Neuroprotective therapy for acute ischemic stroke in the era of endovascular therapy / 国际脑血管病杂志

In recent years, endovascular therapy has become the most important progress in the field of the treatment of acute ischemic stroke caused by large vessel occlusion. However, the vascular recanalization shown by imaging after endovascular treatment cannot fully translate into effective tissue reperfusion and functional outcome, a phenomenon known as "futile recanalization". Combined neuroprotective therapy after vascular recanalization is expected to reduce the occurrence of futile recanalization and improve the outcome of patients. This article briefly summarizes the main application progress of commonly used neuroprotective therapies in clinical practice (edaravone dexborneol, glucocorticoids, hypothermia, and remote ischemic conditioning). It explores the trend and direction of combining endovascular therapy and neuroprotective therapy for patients with acute ischemic stroke caused by large vessel occlusion, and provides further reference and suggestions for intervention measures after endovascular therapy.

New role of astrocytes in neuroprotective mechanisms after ischemic stroke / Novo papel dos astrócitos nos mecanismos neuroprotetores após acidente vascular cerebral isquêmico

Abstract Astrocytes are the most abundant cell subtypes in the central nervous system. Previous studies believed that astrocytes are supporting cells in the brain, which only provide nutrients for neurons. However, recent studies have found that astrocytes have more crucial and complex functions in the brain, such as neurogenesis, phagocytosis, and ischemic tolerance. After an ischemic stroke, the activated astrocytes can exert neuroprotective or neurotoxic effects through a variety of pathways. In this review, we will discuss the neuroprotective mechanisms of astrocytes in cerebral ischemia, and mainly focus on reactive astrocytosis or glial scar, neurogenesis, phagocytosis, and cerebral ischemic tolerance, for providing new strategies for the clinical treatment of stroke.

Resumo Os astrócitos são os subtipos de células mais abundantes no sistema nervoso central. Estudos anteriores acreditavam que os astrócitos são células de suporte no cérebro, que apenas fornecem nutrientes para os neurônios. No entanto, estudos recentes descobriram que os astrócitos têm funções mais cruciais e complexas no cérebro, como neurogênese, fagocitose e tolerância isquêmica. Após um acidente vascular cerebral isquêmico, os astrócitos ativados podem exercer efeitos neuroprotetores ou neurotóxicos através de uma variedade de vias. Nesta revisão, discutiremos os mecanismos neuroprotetores dos astrócitos na isquemia cerebral, e focaremos principalmente na astrocitose reativa ou cicatriz glial, neurogênese, fagocitose e tolerância isquêmica cerebral, para fornecer novas estratégias para o tratamento clínico do acidente vascular cerebral.

Complement system: possible intervention targets for post-stroke cognitive impairment in patients with ischemic stroke / 国际脑血管病杂志

Post-stroke cognitive impairment (PSCI) refers to a clinical syndrome that occurs after a stroke and meets the diagnostic criteria for cognitive impairment, lasting for more than 6 months, and seriously affecting the daily life of patients. The complement system has been confirmed to be associated with PSCI. This article reviews the correlation between complement system and PSCI, as well as the possibility of complement system as an intervention target for PSCI.

Progress in antenatal magnesium sulfate exposure for neuroprotection in preterm infants / 中华围产医学杂志

Magnesium sulfate has been administered to pregnant women at imminent risk of preterm delivery for fetal neuroprotection, but its adverse effects and target population have not been fully studied. This paper summarizes the current protocols according to the existing guidelines and the latest research progress, including the gestational age at intervention, dose, duration of therapy and the need for re-administration, hoping to provide a reference for the clinical use of magnesium sulfate for fetal neuroprotection in China.

Transcription factor EB attenuates neuronal damage following cerebral ischemia via regulating autophagy-lysosomal pathway / 国际脑血管病杂志

The disorder of autophagy lysosomal pathway (ALP) is an important pathogenesis of neuronal damage after cerebral ischemia, and the restoration of ALP may alleviate neuronal damage after cerebral ischemia. As the main transcription factor regulating ALP, transcription factor EB (TFEB) can directly regulate autophagosome generation, autophagosome-lysosome fusion, and autophagic flux by regulating the expression of autophagic genes and lysosomal genes. Therefore, regulating TFEB can alleviate ALP dysfunction and thereby reduce cerebral ischemic damage. This article reviews the structure, biological function of TFEB and its role in regulating ALP to alleviate neuronal damage after cerebral ischemia.

