IMR Press / FBL / Volume 24 / Issue 3 / DOI: 10.2741/4727
Open Access Review
Cerebral ischemic stroke: cellular fate and therapeutic opportunities
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1 Signal Transduction in Cancer and Stem Cells Laboratory, Division of Cancer Biology and Inflammatory Disorder, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), 4 Raja S.C. Mullick Road Kolkata- 700032 and CN-06, Sector-V, Salt Lake, Kolkata-700091, India
Send correspondence to: Mrinal K. Ghosh, Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), 4, Raja S.C. Mullick Road, Kolkata-700032, India, Tel: 913324995889, Fax: 13324735197, E-mail:
Front. Biosci. (Landmark Ed) 2019, 24(3), 415–430;
Published: 1 January 2019

In cerebral tissues, due to continuous and high metabolic demand, energy is produced exclusively by mitochondrial oxidative phosphorylation (OXPHOS). Obstruction of blood flow leads to cerebral ischemia, hypoxia and decreased cellular ATP production. The reactive oxygen species (ROS) generated as by-product of OXPHOS alter many intracellular signaling pathways and result in damaged cellular components. Under such hypoxic conditions, a key factor known as hypoxia inducible factor 1 (HIF1) is stabilized and activated and such activation induces expression of a defined set of target genes which are required for cell survival and angiogenesis. Reperfusion that follows such ischemia alters signaling pathways which are involved in cellular fate. Here, we will review the role of ROS, HIF-1 alpha and other signaling network in mitochondrial dysfunction and cell fate determination in ischemia-reperfusion models in the brain. We will also address both current and future therapeutic strategies for clinical significance that are being developed for treatment of cerebral ischemia.

Cerebral ischemia
Electron transport chain

Brain is the most important organ in human body and also the most susceptible organ for ischemic injury. In cerebral ischemia blood flow to the brain is obstructed which causes damage or death of cerebral tissues. The overall damage caused by ischemic preconditioning can be recovered by reperfusion therapy within a time not beyond the critical level. Several molecular regulatory pathways take regulatory roles in fate determination of brain tissues after blood flow obstruction in ischemic preconditioning for survival of the cells in the ischemic penumbra.

Mitochondrial apoptotic and necrotic pathways are the main causes for brain tissue damage in cerebral ischemia (1-2). Ischemic stroke results in Na+/K+ pump dysfunction as well as cellular calcium homeostasis breakdown by inducing oxidative stress and mitochondrial swelling (3, 4). Immediately after stroke oxidative stress in cerebral tissue stimulates mitochondrial ROS generation and cytosolic NADPH production that causes damage to cellular macromolecules such as lipids, proteins and DNA (5). These excessive intracellular ROS levels show their patho-physiological effects in case of several neurodegenerative diseases as well (6-8). Nitrosative stress in ischemic stroke also triggers protein misfolding and aggregation of mitochondrial components that leads to several neurodegenerative diseases, aging and even cancer.

The hypoxia inducible factors (HIFs) are oxygen regulated transcription factors that play important roles in hypoxia sensing and adaptation (9). They act as critical effectors in response to depleted oxygen levels and a plethora of genes are under their control. HIF-1α expression along with mitochondrial ROS generation are boosted in response to ischemic oxidative stress (10). In hypoxia, HIF-1α is stabilized by accumulated high ROS levels generated from complex III in mitochondria. The mechanism behind this is the oxidative inactivation of non-heme iron in the catalytic site of Prolyl hydroxylase (PHD) enzyme (11). HIF-1α accumulation in neuronal cells is protective whereas endothelial HIF-1α induction is implicated in blood brain barrier (BBB) disruption (12). It is important to keep in mind that hypoxia-driven ROS activates NF-kB (13) and other transcription factors such as NRF2 (14) which play a vital role in regulating transcription of proteins involved in antioxidant defense. ROS can also activate the MAPK pathway leading to the increased expression of VEGF (15). Increased expressions of VEGF and its receptors VEGF-R1 and R2 are also due to the activation of HIF-1α by ROS and have fundamental roles in increased cell survival (16-17). ROS also activates other intracellular signaling pathways that include MAPK, NF-kB and upstream of MMPs. Herein, the authors are majorly discussed the pathophysiological features of cerebral ischemia and reviews some of the major human trials under the current treatment scenario.


Cerebral ischemia occurs when there is insufficient blood flow to the brain (18) so that cerebral hypoxia develops through limited oxygen supply which leads to death of the cerebral tissues. This sudden destruction of brain tissue is called as cerebral infarction or ischemic stroke in the brain (19). Transient cerebral ischemic attack in young adults is commonly considered as a benign event. However, severity increases significantly with aging and is the second leading cause of death (20). According to its origin, there are two major types of cerebral ischemic stroke: focal and global (fig1) (21). Cerebral stroke can be further divided into thrombotic, embolic and hypo-perfusion. Thrombotic and embolic are generally focal in nature whereas hypo-perfusion affects the brain globally.

Figure 1

Pictorial representation of the type of cerebral ischemia.

3.1.1. Focal cerebral ischemia

In focal type, blood flow is restricted to the specific region of the brain and the cell death limited to that particular area. In this type, there is an “ischemic core” and “ischemic penumbra” with severe cerebral blood flow (CBF) reduction in the vascular bed. When a blood clot has formed in a particular region of the brain, it decreases blood flow as well as increases the risk of cell death in that specific area. In focal cerebral ischemic stroke, blood flow stopped in the central core but some blood flows in that area via collateral circulation i.e., a gradient of blood flow occurs from inner core to the ischemic region. Reversible injury to irreversible cellular infarction after focal ischemia largely depends on ischemic severity and duration (22). Focal ischemia reduces CBF in a specific vascular territory and is clinically known as “ischemic stroke”.

3.1.2. Global cerebral ischemia

In global cerebral ischemic stroke blood flow is obstructed due to blockage of carotid arteries in the head and neck region. Severity of brain damage depends on the time required for restoration of blood flow after blockage. If circulation is restored within a short period of time damage is not severe otherwise brain damage can be permanent and fatal. In complete global ischemia, blood flow has stopped completely whereas in case of incomplete type, blood flow is reduced so unable to maintain metabolism and other functions of the brain. Global stroke leads to a cascade of physiological processes culminating with the development of seizures. After cerebral ischemia, excitatory neurotransmitters are also released and play an important role in neuronal ischemic injury. Extracellular glutamate level is elevated after cerebral stroke that leads to ischemic brain damage. Excitatory neurotransmitters are released which play an important role in neuronal ischemic injury (23). Excitatory N-methyl-D-aspartate (NMDA), a sub type of glutamate receptor antagonist and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), the ligand for a distinct non NMDA glutamate receptor subtype are over stimulated by glutamate activation due to extracellular glutamate accumulation in the vulnerable regions of brain especially hippocampus and neo-cortex by promoting Na+ influx and K+ efflux through glutamate receptor activated membrane channels. So, neuronal death can be delayed by blocking NMDA receptor after global cerebral stroke (24).


