Green tea polyphenols inhibit cognitive impairment induced by chronic cerebral hypoperfusion via modulating oxidative stress

Responses to oxidative stress contribute to damage caused by chronic cerebral hypoperfusion, which is characteristic of certain neurodegenerative diseases. We used a rat model of chronic cerebral hypoperfusion to determine whether green tea polyphenols, which are potent antioxidants and free radical scavengers, can reduce vascular cognitive impairment and to investigate their underlying mechanisms of action. Different doses of green tea polyphenols were administered orally to model rats from 4 to 8 weeks after experimentally induced cerebral hypoperfusion, and spatial learning and memory were assessed using the Morris water maze. Following behavioral testing, oxygen free radical levels and antioxidative capability in the cortex and hippocampus were measured biochemically. The levels of lipid peroxidation and oxidative DNA damage were assessed by immunohistochemical staining for 4-hydroxynonenal and 8-hydroxy-2′-deoxyguanosine, respectively. Rats that received green tea polyphenols 400 mg/kg per day had better spatial learning and memory than saline-treated rats. Green tea polyphenols 400 mg/kg per day were found to scavenge oxygen free radicals, enhance antioxidant potential, decrease lipid peroxide production and reduce oxidative DNA damage. However, green tea polyphenols 100 mg/kg per day had no significant effects, particularly in the cortex. This study suggests that green tea polyphenols 400 mg/kg per day improve spatial cognitive abilities following chronic cerebral hypoperfusion and that these effects may be related to the antioxidant effects of these compounds.     

综述与专论: 高压氧疗法治疗脑缺血的相关机制

脑缺血是指大脑各部分血液供应不足导致脑组织缺血缺氧，进而导致密集缺血区脑组织出现不可逆的损伤坏死，其高致残率、高死亡率会对患者及其家庭造成严重的伤害。在脑缺血发生后，及时采取一定的治疗措施控制梗死灶的大小，并挽救半暗带中的细胞是脑缺血预后的关键。高压氧疗法是针对脑缺血的一种潜在治疗方法，在近年来得到了越来越广泛的关注和研究，本文旨在综述近年来国内外关于高压氧疗法治疗脑缺血的相关机制及研究进展，为脑缺血患者的治疗和预后提供新思路。     

Synergism of plant-derived polyphenols in adipogenesis: perspectives and implications

Dietary polyphenols may exert their pharmacological effect via synergistic interactions with multiple targets. Putative effects of polyphenols in the management of obesity should be primarily evaluated in adipose tissue and consequently in well-documented cell model. We used Hibiscus sabdariffa (HS), a widely recognised medicinal plant, as a source of polyphenols with a number of salutary effects previously reported. We present here the full characterisation of bioactive components of HS aqueous extracts and document their effects in a model of adipogenesis from 3T3-L1 cells and in hypertrophic and insulin-resistant adipocytes. Aqueous extracts were up to 100 times more efficient in inhibiting triglyceride accumulation when devoid of fibre and polysaccharides. Significant differences were also observed in reactive oxygen species generation and adipokine secretion. We also found that, when polyphenols were fractionated and isolated, the benefits of the whole extract were greater than the sum of its parts, which indicated a previously unnoticed synergism. In conclusion, polyphenols have interactive and complementary effects, which suggest a possible application in the management of complex diseases and efforts to isolate individual components might be irrelevant for clinical medicine and/or human nutrition.     

Neuroprotection by the soy isoflavone, genistein, via inhibition of mitochondria-dependent apoptosis pathways and reactive oxygen induced-NF-κB activation in a cerebral ischemia mouse model