Protective effect of fibroblast growth factor 21 on ischemic stroke / 国际脑血管病杂志

As a multifunctional signal molecule, fibroblast growth factor 21 (FGF21) has been proved to have a variety of biological effects, including anti-inflammatory, antioxidant stress, and neuroprotection. This article reviews the latest research progress on the protective effect of FGF21 in ischemic stroke and its relationship with cognitive impairment.

Pioglitazone attenuates white matter injury in mice with cerebral ischemia-reperfusion / 国际脑血管病杂志

Objective:To investigate the effect of pioglitazone on white matter injury after cerebral ischemia-reperfusion in mice and its mechanism.Methods:Forty-two young male C57BL/6J mice were randomly divided into sham operation group, model group, and pioglitazone group ( n=14 in each group). The model of cerebral ischemia-reperfusion was induced by transient middle cerebral artery occlusion with suture-occluded method. On the 3 rd and 7 th day after the establishment of the model, the neural function was assessed by the adhesive removal test. The mice were killed on the 7 th day after the establishment of the model. HE staining was used to detect the extent of cerebral infarction. Immunofluorescence staining and Western blot analysis were used to detect the degree of white matter damage and the changes of microglia phenotype. Results:On the 7 th day after cerebral ischemia-reperfusion, the adhesive removal time in the PGZ group was significantly shortened compared with the model group ( P<0.05), the percentage of cerebral infarction volume was significantly reduced ( P<0.05), the ratio of MBP/NF200 fluorescence intensity in the cortical and striatal areas was significantly increased (all P<0.05), and the number of CD16 +/Iba1 + microglia was significantly decreased ( P<0.01), while the number of CD206 +/Iba1 + microglia tended to increase, but there was no statistical difference. Conclusion:Pioglitazone may reduce the degree of white matter injury and nerve function damage in mice with cerebral ischemia-reperfusion, and its mechanism may be associated with regulating the transformation of microglia from M1 type to M2 type.

Neuroprotective effect of cerebroprotein hydrolysate-Ⅰ on ischemia-reperfusion injury in rats / 国际脑血管病杂志

Objective:To investigate the neuroprotective effect of cerebroprotein hydrolysate (CH) -Ⅰ on cerebral ischemia-reperfusion injury in rats and its mechanism.Methods:Eighty adult healthy male SD rats were randomly divided into sham operation group, model group, CH-Ⅰ intervention group and cerebrolysin (CBL) positive control group. The model of ischemia-reperfusion injury was induced by temporarily occluding the left middle cerebral artery with suture-occluded method. The CH-Ⅰ and CBL groups intraperitoneally injected with CH-Ⅰ and CBL at 0, 3, 6 and 12 h after reperfusion at the dose of 20 mg/kg. The sham operation group and the model group were injected with the same volume of normal saline. At 24 h after reperfusion, the behavior changes of the rats were detected by the modified neurological severity score (mNSS). The volume of cerebral infarction was detected by TTC staining. The morphology and structure of neurons in ischemic cortex were observed by Nissl staining. The apoptosis of neurons in ischemic cortex was detected by TUNEL staining. The expression changes of phosphorylated extracellular signal-regulated kinase (pERK) 1/2, phosphorylated mitogen-activated protein kinase/extracellular signal-regulated kinase (pMEK) 1/2, phosphorylated cAMP response element binding protein (pCREB) and brain-derived neurotrophic factor (BDNF) in the ischemic cortex were detected by Western blot.Results:At 24 h after reperfusion, the mNSS score and cerebral infarct volume in the model group were significantly higher and larger than those in the sham group (all P<0.001). The mNSS scores and cerebral infarct volumes in the CH-Ⅰ and CBL groups were significantly reduced compared with those in the model group (all P<0.05), but there was no significant difference between the CH-Ⅰ group and the CBL group. Nissl and TUNEL staining showed that the degenerative cell index and apoptotic cell index in the CH-Ⅰ group were significantly lower than those in the model group (all P<0.01), but there were no significant difference between the CH-Ⅰ group and the CBL group. Western blot analysis showed that compared with the sham operation group, the pMEK1/2, pERK1/2 and pCREB expressions in ischemic cortex were significantly enhanced and the BDNF expression was significantly attenuated in the model group ( P<0.05). Compared with the model group, pMEK1/2, pERK1/2, and pCREB expressions in the CH-Ⅰ group were significantly decreased (all P<0.05), and the BDNF expression was significantly increased ( P<0.05). Conclution:CH-Ⅰ can reduce cerebral infarct volume and improve neurological function, and its mechanism may be associated with the inhibition of the MEK-ERK-CREB pathway as well as the enhancement of BDNF expression.