In cerebral stroke, mitochondrial ROS are generated via electron transfer to oxygen through change in mitochondrial membrane potential by which the potential energy of proton motive force (PMF) drives protons into the mitochondrial matrix for ATP synthesis by oxidative phosphorylation (25).

4.1. ROS generation in mitochondrial electron transport chain (ETC)

In cerebral stroke, mitochondrial redox potential decreases after oxidative stress that leads to generation of ROS from mitochondrial ETC at cytochrome III level (26-28). Cellular ROS, the by-products of respiratory chain reaction are hence accumulated. Under normal conditions, low level of ROS are generated by leaking electrons from the respiratory chain enzyme complexes I and III and reaction with oxygen molecules results in the formation of superoxide radicals (O2.-). These radicals are converted to form H2O2 spontaneously by the enzyme known as superoxide dismutase (SOD) at low pH (29-30). Moreover ETC proteins which are rich in iron-sulfur clusters and heme proteins form highly reactive hydroxyl radicals (OH?) from hydrogen peroxide by providing necessary cofactors (31). In the mitochondrial respiratory chain most of the oxygen is reduced to water by the cytochrome C oxidase through four steps of electron reduction. Only a small amount of oxygen is reduced partially in the midway of ETC to generate O2.- (32). Superoxide is mostly produced at the Q cycle in complex III. A small flux of ROS is generated by ETC under normal condition. But after cerebral ischemic stroke, mitochondrial ETC impairs due to oxidative stress and huge amount of ROS is produced which results in lipid peroxidation, protein oxidation and ultimately DNA damage (33-34).

Under oxidative stress after ischemic stroke, mitochondria produces several ROS as metabolic by-products including superoxide radicals (O2.-), hydrogen peroxide (H2O2) and hydroxyl radicals (OH?) (fig2). Superoxide dismutase detoxifies O2.- to H2O2 and ultimately it is converted to H2O by catalase or glutathione peroxidase. Highly reactive hydroxyl radicals (OH?) are also produced from H2O2 and O2.- radicals. Pro-oxidant enzymes such as xanthine oxidase (XO) and NADPH oxidase (NOX) are also responsible for generation of O2.- radicals (35). Furthermore, nitric oxide (NO) reacts with O2.- radicals to form highly reactive peroxynitrate (ONOO?) anion which also damages cellular DNA, proteins and lipids. Additionally, NO reacts with specific protein thiol groups to induce protein misfolding and mitochondrial fission-fusion process that leads to neurotoxicity in cerebral stroke (36) as NO irreversibly modifies several proteins and lipids (37-38).

Figure 2

Generation, transport and effects of ROS and NOS inside the mitochondria in cerebral ischemia.

4.2. Ischemic ROS leads to mitochondrial dysfunction and neuronal damage

Many biochemical and physiological changes occur as result of interruption of blood flow to the brain including loss of ATP generation, production of lactate anaerobically, compression of brain capillaries and reduced reflow of blood due to the swelling of astrocytes. Electrolyte balance of brain tissue cells gets disturbed with the fall in ATP level which results in potassium leakage from the intracellular compartment and influx of sodium and calcium along with the remarkable increase in cellular water content due to Na+/K+ ATPase and voltage gated calcium channel dysfunctions (39). The reduced cellular ATP in cells by glycolytic mechanism uses glucose and glycogen from the reservoir of the brain cells and accumulates proton and lactate leading to intracellular acidification (40-41).

In cerebral ischemia, mitochondrial ultrastructure is changed due to calcium overloading and free radical generation as well as decrease in adenine nucleotide translocase. Due to the loss of membrane integrity, the efficiency of calcium pump is reduced (41). The increased intracellular calcium activates membrane phospholipases and protein kinases that leads to accumulation of free fatty acids (FFA) and arachidonic acids (AA). FFAs, acyl Co-A and long chain acyl-carnitines are accumulated among which acyl Co-A is deleterious to mitochondrial enzyme systems. AA and FFAs can cause tissue irritation as well as platelet aggregation, vasospasm, clotting and oedema (42). Lactic acidosis injures neuronal cells by increasing lactate levels and decreasing the cellular pH. Lactic acid also degrades NADH as well as it inhibits the synthesis of ATP during post-ischemic events (43). All these conditions can cause irreversible tissue death which ultimately leads to permanent damage of brain tissue in the affected area.

In ischemia excitatory, amino acid particularly glutamate is released excessively to the extracellular compartment and neurotransmitter reuptake is decreased (44-45). As a result, Na+ influxes more to the neurons via monovalent ion channels which also decreases ionic gradient by consuming ATP. Blood flow reduction for a longer time releases more glutamate resulting in acute ischemic stroke of the patients that leads to excitotoxicity induced brain damage and the excessive glutamate concentration destroys central neurons. In the synapses, activation of ionotropic glutamate receptors is known as “excitotoxicity” (46). This excitotoxicity can cause neuronal death and disturbances in mitochondrial function because of increased production of free radicals. This also diminishes antioxidant defense and induces apoptotic cascade. Neuronal insult is also defined as cell death resulting from the toxic actions of excitatory amino acids. Intense exposure of glutamate in the cell leads to injury and death of neurons as well as occurrence of ionic imbalance. Mitochondrial membrane may become more permeable and cytochrome C is released resulting in activation of apoptotic cascade by increased cytosolic calcium concentration (47).


Ischemic hypoxic situation causes depolarization of membrane due to cellular K+ efflux, Na+ influx and activation of the voltage gated calcium channel. Increased intracellular calcium concentration leads to chronic response to hypoxic situation (48).

5.1. Effect of ROS on cellular fate

At lower concentrations, although ROS is beneficial for various normal cellular function, such as regulations of vascular tones, monitoring of oxygen tension, erythropoietin production (49), but increased ROS levels initiate an inherent risk to oxidative stress induced signaling and cell injury by irreversibly oxidizing macromolecules. Free radicals are generated at low levels under normal physiological conditions and play important roles in various signaling and metabolic pathways (50-51). But under stressed condition, large amount of free radicals are generated and they react with biomolecules viz proteins, lipids, carbohydrates and nucleic acids and destroy or alter their biological functions. These radicals aggravate numerous pathologies that ultimately leads to brain damage in different neurodegenerative diseases, aging and cancer.