Recently, the treatment of stroke has focused on antioxidant therapies, where oxidative stress is implicated. The preventive and therapeutic potential of plant compounds on ischemic stroke has been intensively studied because many of them contain antioxidant properties. Genistein, one of the active ingredients in soybean, possesses many bioactivities. In this study, we investigated the potential neuroprotective effects of genistein and its possible mechanism of action in a cerebral ischemia mouse model. Mice were pretreated with genistein (2.5, 5, and 10mg/kg) or vehicle orally once daily for 14 consecutive days before transient middle cerebral artery occlusion was performed. Genistein at doses of 2.5-10mg/kg significantly reduced the infarct volume, improved the neurological deficit and prevented cell apoptosis after ischemia. In addition, genistein pretreatment was shown to inhibit the ischemia-induced reactive oxygen species (ROS) production, enhance the activities of antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx), and decrease levels of malondialdehyde (MDA) in stroke mice. Moreover, genistein reversed the mitochondria dysfunction after ischemia, as evidenced by decreasing mitochondria ROS levels, preventing cytochrome C release to the cytoplasm and inhibiting caspase-3 activation. Western blotting showed ischemia activated the ROS-dependent nuclear factor-κB (NF-κB) signaling pathway, and genistein suppressed phosphorylation and activation of the NF-κB p65 subunit, as well as the phosphorylation and degradation of the inhibitor protein of κBα (IκBα). Our findings suggested that genistein has a neuroprotective effect in transient focal ischemia, which may involve regulation of mitochondria-dependent apoptosis pathways and suppression of ROS-induced NF-κB activation.     

gamma-Aminobutyric acid(A) neurotransmission and cerebral ischemia

In this review, we present evidence for the role of gamma-aminobutyric acid (GABA) neurotransmission in cerebral ischemia-induced neuronal death. While glutamate neurotransmission has received widespread attention in this area of study, relatively few investigators have focused on the ischemia-induced alterations in inhibitory neurotransmission. We present a review of the effects of cerebral ischemia on pre and postsynaptic targets within the GABAergic synapse. Both in vitro and in vivo models of ischemia have been used to measure changes in GABA synthesis, release, reuptake, GABA(A) receptor expression and activity. Cellular events generated by ischemia that have been shown to alter GABA neurotransmission include changes in the Cl(-) gradient, reduction in ATP, increase in intracellular Ca(2+), generation of reactive oxygen species, and accumulation of arachidonic acid and eicosanoids. Neuroprotective strategies to increase GABA neurotransmission target both sides of the synapse as well, by preventing GABA reuptake and metabolism and increasing GABA(A) receptor activity with agonists and allosteric modulators. Some of these strategies are quite efficacious in animal models of cerebral ischemia, with sedation as the only unwanted side-effect. Based on promising animal data, clinical trials with GABAergic drugs are in progress for specific types of stroke. This review attempts to provide an understanding of the mechanisms by which GABA neurotransmission is sensitive to cerebral ischemia. Furthermore, we discuss how dysfunction of GABA neurotransmission may contribute to neuronal death and how neuronal death can be prevented by GABAergic drugs.     

Necrotic death of neurons following an excitotoxic insult is prevented by a peptide inhibitor of c-jun N-terminal kinase

Peptide inhibitors of c-Jun N-terminal kinase (JNK) have been shown to potently protect against cerebral ischemia. The protective effect has been ascribed to prevention of apoptosis, but cell death following cerebral ischemia is a consequence of both apoptotic and necrotic cell death. We evaluated whether a peptide inhibitor (TAT-TIJIP) of JNK could prevent necrotic cell death in an in vitro model of excitotoxic neuronal death. We find that TAT-TIJIP effectively prevented cell death by interfering with several processes which have been identified as leading to cell death by necrosis. In particular, reactive oxygen species production was reduced, as indicated by an 88% decrease in the rate of dihydroethidium fluorescence in the presence of TAT-TIJIP. Furthermore, TAT-TIJIP attenuated the increase in cytosolic calcium following the excitotoxic insult. The potent neuroprotective properties of JNK peptide inhibitors likely reflects their abilities to prevent cell death by necrosis as well as apoptosis.     

Enhancement of the mutagenicity of polyphenols by chlorination and nitrosation in Salmonella typhimurium.

The hydrolytic products of lignins, humic acids and industrial waste including hydroquinone, catechol, resorcinol, pyrogallol and 1,2,4-benzenetriol are widely distributed in water sources. These polyphenols can interact with chlorine or nitrite to yield new derivatives. Generally, these new products possess more mutagenic potential than their original compounds. Furthermore, the mutagenicity of these polyphenols and their derivatives can be dramatically reduced by rodent liver microsomal enzymes (S9). The mutagenicity of polyphenols is in this order: hydroquinone greater than 1,2,4-benzenetriol greater than pyrogallol, while catechol, resorcinol and phloroglucinol are non-mutagenic. The ultimate product of chlorination or nitrosation of hydroquinone has been identified to be p-benzoquinone. The formation of active oxygen species including superoxide anion and hydrogen peroxide by polyphenols has been demonstrated and this may contribute partly to the molecular mechanisms of polyphenol mutagenicity.     

