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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.
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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.
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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.
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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.
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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.
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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.
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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.
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Humans , Male , Female , Postoperative Complications/prevention & control , Coronary Artery Bypass/rehabilitation , Cognition Disorders/prevention & control , Hypotension , Postoperative Complications/etiology , Postoperative Period , Coronary Artery Bypass/adverse effects , Risk Factors , Cognition Disorders/etiology , Extracorporeal Circulation , Arterial Pressure , Neuropsychological TestsABSTRACT
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.
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Animals , Male , Rats , Neuroprotective Agents/pharmacology , Epilepsy/drug therapy , Adenosine A1 Receptor Agonists/pharmacology , Hippocampus/drug effects , Pilocarpine/toxicity , Time Factors , Rats, Sprague-Dawley , Apoptosis/drug effects , Lithium Chloride/toxicity , Disease Models, Animal , Hippocampus/pathology , Neurons/pathologyABSTRACT
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)
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Humans , Female , Pregnancy , Infant, Newborn , Infant, Premature , Cerebral Palsy/prevention & control , Neuroprotection/drug effects , Magnesium/adverse effects , Magnesium Sulfate/therapeutic use , Randomized Controlled Trials as Topic , Databases, Bibliographic , Neuroprotective Agents , Contraindications, DrugABSTRACT
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.
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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.
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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.
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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.
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Objective To observe the effect of remote post-ischemic conditioning(RPIOC)on the cerebral blood flow,neural function and prognosis of patients with acute cerebral infarction and the risk factors for short-term prognosis.Methods 133 patients with acute cerebral infarction in the Second Hospital of Beijing from January 2016 to December 2017 were selected,and randomly divided into the RIPOC group(66 cases,with RPIOC)and the control group(67 cases,without RIPOC).In the first day after hospital,patients in the RIPOC group were given RIPOC,which was tightening the left aim with a tonometer bandage for 5 minutes per time and 2 times a day at an interval of 5 minutes.All patients were provided routine treatment.All patients' cerebral blood flow,neural function and survival data were recorded.Recovery was assessed by modified Rankin Scale(mRS)180 d after stroke.Logistic regression was used to evaluate the risk factors for prognosis.Results Of the 133 patients enrolled,there were 67 males.The mean age was (73.1 ± 10.1)year.Basic clinical characteristics,neural function and cerebral blood flow were similar between groups(P＞0.05).After 10 d treatment,cerebral blood flow and neural function was significantly increased (P＜0.05)in the RIPOC group.After 180 d follow up,the RIPOC group had significantly higher rate of adverse cerebrovascular events(P＜0.05).Logistic regression analyses demonstrated that advanced age(P =0.003),hypertension(P =0.03)and high NIHSS score(P =0.005)were all risk factors for prognosis.Conclusions RIPOC can enhance the cerebral blood flow,activities of daily living,limb function and prognosis.However,it does not reduce the risk of mortality.Advanced age,hypertension and high NIHSS score are risk factors for short-term prognosis.
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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.
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Uric acid is an end product of purine metabolism. A large number of clinical studies have shown that high-level serum uric acid is a good predictor of outcome in patients with acute ischemic stroke. Oxidative stress is the main mechanism of cerebral ischemia-reperfusion injury. As a potent antioxidant, uric acid is considered to have a potential neuroprotective effect in the vascular recanalization treatment, but its specific mechanism remains unclear. This article reviews the neuroprotective mechanism of uric acid in cerebral ischemia-reperfusion injury in order to provide ideas for future research and clinical practice.
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Objective To investigate the effect of serum uric acid level on outcomes after intravenous thrombolysis in patients with acute ischemic stroke. Methods From April 2014 to January 2018I, patients with acute ischemic stroke received intravenous thrombolysis at the stroke unit of Shenzhen Second People's Hospital were enrolled retrospectively. The clinical outcomes were assessed according to the modified Rankin scale at 3 months after onset, > 2 were defined as poor outcome. The demographic and clinical data were compared between the good outcome group and the poor outcome group. Multivariate logistic regression analysis was used to determine the independent influencing factors of clinical outcomes. Results A total of 155 patients were enrolled, including 92 (59. 4％) in the good outcome group and 63 (40. 6％) in the poor outcome group. The serum uric acid level in the good outcome group was significantly higher than that in the poor outcome group (365. 465 ±100. 055 μmol/L vs. 325. 958 ±114. 704 μmol/L; t = -2. 227,P = 0. 027). Multivariate logistic regression analysis showed that there was a significant positive correlation between low serum uric acid levels and poor outcomes (They were divided into 4 levels according to the quantiles. ≥416. 01 μmol/L as reference; 350. 11- 416. 00 μmol/L: odds ratio [ OR ] 1. 414, 95％ confidence interval [CI] 0. 375-5. 339, P = 0. 609; 278. 61-350. 10 μmol/L: OR 3. 020, 95％ CI 0. 878- 10. 390, P = 0. 080; ≤ 278. 60 μmol/L: OR 4. 194, 95％ CI 1. 194-14. 726, P = 0. 025; trend test P =0. 013]. Conclusion Higher serum uric acid level is independently associated with good outcomes after intravenous thrombolysis in patients with acute ischemic stroke.
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Objective To investigate the role of phosphatidyl inositol 3 kinase (PI3K)/Akt pathway in the protection of focal cerebral ischemia reperfusion injury in rats with limb ischemic postconditioning (LIP) by detecting the expression levels of p-Akt protein, and caspase-9 and Bcl-2 mRNAs after remote LIP. Methods Forty-two Wistar rats were randomly assigned to 3 groups: sham operation, ischemia-reperfusion (IR) and LIP groups. The middle cerebral artery ischemia-reperfusion injury model was induced by the suture method in the IR group and the LIP group. In the LIP group, three circulatory LIP ( 5 min ischemia/5 min reperfusion) in the contralateral femoral artery were performed before reperfusion 2 h after cerebral ischemia. Infarct volume was measured by 2,3,5-triphenyltetrazolium chloride staining. The expression of p-Akt protein was detected by immunohistochemical staining and the expression levels of cystin-9 and Bcl-2 mRNAs were detected by in situ hybridization. Results Compared with the IR group, the infarct volume in the LIP group was significantly reduced ( P<0.05). The expression levels of p-Akt protein and Bcl-2 mRNA significantly increased (all P<0.05), and the expression level of caspase-9 mRNA significantly decreased (P<0.05). Conclusions LIP can reduce the volume of cerebral infarction in focal cerebral ischemia-reperfusion injury in rats. Its mechanism may be involved in up-regulation of p-Akt protein and Bcl-2 mRNA expression and down-regulation of caspase-9 mRNA expression, suggesting that LIP can alleviate cerebral ischemia-reperfusion injury through PI3K/Akt pathway.
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Ischemic stroke is a common neurological disease. MicroRNAs not only play an important role in acute phase of ischemic stroke, but also regulate neurogenesis and angiogenesis after stroke. This article reviews the research progress and prospects of microRNAs as a therapeutic target for ischemic stroke.
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Heme oxygenase (HO) -1 is the most bioactive HO type. It reduces tissue damage by exerting antioxidant, anti-inflammatory, and cytoprotective effects during ischemia-reperfusion injury. It is considered to be a new direction for the treatment of ischemia-reperfusion injury. This article reviews the role of HO-1 in ischemia-reperfusion injury and its possible mechanisms.