So, level of ROS determines cellular fate. At low levels, ROS triggers autophagy with constant removal of damaged mitochondria and consequently cell survives. On the contrary high levels of ROS lead to cell death by promoting apoptotic cascade.

5.2. ROS induced apoptosis

Apoptosis can be induced by both intrinsic and extrinsic signals through two major pathways viz. mitochondrial (intrinsic) or death receptor mediated (extrinsic). Intrinsic apoptotic cascade associates with the changes in the permeability of the outer mitochondrial membrane and ROS triggers this pathway by interacting with it. ROS regulated truncated form of Bid protein causes Bax/Bak oligomerization and creates mega-pore formation in the mitochondria. Next, apoptosome complex is formed in the cytosol by activating caspase 9 and then 3 to initiate apoptosis (52). Increased Fas receptor expression triggers mitochondrial permeability transition with the release of ROS which is the basic mechanism of apoptosis induction (53). Bcl2 blocks NO triggered apoptosis suggesting that mitochondria are the main target of apoptosis induction (54). Mitochondrial ROS are responsible for the full activation of caspase cascade. ROS, through disruption of mitochondrial membrane potential, generates mitochondrial pores and can contribute to cytochrome-C release (55). ROS can directly or indirectly increase the gating potential of the pores. In fact, H2O2 has the ability to induce apoptosis through initiation of caspase activation and mitochondrial cytochrome C release. However, at very high doses of H2O2 or other ROS, necrosis in brain tissue occurs (56).

Under normal physiological conditions, free radicals are produced continuously but counteracted by a number of antioxidants and endogenous enzyme systems viz. superoxide dismutase, catalase, vitamin C (ascorbic acid), glutathione, glutathione reductase, peroxidase and peroxiredoxin (57-59). As a result of oxidative stress, various macromolecules are oxidized viz.8-hydoxy-2-deoxyguanosine, an oxidized product of deoxyguanosine are used as biomarkers of in vivo oxidative DNA damage (60). Lipid peroxide generation causes alteration in cell membrane fluidity, increased membrane permeability and decreased membrane ATPase activity leads to severe cell injury after cerebral ischemic stroke. Lipid peroxidation has the most significant impact on plasma membrane permeability, structure and function and its damage leads to disruption of ionic gradients. The entry of Na+ and water leads to cell swelling. Malonaldehyde is formed as a result of decomposition of short lived and unstable lipid peroxides in cerebral stroke. 4-hydoxy-2-Noneneal, a derivative of w-6 family of polyunsaturated free fatty acids is also increased after stroke that causes cellular injury (61).


Development of hypoxia is one of the crucial events in cerebral ischemic stroke. In cerebral ischemia ROS and toxic metabolites are produced in the mitochondrial respiratory chain which are involved in the deregulation of cellular signaling pathways responsible for survival or death of neuronal cells. It is interesting to note that a full activation of HIF and NF-kB occurs by ROS in synergy with specific signaling pathway. Both hypoxia and ROS are involved in the maintenance of redox homeostasis and various cellular signaling pathways (fig3).

Figure 3

Signaling crosstalks of mitochondrial ROS and NOS with major cell signaling components in cerebral ischemia.

6.1. ROS signaling

ROS at low levels play important role in normal physiological signaling and metabolic pathways. But after cerebral ischemia, multiple detrimental processes such as overproduction of oxidants, inactivation of detoxification systems and consumption of antioxidants take place that results in mitochondrial dysfunction. Furthermore, accumulation of calcium and ROS due to excitotoxicity, disrupts natural anti-oxidative defense of the brain tissues. Various gene expressions are also deregulated by the participation of various signaling pathway based transcription factors. All of these events act synergistically to damage cellular proteins, lipids and DNA, which deteriorates cellular architecture and induces cell death by necrosis, apoptosis or both depending on the severity of mitochondrial dysfunction (3-4). They also contribute to numerous pathologies by alteration of the functions of the target molecules and damage the functions of organs.

6.2. HIF-1 signaling

HIF-1, a dimeric protein complex associates with angiogenesis in hypoxia. In ischemic condition HIF-1 plays dual role depending on the various functions of its target proteins in some specific types of brain cells. It has two subunits: HIF-1α and HIF-1β (62). The latter is insensitive to oxygen tension scenario and is constitutively expressed. HIF-1α is continuously synthesized and degraded in normal oxygen tension of the cells. Under hypoxic situation, there is an inhibition of HIF-1α degradation. Hence, it is rapidly accumulated and binds to hypoxia responsive elements (HRE), thereby activating its target genes (63). In the ischemic brain many of them have neuroprotective effect. In hypoxic region of ischemic brain HIF-1α is the principal gene involved in coordinating the shift from aerobic to anaerobic metabolism by inducing a variety of glycolytic enzymes and glucose transporters. HIF-1α regulates the expression of glucose transporter 3 (GLUT3) (64), the main transporter of glucose in neurons.

HIF-1α expression in cerebral ischemia is associated with cellular ROS level (9-10). However it has been shown by recent studies that increased ROS levels lead to reduced HIF-1α expression while other studies have shown that it has no effect. Under hypoxic condition mitochondrial complex III produces ROS that stabilizes HIF-1α. But in cytosol, ROS may be derived from NADPH oxidase, and it plays a major role on HIF-1α expression in normoxia than hypoxia. The complexity of relationships between ROS and HIF-1α in cerebral ischemia is primarily due to the diverse species of ROS generated by mitochondrial O2 metabolism and their properties, such as chemical nature, reactivity, specificity and half-life for their biological targets.

6.3. Casein kinase 2 (CK2) signaling

Casein kinase2 (CK2), a prominent oncogenic kinase plays a key role in ROS development in cerebral ischemia. It acts as a neuroprotectant via inhibition of NADPH oxidase (NOX) by Rec1 regulation (65). Observation from focal ischemia in rat showed that inhibition of CK2 in ischemic region causes PARP-1 accumulation resulting in cytochrome C and AIF release from mitochondria which activates a series of apoptotic events (66). Recent reports also show CK2 directly phosphorylates JAK as well as STAT3 for SOD2 transcription that detoxify ROS (67-68). Moreover, CK2 activates HIF-1α and NF-kB by phosphorylation for production of VEGF and other angiogenic proteins which are needed for angiogenesis and in escaping from hypoxia conditions.