Cell signaling pathways in the neuroprotective actions of the green tea polyphenol (-)-epigallocatechin-3-gallate: implications for neurodegenerative diseases

Accumulating evidence supports the hypothesis that brain iron misregulation and oxidative stress (OS), resulting in reactive oxygen species (ROS) generation from H2O2 and inflammatory processes, trigger a cascade of events leading to apoptotic/necrotic cell death in neurodegenerative disorders, such as Parkinson's (PD), Alzheimer's (AD) and Huntington's diseases, and amyotrophic lateral sclerosis (ALS). Thus, novel therapeutic approaches aimed at neutralization of OS-induced neurotoxicity, support the application of ROS scavengers, transition metals (e.g. iron and copper) chelators and non-vitamin natural antioxidant polyphenols, in monotherapy, or as part of antioxidant cocktail formulation for these diseases. Both experimental and epidemiological evidence demonstrate that flavonoid polyphenols, particularly from green tea and blueberries, improve age-related cognitive decline and are neuroprotective in models of PD, AD and cerebral ischemia/reperfusion injuries. However, recent studies indicate that the radical scavenger property of green tea polyphenols is unlikely to be the sole explanation for their neuroprotective capacity and in fact, a wide spectrum of cellular signaling events may well account for their biological actions. In this article, the currently established mechanisms involved in the beneficial health action and emerging studies concerning the putative novel molecular neuroprotective activity of green tea and its major polyphenol (-)-epigallocatechin-3-gallate (EGCG), will be reviewed and discussed.     

Effects of major ozonated autoheamotherapy on functional recovery,ischemic brain tissue apoptosis and oxygen free radical damage in the rat model of cerebral ischemia

Stroke is the second leading cause of death and disability in the world, with a heavy burden on patients, their families, and society. At present, a major focus of cerebrovascular disease research is to find a safe and effective new method to promote early functional recovery in the acute phase of cerebral infarction. Major ozonated autohemotherapy (MOAH) can maintain ATP and energy metabolism in cerebral ischemia and hypoxia, and reduce cell apoptosis. In the current study, the model of middle cerebral artery occlusion in the Sprague Dawley rat was established and evaluated by the clinical functional score, Hoechst staining, immunohistochemistry, Western blot analysis, and biochemical detection. Then, the effects of MOAH on neurological function, apoptosis, and oxygen free radical damage after acute ischemia in middle cerebral artery were evaluated. Moreover, the potential two mechanisms have been illustrated for MOAH effects. This study would lay a theoretical foundation for the application of MOAH and find an effective and early treatment method for the cerebral infarction.     

Phospholipase A2, reactive oxygen species, and lipid peroxidation in cerebral ischemia

Ischemic stroke is caused by obstruction of blood flow to the brain, resulting in energy failure that initiates a complex series of metabolic events, ultimately causing neuronal death. One such critical metabolic event is the activation of phospholipase A2 (PLA2), resulting in hydrolysis of membrane phospholipids and release of free fatty acids including arachidonic acid, a metabolic precursor for important cell-signaling eicosanoids. PLA2 enzymes have been classified as calcium-dependent cytosolic (cPLA2) and secretory (sPLA2) and calcium-independent (iPLA2) forms. Cardiolipin hydrolysis by mitochondrial sPLA2 disrupts the mitochondrial respiratory chain and increases production of reactive oxygen species (ROS). Oxidative metabolism of arachidonic acid also generates ROS. These two processes contribute to formation of lipid peroxides, which degrade to reactive aldehyde products (malondialdehyde, 4-hydroxynonenal, and acrolein) that covalently bind to proteins/nucleic acids, altering their function and causing cellular damage. Activation of PLA2 in cerebral ischemia has been shown while other studies have separately demonstrated increased lipid peroxidation. To the best of our knowledge no study has directly shown the role of PLA2 in lipid peroxidation in cerebral ischemia. To date, there are very limited data on PLA2 protein by Western blotting after cerebral ischemia, though some immunohistochemical studies (for cPLA2 and sPLA2) have been reported. Dissecting the contribution of PLA2 to lipid peroxidation in cerebral ischemia is challenging due to multiple forms of PLA2, cardiolipin hydrolysis, diverse sources of ROS arising from arachidonic acid metabolism, catecholamine autoxidation, xanthine oxidase activity, mitochondrial dysfunction, activated neutrophils coupled with NADPH oxidase activity, and lack of specific inhibitors. Although increased activity and expression of various PLA2 isoforms have been demonstrated in stroke, more studies are needed to clarify the cellular origin and localization of these isoforms in the brain, their responses in cerebral ischemic injury, and their role in oxidative stress.     