Neuroprotective effect of low mean arterial pressure on postoperative cognitive deficit attenuated by prolonged coronary artery bypass time: a meta-analysis

Abstract Introduction: The true influence of the low mean arterial pressure (low MAP) during coronary artery bypass grafting (CABG) on the development of postoperative cognitive deficit (POCD) remains controversial. We aimed to perform a meta-analysis and meta-regression to determine the effect of low MAP on POCD, as well as moderator variables between low MAP and POCD. Methods: The Web of Science, PubMed database, Scopus and the Cochrane Library database (up to June 2018) were searched and retrieved articles systematically reviewed. Only randomized controlled trials (RCTs) comparing maintenance of low MAP (<80 mmHg) and high MAP (>80 mmHg) during cardiopulmonary bypass (CPB) were included in our final review. Statistical analysis of the risk ratio (RR) and corresponding 95% confidence interval (CI) was used to report the overall effect. The overall effect and meta-regression analysis were done using Mantel-Haenszel risk ratio (MHRR) and the corresponding 95% confidence interval (CI). Results: A total of 731 patients in three RCTs were included in this study. POCD occurred in 6.4% of all cases. Maintenance of low MAP did not reduce the occurrence of POCD (MHRR 1.012 [95% CI 0.277-3.688]; Z=0.018; P=0.986; I2=66%). Shorter CPB time reduced the occurrence of POCD regardless of group assignment (MH log risk ratio -0.519 [95% CI -0.949 - -0.089]; Z= -2.367; P=0.017). Conclusion: POCD is a common event among CABG patients. The neuroprotective effect of low MAP on POCD was attenuated by the prolonged CPB time.

Adenosine a1 receptor agonist protects against hippocampal neuronal injury after lithium chloride-pilocarpine-induced epilepsy

Abstract Background Adenosine A1 receptor (AA1R) is widely present in the central nervous system, exerting brain protective antiepileptic effects, mainly by binding corresponding G proteins. We evaluated the neuroprotective effects of AA1R on hippocampal neuronal injury after lithium chloride-pilocarpine-induced epilepsy in rats. Materials and Methods A total of 60 male SD rats were randomly divided into four groups (n = 15/group): normal control, epilepsy, epilepsy + AA1R antagonist (DPCPX), and epilepsy + AA1R agonist (2-CAdo). An epilepsy model was established through kindling by lithium chloride-pilocarpine. The four groups were observed on days 1, 14, and 30. Pathological and morphological changes of hippocampal neurons were observed by HE staining; apoptosis was detected by TUNEL assay. Caspase-3 and GABA receptor expressions were detected by Western blot. Results In the hippocampal CA3 area of the epilepsy group, the cellular structure was not neatly arranged, and some neurons were swelling, thick, and incomplete. Compared with the epilepsy group at the same time point, cells in the epilepsy + DPCPX group had an increased distortion, disorganization, edema, cytoplasmic vacuoles, and degeneration. In the epilepsy + 2-CAdo group, cell arrangement was regular and orderly, and structural damages were lessened. Compared with the normal control group at the same time point, the epilepsy group underwent evident neuronal apoptosis, with a significantly higher apoptotic index (AI) (p < 0.05). Compared with the epilepsy group, the neuronal apoptosis of the epilepsy + DPCPX group was boosted, and the AI significantly increased (p < 0.05). The neuronal apoptosis of the epilepsy + 2-CAdo group was inhibited, and the AI significantly decreased (p < 0.05). Compared with the epilepsy group, the caspase-3 expression levels of the epilepsy + DPCPX group on days 14 and 30 were significantly upregulated (p < 0.05), but those of the epilepsy + 2-CAdo group were significantly downregulated (p < 0.05). Conclusions AA1R abated cell edema and reduced apoptosis, exerting neuroprotective effects on hippocampal neuronal injury after lithium chloride-pilocarpine-induced epilepsy.