6.4. EGFR signaling

Several reports describe the hyper activation of EGFR pathway in both ischemia and reperfusion conditions where transactivation of EGFR via phosphorylation leads to AKT activation (69). AKT plays most prominent role in neuroprotection by regulating forkhead transcription factor (FKHR) and glycogen synthase kinase 3 beta (GSK3β); BAD or caspase-9 or other apoptogenic components, for bypassing apoptosis (70-71). It is also reported that AKT, activated by ischemic ROS, provided hypothermic conditions to negatively regulate ROS production (72). Interestingly, AKT inhibits Raf so that ERK1/2 gets activated in ischemic condition but the scenario is reversed in reperfusion (73).

6.5. TGF-β signaling

TGF-β is one of the cytokine mediated factor that highly express in cerebral ischemia. Mainly it regulates the expression of apoptotic (Bad) and anti-apoptotic (Bcl-2, Bcl-x1) proteins. It also crosstalks with MAPK pathway by transactivation of ERK1/2 for neuroprotection (74). Recent studies have shown that TGF-β1 save neurons from excitotoxicity by up-regulation of the type-1 plasminogen activator inhibitor (PAI-1) to nullify the t-PA-potentiated NMDA-induced neuronal death in ischemia (75).

6.6. NF-kB signaling

NF-kB pathway plays an important role in cerebral ischemia (76). ROS activated NF-kB regulates Bim and Noxa (77), TNF (78), IL-1, IL-6 (79), iNOS, ICAM-1 and MMP9, cytosolic phospholipase A2, COX-2, and microsomal prostaglandin E synthase 1 (80). It can also directly regulates HIF-1α (81). All those downstream factors may cause apoptosis, cellular damage or even promote cell survival in a context dependent manner.

6.7. Calcium signaling

Another most important pathway found in cerebral ischemia is calcium signaling. Generally, Ca2+ signals are needed for cell-to-cell communication and survival, by playing role as secondary messenger, but Ca2+ overload in ischemic area leads to calpain mediated inhibition of sodium-calcium exchanger (NCX) (82) as well as caspase and Ca2+ dependent endonucleases activation which leads to apoptosis (83). It also helps in nitric oxide (NO) production via calmodulin-NOS pathway (84). Excessive NO can combine with other ROS to produce peroxynitrite (ONOO?), which causes damage to proteins, membrane lipids, and DNA (85).


Improved recognition of signs and symptoms in cerebral ischemic stroke has paralleled the development of multiple pharmacological strategies to reduce the mortality and morbidity. The reluctance to use any therapeutic strategy for the treatment of acute cerebral ischemia is because of the narrow therapeutic window of time. Neuroprotective strategies are intended to rescue the penumbral tissue cells and to extend the window of time for revascularization. However, under the present scenario, no neuroprotective agents have been shown to impact clinical outcomes in ischemic stroke. Heterogeneous class of drugs like antiplatelet agents (viz. aspirin, dipyridamole, ticlopidine and clopidogrel) (86) have been successfully used for more than 2 decades for secondary stroke prevention (fig4).

Figure 4

Major therapeutic approaches for cerebral ischemia and their mode of actions.

7.1. Therapeutic strategies based on antioxidant defense and fate of ROS

In normal brain tissue, ROS are constantly generated during physiological procedures. These are however adjusted by endogenous defense mechanism carried by antioxidants. After Ischemic damage, free radical generation is incredibly expanded and causes redox disequilibrium in the characteristic endogenous antioxidant system. In this scenario detoxifications are inactivated and oxidants are overproduced. An expansion in ROS levels after ischemia brings about obvious oxidative anxiety and results in neuronal damage making free radicals as substantial helpful target, and much research has concentrated on evaluating the restorative impacts of antioxidants. There are three primary methodologies by which antioxidants work: (i) hindrance of free radical generation; (ii) scavenging of generated free radicals and (iii) escalating degradation of free radicals. Biological systems can either concentrate on the upregulation of endogenous antioxidants or on the conveyance of exogenous antioxidants.63

7.1.1. Hindrance of free radical generation

In this approach, the main source of ROS generation in diseased condition is targeted by some inhibitors of specific enzymes causing ROS generation. One fundamental source of ROS generation in ischemia reperfusion damage is the NADPH oxidases (NOXs). Hindrance of NADPH oxidase complexes with the pharmacological inhibitor apocynin (87) preceding reperfusion has shown reduction in ischemia in rodent models of stroke featuring the contributory part of NOX in brain damage.

Xanthine Oxidase (XO) is another protein that is associated with redox signaling pathways and is a vital source of ROS in the process of ischemic damage. Hindrance of XO is a potential restorative approach for the treatment of ischemia. Allopurinol is a normally utilized XO inhibitor that reduces levels of uric acid, as well as decreases the level of superoxide anion. Introductory trials with this medication are promising. Improvement in vascular and beneficial effects on inflammatory indices compared to placebo can be noticed in the patients treated with allopurinol (88).

7.1.2. Scavenging of generated free radicals

Although pre-clinical to clinical trials has largely been disappointing, some compounds are capable of scavenging free radicals generated in ischemic stroke. Tirilazadmesylate (U-74006F) (89) is one of these compounds. It is an inhibitor of lipid peroxidation which has reported to reduce infarction size in rodents following transient focal ischemia. In the clinical trial of Tirilazad, when administered in 660 patients prior to focal ischemia showed maximum efficiency, whereas a decreasing efficiency can be observed with administration time from ischemic onset to thereafter (90). Another promising drug was NXY-059 which failed to show clinical efficacy in a clinical trial on 4000 patients (91). It is evident from different reports that NXY-pre059 has neuroprotective action, which causes neurological recovery in different stroke models in both rodents and non-human primates.

Edaravone (Radicava) is another free radical scavenger which is widely used by clinicians of Japan for the treatment of infarctions. The effectiveness of edaravone is still unclear, however it is known that it can scavenge peroxyl, hydroxyl and superoxide radicals (92).

7.1.3. Escalating degradation of free radicals

Increasing levels of the antioxidant superoxide dismutase (SOD) is associated with ROS in lesion progression. Strategies are being aimed at reducing oxidative stress by targeting SOD. The overall efficacy of SOD is induced by its catalytic activity in the conversion of O2.- to less reactive H2O2. It is evident that catalase (CAT) and glutathione peroxidase (GPx) help to eliminate the by-product of H2O2. In vitro efficacy of CAT against ischemic injury was discerned when the overexpression of CAT by adenoviral vectors and transduction with PEP-1-CAT fusion protein demonstrated its neuroprotection ability (93).