Thymus quinquecostatus Celak. ameliorates cerebral ischemia-reperfusion injury via dual antioxidant actions: Activating Keap1/Nrf2/HO-1 signaling pathway and directly scavenging ROS

BackgroundThymus quinquecostatus Celak. has been widely used as a spice and a folk medicine for relieving exterior syndrome and alleviating pain in China.PurposeTo explore the protective effects and the underlying mechanism against cerebral ischemia-reperfusion injury (CIRI) of the T. quinquecostatus combining with its chemical composition.Study design and methodsHigh-polar extract (HPE) was extracted from T. quinquecostatus and polyphenols in HPE were enriched to obtain polyphenol-rich fraction (PRF) using Macroporous resin. The free radicals and zebrafish embryos were used to compare the antioxidant activities of HPE and PRF in vitro and in vivo. Then, the transient middle cerebral artery occlusion (tMCAO) model was established in rats. Neurological deficit score, infarction rate, morphology and apoptosis of neurons were examined to investigate the protective effects of PRF on CIRI. The mRNA and protein levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and hemeoxygenase-1 (HO-1) and the activities of downstream antioxidant enzymes in ischemia tissues were determined to clarify the underlying mechanisms. Also, reactive oxygen species (ROS) level in zebrafish embryos were detected after incubation with PRF for a short time (2 h) to investigate whether PRF could directly eliminate free radicals. Finally, chemical composition of PRF were analyzed to investigate the material basis for antioxidant activity and anti-CIRI effect.ResultsCompared with HPE, PRF showed stronger antioxidant activities. PRF exhibited obvious protective effects including ameliorating neurological deficit, lowering infarction rate, and improving the cellular morphology in hippocampus CA1 and cortex after tMCAO. TUNEL staining suggested PRF dose-dependently improved the apoptosis of the neurons in ischemic cortex. RT-qPCR and Western Blot results suggested that PRF regulated oxidative stress (OS) via activating the Keap1/Nrf2/HO-1 signaling pathway. Also, PRF could directly scavenge excessive ROS in zebrafish embryos after a short-time PRF incubation. The anti-CIRI effect might be primarily attributed to the abundant polyphenols in PRF, including flavonoids, polymethoxylated flavonoids, flavonoid glycosides, and phenolic acids.ConclusionT. quinquecostatus contains abundant polyphenols and exhibited a good protective effect against CIRI via dual antioxidant mechanisms, providing a reference for further research and application for this plant.     

Protections of SMND-309, a novel derivate of salvianolic acid B,on brain mitochondria contribute to injury amelioration in cerebral ischemia rats

SMND-309, a novel compound named (2E)-2-{6-[(E)-2-carboxylvinyl]-2,3-dihydroxyphenyl}-3-(3,4-dihydroxyphenyl) propenoic acid, is a new derivate of salvianolic acid B. The present study was conducted to investigate whether SMND-309 has a protective effect on brain injury after focal cerebral ischemia, and if it did so, to investigate its effects on brain mitochondria. Adult male SD rats were subjected to middle cerebral artery occlusion (MCAO) by bipolar electro-coagulation. Behavioral tests and brain patho-physiological tests were used to evaluate the damage to central nervous system. Origin targets including mitochondria production of reactive oxygen species, antioxidant potentia, membrane potential, energy metabolism, mitochondrial respiratory enzymes activities and mitochondria swelling degree were evaluated. The results showed that SMND-309 decreased neurological deficit scores, reduced the number of dead hippocampal neuronal cells in accordance with its depression on mitochondria swelling degree, reactive oxygen species production, improvements on mitochondria swelling, energy metabolism, membrane potential level and mitochondrial respiratory chain complex activities. All of these findings indicate that SMND-309 exerted potent neuroprotective effects in the model of permanent cerebral ischemia, contributed to its protections on brain mitochondrial structure and function.     