Roles and mechanisms of chemokine CX3CL1 in cerebral ischemia / 国际脑血管病杂志

Chemokine CX3CL1 mainly participates in the physiological and pathological processes of nervous system by activating its receptor CX3CR1.Under physiological conditions,CX3CL1 can inhibit the activation of microglia;when cerebral ischemia and hypoxia,CX3CL1 can affect the expression of multiple downstream target genes involved in activation of adenosine receptor,inhibition of Ca 2+ influx,and promotion of blood vessel growth.It is of great significance to improve the energy metabolism disorder and to establish microcirculation around infarcts after cerebral ischemia.

Roles and mechanisms of chemokine CX3CL1 in cerebral ischemia / 国际脑血管病杂志

Chemokine CX3CL1 mainly participates in the physiological and pathological processes of nervous system by activating its receptor CX3CR1. Under physiological conditions, CX3CL1 can inhibit the activation of microglia; when cerebral ischemia and hypoxia, CX3CL1 can affect the expression of multiple downstream target genes involved in activation of adenosine receptor, inhibition of Ca2+ influx, and promotion of blood vessel growth. It is of great significance to improve the energy metabolism disorder and to establish microcirculation around infarcts after cerebral ischemia.

Roles of sphingosine 1-phosphate in ischemic stroke: a potential therapeutic target for neuroprotection / 国际脑血管病杂志

Ischemic stroke is one of the most important causes of death and disability in humans,but the effective methods for treating brain injury after stroke are quite limited.Sphingosine 1-phosphate (S1P) is a pleiotropic lipid.There is certain interdependence between its metabolism and regulation and the molecular mechanisms involved in important biological events following cerebral ischemia.Membrane lipid therapy with S1P as the core may be an effective neuroprotective strategy of ischemic stroke.

Role of microRNA in ischemic brain injury / 国际脑血管病杂志

MicroRNAs (miRNAs) are a class of short non-coding single-stranded RNAs.They can regulate gene expression at the post-transcriptional level by binding to the T-untranslated region of the target gene mRNA and participate in the regulation of almost all biological processes.Recent studies have shown that MiRNAs are widely involved in a variety of pathophysiological processes in ischemic brain injury,such as excitotoxicity,oxidative stress,inflammation,apoptosis,and cerebral edema,suggesting that they may serve as a biomarker for ischemic stroke,assisting early diagnosis and outcome assessment,and becoming a drug treatment target.

Neuroproteção fetal: uma utilização contemporânea do sulfato de magnésio / Fetal neuroprotection: a contemporary use of magnesium sulfate

Os principais usos contemporâneos do sulfato de magnésio na prática obstétrica incluem a prevenção e o tratamento de convulsões em portadoras de pré-eclâmpsia e eclâmpsia, o prolongamento da gravidez para administração antenatal de corticosteroides e a neuroproteção fetal na iminência de interrupção prematura da gestação, uma indicação mais recente. A paralisia cerebral é a causa mais comum de deficiência motora na infância e apresenta como fator de risco mais importante o nascimento pré-termo, cuja incidência tem aumentado significativamente. Como consequência, a ocorrência da paralisia cerebral também tem aumentado, a despeito da melhoria da sobrevida dos fetos pré-termos. No atual contexto de procura por estratégias que se mostrem efetivas na redução da paralisia cerebral nos recém-nascidos prematuros e que deveriam ser implementadas com o objetivo de diminuir os seus efeitos danosos nos indivíduos e suas famílias, nos serviços de saúde e na sociedade como um todo, o sulfato de magnésio tem se mostrado como o mais promissor agente neuroprotetor fetal. Desde a década de 1990, estudos resultantes das suas indicações para a prevenção das convulsões eclâmpticas ou para tocólise têm evidenciado redução nas taxas de paralisia cerebral e leucomalácia periventricular em prematuros. Diretrizes nacionais e internacionais mais recentes, baseando-se em resultados de ensaios randomizados controlados e metanálises de boa qualidade, têm avançado na recomendação sobre os regimes terapêuticos e na construção de algoritmos para utilização do sulfato de magnésio na neuroproteção fetal.(AU)