Ebselen is an inhibitor of glutathione peroxidase-like activity which reacts with ONOO? and subsequently scavenges it (94). Another novel antioxidant approach is the inhalation of gases after or during ischemia. The use of inhaled hydrogen gas to selectively reduce the hydroxyl radical in a transient model of ischemia elicits beneficial effect. Other than this, normobaric oxygen (NBO) has been demonstrated in several studies to reduce infarct volume and neurological deficits in rodent models of focal ischemia. Moreover, combination therapy with NBO and ethanol was shown to have neuroprotective effects after ischemic injury in rodents (95).

Another approach to treat ischemic injury is the induction of a natural cell protection molecule NO, which is a vasoactive molecule produced by either endothelial NO synthase (eNOS), inducible NO synthase (iNOS) or neuronal NO synthase (nNOS). It is a short-lived, highly reactive intermediate that is receiving attention for its contribution to the cerebrovascular circulation during both physiological and pathological states. From a recent study it was evident that inhalation of NO could significantly reduce ischemic brain damage and improve neurological outcome in rodent stroke models. There are several advantages of gaseous treatment since it can rapidly penetrate biomembranes and diffuse into the cytosol, mitochondria and nucleus.

Lubeluzole causes reduction in NO levels and subsequent ONOO? production in hypoxic cells by inhibiting glutamate-mediated nitric oxide synthase pathway (96). A large clinical study with more than 1700 patients was initiated, but unfortunately no noticeable variation was observed between lubeluzole or placebo groups. Therefore, finding a prominent therapeutic modality is still now in hype (97).

7.2. Reperfusion therapy

Reperfusion injury occurs when blood supply returns to the tissue after lack of oxygen during ischemia. Scarcity of oxygen and nutrient supply from the obstruction of blood during ischemia creates a condition in which the restoration of circulation results in inflammation and oxidative damage with the induction of oxidative stress. Though reperfusion is essential to protect brain tissue, it also leads to secondary injury from influx of neutrophils. This often leads to the development of seizures. Cerebral reperfusion syndrome presents as a triad of ipsilateral headache, contralateral neurological deficits, intracerebral hemorrhage (ICH) and seizure. The symptoms arise can be from immediately after restoration of blood flow to up to one month since restoration. Acute stroke patients who receive reperfusion therapy with intravenous tissue plasminogen activator and intra-arterial therapy are at greater risk of developing seizures than patients who do not receive acute therapies (98-99)


In conclusion, this review illustrates our current knowledge of cerebral ischemic stroke, its cause, involvement of multiple signalling networks in connection with mitochondrial dysfunction, therapeutic strategies including clinical trials and its pros and cons. In fact, HIF1α, NF-kB, Stat3 and other signaling pathways are induced by ROS and, in turn, can regulate ROS production under cerebral ischemia. From a molecular point of view, transcription factors HIF1α, Stat3 and NF-kB may be considered as master regulators in this context. The combinational therapeutic strategies such as aspirin and streptokinase inhibitor may have adverse outcomes and thus should be carefully studied at preclinical level using appropriate animal models. The antiplatelet drugs have the ability to reduce platelet activity through a variety of mechanisms. Their biological activities go well beyond the platelet and include effects on other cell types throughout the body. The treatment of acute cerebral ischemia is dependent on clear understanding of the activity of the agents on the cerebrovasculature and within the brain parenchyma, especially on cerebral blood flow, the BBB, and neuronal cells. The most beneficial pharmacological regimen will minimize brain injury in cerebral ischemia.


This work was supported by grants received from Council of Scientific and Industrial Research (CSIR), DST (SERB: EMR/2017/000992/HS and Nanomission: SR/NM/NS-1058/2015) and DBT (Biocluster-Kolkata), Govt. of India and ICMR (WOS-DHR).

Abbreviations: ROS: Reactive oxygen species; VEGF: Vascular endothelial growth factor; TGF: Transforming growth factor; PDGF: Platelet derived growth factor; NO: Nitric oxide; ATP: Adenosine triphosphate ; HIF: Hypoxia-inducible factors; NADPH: Nicotinamide adenine dinucleotide phosphate; PHD: Prolyl Hydroxylase Domain; BBB: Blood brain barrier; NF-kB: Nuclear factor-Kappa B; MAPK: Mitogen-activated protein kinase; MMP: Matrix metalloproteinases; CBF: Cerebral blood flow; NMDA: N-Methyl-D-aspartic acid; AMPA: Aminomethylphosphonic acid; PMF: Proton motive force; ETC: Electron transport chain; FFAs: Free fatty acids; Bcl2: B-cell lymphoma 2; GLUT3: Glucose transporter 3; JAK: Janus kinase; NOX: NADPH oxidases; PARP-1: Poly (ADP-ribose) polymerase 1; STAT3: Signal transducer and activator of transcription 3; SOD2: Superoxide dismutase2; EGFR: Epidermal growth factor receptor; FKHR: Forkhead box protein O1; GSK3β: Glycogen synthase kinase 3 beta; ERK: Extracellular signal–regulated kinases; PAI-1: Plasminogen activator inhibitor-1; IKK: inhibitor of IK-B kinase; TNF: Tumor necrosis factor; COX-2: Cyclooxygenase-2; NCX: Sodium-calcium exchanger; XO: Xanthine Oxidase; CAT: Catalase; GPx: Glutathione peroxidase; NBO: Normobaric oxygen; eNOS: Endothelial NO synthase; ICH: Intracerebral hemorrhage