Mitochondrial respiratory chain and free radical generation in stroke

Being the second most common cause of death in the industrial countries and one of the major causes of death and disability, stroke has a great effect on public health and is the neurological disease which accounts for the largest number of hospitalizations. In order to develop new treatments, biochemical mechanisms involved in brain damage have been investigated. Among them, oxidant species generated during stroke have been implicated as critical mediators of neuronal injury in this condition, although neuroprotective roles have also been demonstrated. This review is focused on the role of the mitochondrial respiratory chain as both source and target of reactive oxygen and nitrogen species such as nitric oxide, superoxide and peroxynitrite produced in cerebral ischemia. The neuroprotective role of antioxidants or other molecules acting on the mitochondrial respiratory chain and ATP synthesis in the setting of cerebral ischemia is discussed.     

The Involvement of Mitochondrial Biogenesis in Selenium Reduced Hyperglycemia-Aggravated Cerebral Ischemia Injury

Selenium has been shown to possess antioxidant and neuroprotective effects by modulating mitochondrial function and activating mitochondrial biogenesis. Our previous study has also suggested that selenium protected neurons against glutamate toxicity and hyperglycemia-induced damage by regulating mitochondrial fission and fusion. However, it is still not known whether the mitochondrial biogenesis is involved in selenium alleviating hyperglycemia-aggravated cerebral ischemia reperfusion (I/R) injury. The object of this study is to define whether selenium protects neurons against hyperglycemia-aggravated cerebral I/R injury by promoting mitochondrial biogenesis. In vitro oxygen deprivation plus high glucose model decreased cell viability, enhanced reactive oxygen species production, and meanwhile stimulated mitochondrial biogenesis signaling. Pretreated with selenium significantly decreased cell death and further activated the mitochondrial biogenesis signaling. In vivo 30 min of middle cerebral artery occlusion in the rats under hyperglycemic condition enhanced neurological deficits, enlarged infarct volume, exacerbated neuronal damage and oxidative stress compared with normoglycemic ischemic rats after 24 h reperfusion. Consistent to the in vitro results, selenium treatment alleviated ischemic damage in hyperglycemic ischemic animals. Furthermore, selenium reduced the structural changes of mitochondria caused by hyperglycemic ischemia and further promoted the mitochondrial biogenesis signaling. Selenium activates mitochondrial biogenesis signaling, protects mitochondrial structure integrity and ameliorates cerebral I/R injury in hyperglycemic rats.

     

Plant polyphenols mobilize nuclear copper in human peripheral lymphocytes leading to oxidatively generated DNA breakage: Implications for an anticancer mechanism

It was earlier proposed that an important anti-cancer mechanism of plant polyphenols may involve mobilization of endogenous copper ions, possibly chromatin-bound copper and the consequent pro-oxidant action. This paper shows that plant polyphenols are able to mobilize nuclear copper in human lymphocytes, leading to degradation of cellular DNA. A cellular system of lymphocytes isolated from human peripheral blood and comet assay was used for this purpose. Incubation of lymphocytes with neocuproine (a cell membrane permeable copper chelator) inhibited DNA degradation in intact lymphocytes. Bathocuproine, which is unable to permeate through the cell membrane, did not cause such inhibition. This study has further shown that polyphenols are able to degrade DNA in cell nuclei and that such DNA degradation is inhibited by neocuproine as well as bathocuproine (both of which are able to permeate the nuclear pore complex), suggesting that nuclear copper is mobilized in this reaction. Pre-incubation of lymphocyte nuclei with polyphenols indicates that it is capable of traversing the nuclear membrane. This study has also shown that polyphenols generate oxidative stress in lymphocyte nuclei which is inhibited by scavengers of reactive oxygen species (ROS) and neocuproine. These results indicate that the generation of ROS occurs through mobilization of nuclear copper resulting in oxidatively generated DNA breakage.     