The main contemporary uses of magnesium sulfate in obstetric practice include the prevention and treatment of seizures in patients with preeclampsia and eclampsia, prolongation of pregnancy for antenatal administration of corticosteroids and fetal neuroprotection at the imminence of premature termination of pregnancy, a more recent indication. Cerebral palsy is the most common cause of motor deficits in childhood and has a significant increase in preterm birth as a major risk factor. As a result, the occurrence of cerebral palsy has also increased, despite the improvement in the survival of preterm fetuses. In the current context of search for strategies that are effective in reducing cerebral palsy in preterm newborns and that should be implemented with the aim of reducing their harmful effects on individuals and their families, health services and society as a whole, magnesium sulfate has been shown to be the most promising fetal neuroprotective agent. Since the 1990s, studies arising from its indications for prevention of eclamptic seizures or tocolysis have shown a reduction in the rates of cerebral palsy and periventricular leukomalacia in preterm infants. More recent national and international guidelines, based on results from randomized controlled trials and good quality meta-analyzes, have advanced the recommendation on therapeutic regimens and the construction of algorithms for the use of magnesium sulphate in fetal neuroprotection.(AU)

Neuroprotective effects of brimonidine on retinal ganglion cells induced by oxidative stress mitochondrial dysfunction / 中华实验眼科杂志

Objective To explore whether brimonidine has a protective effect on retinal ganglion cells (RGCs) through improving mitochondrial function under the oxidative stress.Methods Mouse RGC-5 cells were cultured in DMEM medium containing low concentration of glucose (1 g/L),10％ fetal bovine serum and 100 U/ml penicillin-streptomycin solution.The cells were divided into normal control group,H2O2-treated group and brimonidine+ H2O2 group.H2O2 at the concentration of 800 μmol/L was added into the medium in the H2O2-treated group,and 1 μmol/L brimonidine was added into the medium for 2 hours prior to the addition of H2O2 in the brimonidine+H2O2 group.The cells were sequently cultured for 24 hours.The morphology of the cell nucleus was examined by Hoechst fluorscence staining.The expressions of apoptosis-related protein in the cells were detected by Western blot assay.Mitochondrial membrane potential was assessed by JC-1 staining.Results The cell nuclei showed round or oval in shape with consistent size in the normal control group.The pycnosis and karyorrhexis of the cell nuclei were seen in the H2O2-treated group,and less abnormal nuclei were found in the brimonidine+H2O2 group.The relative expression level of bcl-2 protein in the cells was 0.76±0.15,0.50±0.13 and 0.75±0.17 in the normal control group,H2O2-treated group and brimonidine + H2O2 group,respectively,and the expression of bcl-2 protein in the H2O2-treated group was significantly lower than that in the normal control group and brimonidine+H2O2 group (both at P＜0.05).The relative expression level of bax protein in the cells was 0.65±0.13,0.83±0.07 and 0.70±0.10 in the normal control group,H2O2-treated group and brimonidine+H2O2 group,respectively,and the expression of bax protein in the H2O2-treated group was significantly higher than that in the normal control group and brimonidine+H2O2 group (both at P＜0.05).A strong orange fluorescence was seen in the mitochondrial membrane of RGC-5 in the normal control group with a coexpression with the green fluorescence of cell membrane.In the H2O2-treated group,the orange fluorescence intensity in the cells was evidently weakened,and the number of JC-1 responsed cells was considerably increased and the orange fluorescence intensity was enhanced in the brimonidine + H2O2 group.Conclusions Brimonidine can prevent RGCs from oxidative-stress damage by improving the mitochondrial function and therefore play a potential neuroprotective effect on optic nerve.