C.ThorntonH.HagbergRole of mitochondria in apoptotic and necroptotic cell death in the developing brain. Clin Chim Acta 4513538 2015 PMCid:PMC4661434
K.Niizuma H.Yoshioka H.Chen G.S.Kim J.E.Jung M.KatsuMitochondrial and apoptotic neuronal death signaling pathways in cerebral ischemia. Biochim Biophys Acta 18029299 2010 PMCid:PMC2790539
N.J.Solenski C.G.diPierro P.A.Trimmer A-L.Kwan G.A.HelmUltrastructural changes of neuronal mitochondria after transient and permanent cerebral ischemia. Stroke 33816824 2002
M.Ruiz-Meana D.Garcia-Dorado E.Miró-CasasA.Abellán J.Soler-SolerMitochondrial Ca2+ uptake during simulated ischemia does not affect permeability transition pore opening upon simulated reperfusion. Cardiovasc Res 71715724 2006
T.H.Sanderson C.A.Reynolds R.Kumar K.Przyklenk M.HüttemannMolecular mechanisms of ischemia-reperfusion injury in brain: pivotal role of the mitochondrial membrane potential in reactive oxygen species generation. Mol Neurobiol 47923 2013 PMCid:PMC3725766
Z.Liu T.Zhou A.C.Ziegler P.Dimitrion L.ZuoOxidative Stress in Neurodegenerative Diseases: From Molecular Mechanisms to Clinical Applications. Oxidative Medicine and Cellular Longevity. 111 2017
S.Gandhi A.Y.AbramovMechanism of Oxidative Stress in Neurodegeneration. Oxidative Medicine and Cellular Longevity. 2012
B.Uttara A.V.Singh P.Zamboni R.MahajanOxidative Stress and Neurodegenerative Diseases: A Review of Upstream and Downstream Antioxidant Therapeutic Options. Curr Neuropharmacol 76574 2009 PMCid:PMC2724665
J.E.Ziello I.S.Jovin Y.HuangHypoxia-Inducible Factor (HIF)-1 Regulatory Pathway and its Potential for Therapeutic Intervention in Malignancy and Ischemia. Yale J Biol Med 805160 2007
A.A.Qutub A.S.PopelReactive Oxygen Species Regulate Hypoxia-Inducible Factor 1α Differentially in Cancer and Ischemia. Mol Cell Biol 2851065119 2008 PMCid:PMC2519710
K.V.Tormos N. S.ChandelInter-connection between mitochondria and HIFs. J Cell Mol Med 14795804 2010 PMCid:PMC2987233
S.Engelhardt S-FHuang S.Patkar M.Gassmann O.O.OgunsholaDifferential responses of blood-brain barrier associated cells to hypoxia and ischemia: a comparative study. Fluids Barriers CNS 12,-124 2015
D.A.Ridder M.SchwaningerNF-kappaB signaling in cerebral ischemia. Neuroscience 1589951006 2009
Z.A.Shah R-C.Li R.K.Thimmulappa T.W.Kensler M.Yamamoto S.BiswalRole of reactive oxygen species in modulation of Nrf2 following ischemic reperfusion injury. Neuroscience 1475359 2007 PMCid:PMC1961622
M.Drigotas A.Affolter W.J.Mann J.BriegerReactive oxygen species activation of MAPK pathway results in VEGF upregulation as an undesired irradiation response. J Oral Pathol Med 42612619 2013
D.Mu X.Jiang R.A.Sheldon C.K.Fox S.E.GHamrick Z.S.VexlerRegulation of hypoxia-inducible factor 1alpha and induction of vascular endothelial growth factor in a rat neonatal stroke model. Neurobiol Dis 14524534 2003
P.Pichiule F.Agani J.C.Chavez K.Xu J.C.LaMannaHIF-1 alpha and VEGF expression after transient global cerebral ischemia. Adv Exp Med Biol 530611617 2003
V.Janardhan A.I.QureshiMechanisms of ischemic brain injury. Curr Cardiol Rep 6117123 2004
J.L.Hinkle M.M.GuanciAcute ischemic stroke review. J Neurosci Nurs 39285293 2007
E.P.Soler V.C.RuizEpidemiology and Risk Factors of Cerebral and Ischemic Heart Diseases: Similarities and Differences. Curr Cardiol Rev 6138149 2010 PMCid:PMC2994106
R.J.TraystmanAnimal models of focal and global cerebral ischemia. ILAR J 448595 2003
M.Paciaroni V.Caso G.AgnelliThe concept of ischemic penumbra in acute stroke and therapeutic opportunities. Eur Neurol 61321330 2009
R.S.Pandya L.Mao H.Zhou S.Zhou J.Zeng A.J.PoppCentral Nervous System Agents for Ischemic Stroke: Neuroprotection Mechanisms. Cent Nerv Syst Agents Med Chem 118197 2011 PMCid:PMC3146965
T-C.Kang I.K.Hwang S-K.Park S-J.An D-KYoon S.M.MoonChronological changes of N-methyl-D-aspartate receptors and excitatory amino acid carrier 1 immunoreactivities in CA1 area and subiculum after transient forebrain ischemia. J Neurocytol 30945955 2001
R.Anandakrishnan Z.Zhang R.Donovan-Maiye D.M.ZuckermanBiophysical comparison of ATP synthesis mechanisms shows a kinetic advantage for the rotary process. ProcNatlAcadSci U S A 1131122011225 2016 PMCid:PMC5056049
M.P.MurphyHow mitochondria produce reactive oxygen species. Biochem J 417113 2009 PMCid:PMC2605959
Y.Liu G.Fiskum D.SchubertGeneration of reactive oxygen species by the mitochondrial electron transport chain. J Neurochem 80780787 2002
Q Chen, E.J.Vazquez S.Moghaddas C.L.Hoppel E.J.LesnefskyProduction of Reactive Oxygen Species by Mitochondria CENTRAL ROLE OF COMPLEX III. J BiolChem 2783602736031 2003
T.Fukai M. M.Ushio-FukaSuperoxide Dismutases: Role in Redox Signaling, Vascular Function, and Diseases. Antioxid Redox Signal 1515831606 2011 PMCid:PMC3151424
G.R.BuettnerSuperoxide Dismutase in Redox Biology: The roles of superoxide and hydrogen peroxide. Anticancer Agents Med Chem, 11341346 2011 PMCid:PMC3131414
F.W.Outten E.C.TheilIron-Based Redox Switches in Biology. Antioxid Redox Signal 1110291046 2009 PMCid:PMC2842161
S. Dröse U.BrandtThe Mechanism of Mitochondrial Superoxide Production by the Cytochrome bc1 Complex. J Biol Chem 2832164921654 2008
M.K.Ghosh M.Mukhopadhyay I.B.ChatterjeeNADPH-initiated cytochrome P450-dependent free iron-independent microsomal lipid peroxidation: specific prevention by ascorbic acid. Mol Cell Biochem 1663544 1997
C.K.Mukhopadhyay M.K.Ghosh I.B.ChatterjeeAscorbic acid prevents lipid peroxidation and oxidative damage of proteins in guinea pig extrahepatic tissue microsomes. Mol Cell Biochem 1427178 1995