Plant polyphenols mobilize nuclear copper in human peripheral lymphocytes leading to oxidatively generated DNA breakage: implications for an anticancer mechanism

It was earlier proposed that an important anti-cancer mechanism of plant polyphenols may involve mobilization of endogenous copper ions, possibly chromatin-bound copper and the consequent pro-oxidant action. This paper shows that plant polyphenols are able to mobilize nuclear copper in human lymphocytes, leading to degradation of cellular DNA. A cellular system of lymphocytes isolated from human peripheral blood and comet assay was used for this purpose. Incubation of lymphocytes with neocuproine (a cell membrane permeable copper chelator) inhibited DNA degradation in intact lymphocytes. Bathocuproine, which is unable to permeate through the cell membrane, did not cause such inhibition. This study has further shown that polyphenols are able to degrade DNA in cell nuclei and that such DNA degradation is inhibited by neocuproine as well as bathocuproine (both of which are able to permeate the nuclear pore complex), suggesting that nuclear copper is mobilized in this reaction. Pre-incubation of lymphocyte nuclei with polyphenols indicates that it is capable of traversing the nuclear membrane. This study has also shown that polyphenols generate oxidative stress in lymphocyte nuclei which is inhibited by scavengers of reactive oxygen species (ROS) and neocuproine. These results indicate that the generation of ROS occurs through mobilization of nuclear copper resulting in oxidatively generated DNA breakage.     

Mechanisms of the anticancer effects of plant polyphenols. I. Blockade of initiation of carcinogenesis

Mechanisms of the anticancer effects of polyphenols, found in fruits, vegetables, spices and representing parts of daily nutrition, have been considered. These compounds may be the basis for the development of cancer preventive preparations. They can block initiation of carcinogenesis by inactivating exogenous or endogenous genotoxic molecules including reactive oxygen species (ROS). The other mechanism underlying polyphenol effects consists in inhibition of activity and synthesis of carcinogen-metabolizing enzymes. Plant polyphenols can induce expression of genes encoding antioxidant and detoxification enzymes and this also prevents initiation of carcinogenesis.     

The role of free radicals in cerebral hypoxia and ischemia

This review focuses on the effects that ischemia and hypoxia have on the cerebral cortex and the cerebellum during different periods of life. The acute interruption or reduction of cerebral blood flow, that can be induced by several factors and clinical pathologies, reduces available oxygen to the nervous system and this causes either focal or global brain damage, with characteristic biochemical and molecular alterations that can result in permanent or transitory neurological sequelae or even death. Under these circumstances, an increase in the activity of different isoforms of nitric oxide synthase occurs and nitric oxide is produced. This excess of nitric oxide reacts with cellular proteins yielding nitrotyrosine, thus contributing to cerebral damage. This phenomenon has been studied at different stages of perinatal and postnatal development, including aging animals. Both the duration and the intensity of the ischemic injury were evaluated. In all cases there is overproduction of nitric oxide in ischemia, which may represent an effort to reestablish normal blood flow. Unfortunately, in many cases this response becomes excessive and it triggers a cascade of free-radical reactions, leading to modifications of cerebral plasticity and overt injury.     

转基因鼠在脑缺血氧化应激研究中的应用

活性氧自由基作为脑内一类重要的病理因素直接或间接地参与脑缺血/再灌注的损伤过程。氧自由基不仅受到脑内促氧化酶与抗氧化酶间平衡的调节,同时也参与了细胞内信号转导通路,在神经元死亡中发挥着决定性作用。近年来,转基因及基因敲除鼠已广泛应用于这些影响活性氧自由基的形成和清除过程的酶类物质及各种介导细胞死亡与凋亡过程的蛋白质的研究中,为脑缺血/再灌注损伤治疗的基础及应用提供了必要条件。     

Oxidative stress and neuronal death/survival signaling in cerebral ischemia

It has been demonstrated by numerous studies that apoptotic cell death pathways are implicated in ischemic cerebral injury in ischemia models in vivo. Experimental ischemia and reperfusion models, such as transient focal/global ischemia in rodents, have been thoroughly studied and the numerous reports suggest the involvement of cell survival/death signaling pathways in the pathogenesis of apoptotic cell death in ischemic lesions. In these models, reoxygenation during reperfusion provides oxygen as a substrate for numerous enzymatic oxidation reactions and for mitochondrial oxidative phosphorylation to produce adenosine triphosphate. Oxygen radicals, the products of these biochemical and physiological reactions, are known to damage cellular lipids, proteins, and nucleic acids and to initiate cell signaling pathways after cerebral ischemia. Genetic manipulation of intrinsic antioxidants and factors in the signaling pathways has provided substantial understanding of the mechanisms involved in cell death/survival signaling pathways and the role of oxygen radicals in ischemic cerebral injury. Future studies of these pathways could provide novel therapeutic strategies in clinical stroke.