TLR2 antagonist T2.5 attenuates cerebral ischemic injury by down-regulating of MMP-9 through MyD88 signaling pathway / 国际脑血管病杂志

Objective To investigate the mechanism of action of toll-like receptor 2 (TLR2),myeloid differentiation factor 88 (MyD88),and matrix metalloproteinase-9 (MMP-9) in cerebral ischemia-reperfusion injury in rats.Methods One hundred twenty-fiwe adult male SD rats were randomly divided into sham operation group,cerebral ischemia group and T2.5 (TLR2 antagonist) treatment group.A model of middle cerebral artery occlusion was induced by suture method.T2.5 (0.121 2 μg/g) was injected into jugular vein at the beginning of reperfusion in the T2.5 treatment group.Cerebral infarction volume,brain edema,bloodbrain barrier permeability and neurological deficit score were measured at 24 h after reperfusion.Western blotting was used to determine the expression levels of TLR2,MyD88 and MMP-9 at different time points in the ischemic cortex.Results Western blot analysis showed that compared with the sham operation group,the expression levels of TLR2 and MyD88 in the ischemic group increased significantly from 6 h after ischemia-reperfusion and lasted for 24 h (all P ＜ 0.05),while MMP-9 increased significantly at 24 h after ischemia-reperfusion (P ＜ 0.05).At 24 h after ischemia-reperfusion,the blood-brain barrier permeability,brain edema degree,cerebral infarction volume,and neurological deficit score in the ischemic group were significantly higher than those in the sham operation group (all P ＜0.05);at this time,the expression levels of TLR2,MyD88 and MMP-9 in the T2.5 treatment group were significantly lower than those in the ischemic group (all P＜ 0.05),and the blood-brain barrier permeability,brain edema degree,cerebral infarction volume,and neurological deficit score were significantly reduced (all P＜ 0.05).Conclusion TLR2,MyD88 and MMP-9 might be involved in cerebral ischemia-reperfusion injury.TLR2 antagonist T2.5 might inhibit the expression of MMP-9 through TLR2-MyD88 signaling pathway,thus alleviating cerebral ischemia-reperfusion injury.

Neuroprotective effect of lipopolysaccharide preconditioning on cerebral ischemia and its mechanism / 国际脑血管病杂志

Cerebral ischemic preconditioning can make the brain tissue resistant to subsequent ischemic injury,i.e.ischemic tolerance,thereby reducing ischemia-reperfusion injury.A large number of studies have shown that lipopolysaccharide preconditioning can exert neuroprotective effects against cerebral ischemic injury by initiating endogenous protective mechanisms.This article reviews the cellular and molecular mechanisms of lipopolysaccharide preconditioning induced cerebral ischemic tolerance.

Melatonin attenuates cerebral ischemia-reperfusion injury in mice by inhibiting endoplasmic reticulum stress / 国际脑血管病杂志

Objective To investigate the effect of melatonin against cerebral ischemia reperfusion injury (CIRI) in mice and its mechanism.Methods Thirty male C57BL/6 mice were randomly divided into sham operation group,CIRI group,and melatonin treatment group (n =10 in each group).A middle cerebral artery occlusion model was induced by suture method.The degree of brain injury was evaluated by neurological function score,brain water content,and cerebral infarction volume.Western blot analysis was used to detect apoptosis-related proteins Bim,Bcl-2,and endoplasmic reticuhm stress-related molecules C/ EBP homologous protein (C/EBP) expression.Results Compared with the CIRI group,the neurological function score was significantly improved,the degree of cerebral edema was significantly reduced,and the volume of cerebral infarction was significantly reduced in the melatonin treatment group (all P ＜0.05).In addition,the expression of Bcl-2 was significantly up-regulated in the melatonin treatment group,and the expression of Bim and CHOP was significantly down-regulated (all P ＜ 0.05).Conclusion Melatonin may play an anti-CIRI role by regulating CHOP,and endoplasmic reticulum stress plays an important role in CIRI.

Vascular endothelial growth factor: a potential therapeutic target for ischemic stroke / 国际脑血管病杂志

Vascular endothelial growth factor (VEGF) plays an important role in angiogenesis and vascular regeneration after cerebral ischemia.On one hand,VEGF plays a neuroprotective effect by promoting angiogenesis and neurogenesis;on the other hand,VEGF induced endothelial permeability can cause blood-brain barrier (BBB) dysfunction.Exercise preconditioning can up-regulate the expression of VEGF and reduce the ischemic brain damage by enhancing the cerebral microvascular integrity.VEGF can be used as a therapeutic target for ischemic stroke.