P.Vallet Y.Charnay K.Steger E.Ogier-Denis E.Kovari F.HerrmannNeuronal expression of the NADPH oxidase NOX4, and its regulation in mouse experimental brain ischemia. Neuroscience132233238 2005
N.Fukuyama S.Takizawa H.Ishida K.Hoshiai Y.Shinohara H.NakazawaPeroxynitrite formation in focal cerebral ischemia-reperfusion in rats occurs predominantly in the peri-infarct region. J Cereb Blood Flow Metab18123129 1998
C.Guo L.Sun X.Chen D.ZhangOxidative stress, mitochondrial damage and neurodegenerative diseases. Neural Regen Res820032014 2013
G.E.Gibson A.Starkov J.P.Blass R.R.Ratan M.F.BealCause and Consequence: Mitochondrial Dysfunction Initiates and Propagates Neuronal Dysfunction, Neuronal Death and Behavioral Abnormalities in Age Associated Neurodegenerative Diseases. Biochim Biophys Acta1802122134 2010 PMCid:PMC2790547
M.Gleichmann M.P.MattsonNeuronal Calcium Homeostasis and Dysregulation. Antioxid Redox Signal1412611273 2011 PMCid:PMC3048837
Y.Yamazaki S.Harada T.Wada S.Yoshida S.TokuyamaSodium transport through the cerebral sodium-glucose transporter exacerbates neuron damage during cerebral ischaemia. J Pharm Pharmacol68922931 2016
C.Xing K.Arai EH.Lo M.HommelPathophysiologic cascades in ischemic stroke. Int J Stroke7378385 2012 PMCid:PMC3985770
D.Sun D.D.GilboeIschemia-induced changes in cerebral mitochondrial free fatty acids, phospholipids, and respiration in the rat. J Neurochem6219211928 1994
P.Proia C.M.Di Liegro G.Schiera A.Fricano I.Di LiegroLactate as a Metabolite and a Regulator in the Central Nervous System. Int J Mol Sci172016
Y.NishizawaGlutamate release and neuronal damage in ischemia. Life Sci69369381 2001
W.PaschenGlutamate excitotoxicity in transient global cerebral ischemia. Acta Neurobiol Exp (Wars)56313322 1996
K.A.HossmannGlutamate-mediated injury in focal cerebral ischemia: the excitotoxin hypothesis revised. Brain Pathol42336 1994
A.Andreyev P.Tamrakar R.E.Rosenthal G.FiskumCalcium uptake and cytochrome c release from normal and ischemic brain mitochondria. Neurochemistry International 2017
J.N.Weiss N.Venkatesh S.T.LampATP-sensitive K+ channels and cellular K+ loss in hypoxic and ischaemic mammalian ventricle. J Physiol447649673 1992 PMCid:PMC1176056
S-T.Luo D-M.Zhang Q.Qin L.Lu M.Luo F-C.Guo The Promotion of Erythropoiesis via the Regulation of Reactive Oxygen Species by Lactic Acid. Scientific Reports738105 2017
N.S.Chandel D.S.McClintock C.E.Feliciano T.M.Wood J.A.Melendez A.M.RodriguezReactive Oxygen Species Generated at Mitochondrial Complex III Stabilize Hypoxia-inducible Factor-1α during Hypoxia- a mechanism of O2 sensing. J Biol Chem2752513025138 2000
H.Chan. PakReactive Oxygen Radicals in Signaling and Damage in the Ischemic Brain. J Cereb Blood Flow Metab21214 2001
K.Niizuma H.Endo PH.ChanOxidative stress and mitochondrial dysfunction as determinants of ischemic neuronal death and survival. J Neurochem109133138 2009 PMCid:PMC2679225
E.Rekuviene L.Ivanoviene V.Borutaite R.MorkunieneRotenone decreases ischemia-induced injury by inhibiting mitochondrial permeability transition in mature brains. Neurosci Lett6534550 2017
R.K.Srivastava S.J.Sollott L.Khan R.Hansford E.G.Lakatta D.L.LongoBcl-2 and Bcl-XL Block Thapsigargin-Induced Nitric Oxide Generation, c-Jun NH2-Terminal Kinase Activity, and Apoptosis. Mol Cell Biol1956595674 1999 PMCid:PMC84418
A.Atlante P.Calissano A.Bobba A.Azzariti E.Marra S.PassarellaCytochrome c Is Released from Mitochondria in a Reactive Oxygen Species (ROS)-dependent Fashion and Can Operate as a ROS Scavenger and as a Respiratory Substrate in Cerebellar Neurons Undergoing Excitotoxic Death. J Biol Chem2753715937166 2000
D.N.Granger P.R.KvietysReperfusion injury and reactive oxygen species: The evolution of a concept. Redox Biol6524551 2015 PMCid:PMC4625011
M.Fujimura T.Tominaga P.H.ChanNeuroprotective effect of an antioxidant in ischemic brain injury: involvement of neuronal apoptosis. Neurocrit Care25966 2005
K.Panda R.Chattopadhyay M.K.Ghosh D.J.Chattopadhyay I.B.ChatterjeeVitamin C prevents cigarette smoke induced oxidative damage of proteins and increased proteolysis. Free Radic Biol Med2710641079 1999
M.K.Ghosh D.J.Chattopadhyay I.B.ChatterjeeVitamin C prevents oxidative damage. Free Radic Res25173179 1996
L.H.Lin S.Cao L.Yu J.Cui W.J.Hamilton P.K.LiuUp-regulation of base excision repair activity for 8-hydroxy-2’-deoxyguanosine in the mouse brain after forebrain ischemia-reperfusion. J Neurochem7410981105 2000 PMCid:PMC2726712
M.Perluigi R.Coccia D.A.Butterfield4-Hydroxy-2-Nonenal, a Reactive Product of Lipid Peroxidation, and Neurodegenerative Diseases: A Toxic Combination Illuminated by Redox Proteomics Studies. Antioxid Redox Signal1715901609 2012 PMCid:PMC3449441
N.Singh G.Sharma V.MishraHypoxia inducible factor-1: its potential role in cerebral ischemia. Cell Mol Neurobiol32491507 2012
O.Baranova L.F.Miranda P.Pichiule I.Dragatsis R.S.Johnson J.C.ChavezNeuron-specific inactivation of the hypoxia inducible factor 1 alpha increases brain injury in a mouse model of transient focal cerebral ischemia. J Neurosci2763206332 2007
Y.Liu Y.Li R.Tian W.Liu Z.Fei Q.LongThe expression and significance of HIF-1α and GLUT-3 in glioma. Brain Research1304149154 2009
G.S.Kim J.E.Jung K.Niizuma P.H.ChanNeurosci291477914789 2009
G.S.Kim J.E.Jung P.Narasimhan H.Sakata H.Yoshioka Y.S.SongRelease of mitochondrial apoptogenic factors and cell death are mediated by CK2 and NADPH oxidase. J Cereb Blood Flow Metab32720730 2012 PMCid:PMC3318149
