsombor Lacza ◽

Nishadi Rajapakse ◽

Takashi Horiguchi ◽

James Snipes ◽

...

Keyword(s):

Middle Cerebral Artery ◽

Middle Cerebral Artery Occlusion ◽

Cerebral Artery ◽

Ischemia Reperfusion Injury ◽

Neuronal Damage ◽

Infarct Volume ◽

Ischemia Reperfusion ◽

Artery Occlusion ◽

Sham Treatment ◽

Cerebral Artery Occlusion

We investigated effects of diazoxide, a selective opener of mitochondrial ATP-sensitive K+ (mitoKATP) channels, against brain damage after middle cerebral artery occlusion (MCAO) in male Wistar rats. Diazoxide (0.4 or 2 mM in 30 μl saline) or saline (sham) was infused into the right lateral ventricle 15 min before MCAO. Neurological score was improved 24 h later in the animals treated with 2 mM diazoxide (13.8 ± 0.7, n = 13) compared with sham treatment (9.5 ± 0.2, n = 6, P < 0.01). The total percent infarct volume (MCAO vs. contralateral side) of sham treatment animals was 43.6 ± 3.6% ( n = 12). Treatment with 2 mM diazoxide reduced the infarct volume to 20.9 ± 4.8% ( n = 13, P < 0.05). Effects of diazoxide were prominent in the cerebral cortex. The protective effect of diazoxide was completely prevented by the pretreatment with 5-hydroxydecanoate (100 mM in 10 μl saline), a selective blocker of mitoKATP channels ( n = 6). These results indicate that selective opening of the mitoKATP channel has neuroprotective effects against ischemia-reperfusion injury in the rat brain.

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