T, Mandal, A.Bhowmik A.Chatterjee U.Chatterjee S.Chatterjee M.K.GhoshReduced phosphorylation of Stat3 at Ser-727 mediated by casein kinase 2 — Protein phosphatase 2A enhances Stat3 Tyr-705 induced tumorigenic potential of glioma cells. Cellular Signalling2617251734 2014
J.E.Jung G.S.Kim P.H.ChanNeuroprotection by IL-6 Is Mediated by STAT3 and Antioxidative Signaling in Ischemic Stroke. Stroke4235743579 2011 PMCid:PMC3395465
J.Zhou T.Du B.Li Y.Rong A.Verkhratsky L.PengCrosstalk Between MAPK/ERK and PI3K/AKT Signal Pathways During Brain Ischemia/Reperfusion. ASN Neuro72015
T.Kawano M.Morioka S.Yano J-IHamada Y.Ushio E.MiyamotoDecreased akt activity is associated with activation of forkhead transcription factor after transient forebrain ischemia in gerbil hippocampus. J Cereb Blood Flow Metab22926934 2002
X-S.Xing F.Liu Z-Y.HeAkt regulates β-catenin in a rat model of focal cerebral ischemia-reperfusion injury. Mol Med Rep1131223128 2015
H.Zhao T.Shimohata J.Q.Wang G.Sun D.W.Schaal R.M.SapolskyAkt contributes to neuroprotection by hypothermia against cerebral ischemia in rats. J Neurosci2597949806 2005
K.Ban Z.Peng R.A.KozarInhibition of ERK1/2 Worsens Intestinal Ischemia/Reperfusion Injury. PLOS ONE8e76790 2013
K.M.Dhandapani D.W.Brann Transforming growth factor-beta: a neuroprotective factor in cerebral ischemia. Cell BiochemBiophys391322 2003
A.Buisson S.Lesne F.Docagne, C.Ali O.Nicole E.T.MacKenzieTransforming Growth Factor-β and Ischemic Brain Injury. Cell Mol Neurobiol 23 539550 2003
D.A.Ridder M.SchwaningerNF-kappaB signaling in cerebral ischemia. Neuroscience1589951006 2009
I.Inta S.Paxian I.Maegele W.Zhang M.Pizzi P.SpanoBim and Noxa are candidates to mediate the deleterious effect of the NF-kappa B subunit RelA in cerebral ischemia. J Neurosci261289612903 2006
G.I.Botchkina E.Geimonen M.L.Bilof O.Villarreal K.J.TraceyLoss of NF-kappaB activity during cerebral ischemia and TNF cytotoxicity. Mol Med53723811999
O.A.Harari J.K.LiaoNF-κB and innate immunity in ischemic stroke. Ann N Y Acad Sci12073240 2010 PMCid:PMC3807097
Y.Ikeda-Matsuo Y.Hirayama A.Ota S.Uematsu S.Akira Y.SasakiMicrosomal prostaglandin E synthase-1 and cyclooxygenase-2 are both required for ischaemic excitotoxicity. Br J Pharmacol15911741186 2010 PMCid:PMC2839275
W.Zhang I.Potrovita V.Tarabin O.Herrmann V.Beer F.WeihNeuronal activation of NF-kappaB contributes to cell death in cerebral ischemia. J Cereb Blood Flow Metab253040 2005
T.Brustovetsky A.Bolshakov N.BrustovetskyCalpain Activation and Na/Ca Exchanger Degradation Occur Downstream of Calcium Deregulation in Hippocampal Neurons Exposed to Excitotoxic Glutamate. J Neurosci Res 88 13171328 2010
D.BanoP.NicoteraCa2+ signals and neuronal death in brain ischemia. Stroke38674676 2007
J.P. Bolaños, A.AlmeidaRoles of nitric oxide in brain hypoxia-ischemia. Biochimica et Biophysica Acta (BBA) - Bioenergetics1411415436 1999
L.J.Forman P.Liu R.G.Nagele K.Yin P.Y.WongAugmentation of nitric oxide, superoxide, and peroxynitrite production during cerebral ischemia and reperfusion in the rat. Neurochem Res23141148 1998
M.M.Bednar C.E.GrossAntiplatelet therapy in acute cerebral ischemia. Stroke30887893 1999
B.J.Connell M.C.Saleh B.V.Khan T.M.SalehApocynin may limit total cell death following cerebral ischemia and reperfusion by enhancing apoptosis. Food Chem Toxicol4930633069 2011
N.Işik M.Z.Berkman M.N.Pamir M.Kalelioğlu A.SavEffect of allopurinol in focal cerebral ischemia in rats: an experimental study. Surg Neurol 64Suppl 2, S510 2005
E.D.Hall K.E.Pazara J.M.Braughler21-Aminosteroid lipid peroxidation inhibitor U74006F protects against cerebral ischemia in gerbils. Stroke199971002 1988
W.J.Perkins L.N.Milde J.H.Milde J.D.MichenfelderPretreatment with U74006F improves neurologic outcome following complete cerebral ischemia in dogs. Stroke22902909 1991
S.Kuroda R.Tsuchidate M.L.Smith K.R.Maples B.K.SiesjöNeuroprotective effects of a novel nitrone, NXY-059, after transient focal cerebral ischemia in the rat. J Cereb Blood Flow Metab19778787 1999
H.Shichinohe S.Kuroda H.Yasuda T.Ishikawa M.Iwai M.HoriuchiNeuroprotective effects of the free radical scavenger Edaravone (MCI-186) in mice permanent focal brain ischemia. Brain Res1029200206 2004
Y.Zhang S.Fu X.Li P.Chen J.Wang J.ChePEP-1-SOD1 protects brain from ischemic insult following asphyxial cardiac arrest in rats. Resuscitation8210811086 2011 PMCid:PMC3138811
H.Imai D.I.Graham H.Masayasu I.M.MacraeAntioxidant ebselen reduces oxidative damage in focal cerebral ischemia. Free Radic Biol Med345663 2003
S.Shi Z.Qi Y.Luo X.Ji K.J.LiuNormobaric oxygen treatment in acute ischemic stroke: a clinical perspective. Med Gas Res6147153 2016 PMCid:PMC5110139
C.Gandolfo P.Sandercock M.ContiLubeluzole for acute ischaemic stroke. Cochrane Database Syst Rev CD001924 2002
Y.Garnier T.Löbbert A.Jensen R.BergerLubeluzole pretreatment does not provide neuroprotection against transient global cerebral ischemia in fetal sheep near term. Pediatr Res51517522 2002
J.Pan A-A.Konstas B.Bateman G.A. J.OrtolanoPile-Spellman Reperfusion injury following cerebral ischemia: pathophysiology, MR imaging, and potential therapies. Neuroradiology4993102 2007 PMCid:PMC1786189
B.SchallerR.GrafCerebral ischemia and reperfusion: the pathophysiologic concept as a basis for clinical therapy. J Cereb Blood Flow Metab24351371 200499.
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