Editorial

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Open AccessEditorial Brain Sciences Special Issue: Neuroprotection against Ischemic Brain Injury

Brain Sci. 2013, 3(3), 1415-1416; doi:10.3390/brainsci3031415

Received: 20 August 2013 / Accepted: 20 August 2013 / Published: 24 September 2013

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Abstract

It was my great pleasure to have acted as the guest editor for the Brain Sciences Special Issue on Neuroprotection against Ischemic Brain Injury. This Special Issue consists of a total of 18 articles covering a range of topics with the purpose of

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It was my great pleasure to have acted as the guest editor for the Brain Sciences Special Issue on Neuroprotection against Ischemic Brain Injury. This Special Issue consists of a total of 18 articles covering a range of topics with the purpose of providing new knowledge and exploring novel interventions that one day may be used to better protect and repair the brain after ischemia. [...] Full article

(This article belongs to the Special Issue Neuroprotection against Ischemic Brain Injury)

Research

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Open AccessArticle Sex Differences in Behavioral Outcomes Following Temperature Modulation During Induced Neonatal Hypoxic Ischemic Injury in Rats

by Amanda L. Smith, Haley Garbus, Ted S. Rosenkrantz and Roslyn Holly Fitch

Brain Sci. 2015, 5(2), 220-240; doi:10.3390/brainsci5020220

Received: 6 March 2015 / Revised: 24 April 2015 / Accepted: 12 May 2015 / Published: 22 May 2015

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Abstract

Neonatal hypoxia ischemia (HI; reduced oxygen and/or blood flow to the brain) can cause various degrees of tissue damage, as well as subsequent cognitive/behavioral deficits such as motor, learning/memory, and auditory impairments. These outcomes frequently result from cardiovascular and/or respiratory events observed in

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Neonatal hypoxia ischemia (HI; reduced oxygen and/or blood flow to the brain) can cause various degrees of tissue damage, as well as subsequent cognitive/behavioral deficits such as motor, learning/memory, and auditory impairments. These outcomes frequently result from cardiovascular and/or respiratory events observed in premature infants. Data suggests that there is a sex difference in HI outcome, with males being more adversely affected relative to comparably injured females. Brain/body temperature may play a role in modulating the severity of an HI insult, with hypothermia during an insult yielding more favorable anatomical and behavioral outcomes. The current study utilized a postnatal day (P) 7 rodent model of HI injury to assess the effect of temperature modulation during injury in each sex. We hypothesized that female P7 rats would benefit more from lowered body temperatures as compared to male P7 rats. We assessed all subjects on rota-rod, auditory discrimination, and spatial/non-spatial maze tasks. Our results revealed a significant benefit of temperature reduction in HI females as measured by most of the employed behavioral tasks. However, HI males benefitted from temperature reduction as measured on auditory and non-spatial tasks. Our data suggest that temperature reduction protects both sexes from the deleterious effects of HI injury, but task and sex specific patterns of relative efficacy are seen. Full article

(This article belongs to the Special Issue Neuroprotection against Ischemic Brain Injury)

Open AccessArticle The Hypothermic Influence on CHOP and Ero1-α in an Endoplasmic Reticulum Stress Model of Cerebral Ischemia

by Gagandip K. Poone, Henrik Hasseldam, Nina Munkholm, Rune S. Rasmussen, Nina V. Grønberg and Flemming F. Johansen

Brain Sci. 2015, 5(2), 178-187; doi:10.3390/brainsci5020178

Received: 6 February 2015 / Revised: 20 April 2015 / Accepted: 7 May 2015 / Published: 15 May 2015

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Abstract

Hypoxia induced endoplasmic reticulum stress causes accumulation of unfolded proteins in the endoplasmic reticulum and activates the unfolded protein response, resulting in apoptosis through CCAAT-enhancer-binding protein homologous protein (CHOP) activation. In an in vitro and in vivo model of ischemic stroke, we investigated

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Hypoxia induced endoplasmic reticulum stress causes accumulation of unfolded proteins in the endoplasmic reticulum and activates the unfolded protein response, resulting in apoptosis through CCAAT-enhancer-binding protein homologous protein (CHOP) activation. In an in vitro and in vivo model of ischemic stroke, we investigated whether hypothermia regulates the unfolded protein response of CHOP and Endoplasmic reticulum oxidoreductin-α (Ero1-α), because Ero1-α is suggested to be a downstream CHOP target. The gene expression of CHOP and Ero1-α was measured using Quantitative-PCR (Q-PCR) in rat hippocampi following global cerebral ischemia, and in hypoxic pheochromocytoma cells during normothermic (37 °C) and hypothermic (31 °C) conditions. As a result of ischemia, a significant increase in expression of CHOP and Ero1-α was observed after three, six and twelve hours of reperfusion following global ischemia. A stable increase in CHOP expression was observed throughout the time course (p < 0.01, p < 0.0001), whereas Ero1-α expression peaked at three to six hours (p < 0.0001). Induced hypothermia in hypoxia stressed PC12 cells resulted in a decreased expression of CHOP after three, six and twelve hours (p < 0.0001). On the contrary, the gene expression of Ero1-α increased as a result of hypothermia and peaked at twelve hours (p < 0.0001). Hypothermia attenuated the expression of CHOP, supporting that hypothermia suppress endoplasmic reticulum stress induced apoptosis in stroke. As hypothermia further induced up-regulation of Ero1-α, and since CHOP and Ero1-α showed differential regulation as a consequence of both disease (hypoxia) and treatment (hypothermia), we conclude that they are regulated independently. Full article

(This article belongs to the Special Issue Neuroprotection against Ischemic Brain Injury)

Open AccessArticle Increasing the Biological Stability Profile of a New Chemical Entity, UPEI-104, and Potential Use as a Neuroprotectant Against Reperfusion-Injury

by Tarek M. Saleh, Barry J. Connell, Inan Kucukkaya and Alaa S. Abd-El-Aziz

Brain Sci. 2015, 5(2), 130-143; doi:10.3390/brainsci5020130

Received: 11 March 2015 / Revised: 1 April 2015 / Accepted: 13 April 2015 / Published: 21 April 2015

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Abstract

Previous work in our laboratory demonstrated the utility of synthetic combinations of two naturally occurring, biologically active compounds. In particular, we combined two known anti-oxidant compounds, lipoic acid and apocynin, covalently linked via an ester bond (named UPEI-100). In an animal model of

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Previous work in our laboratory demonstrated the utility of synthetic combinations of two naturally occurring, biologically active compounds. In particular, we combined two known anti-oxidant compounds, lipoic acid and apocynin, covalently linked via an ester bond (named UPEI-100). In an animal model of ischemia-reperfusion injury (tMCAO), UPEI-100 was shown to produce equivalent neuroprotection compared to each parent compound, but at a 100-fold lower dose. However, it was determined that UPEI-100 was undetectable in any tissue samples almost immediately following intravenous injection. Therefore, the present investigation was done to determine if biological stability of UPEI-100 could be improved by replacing the ester bond with a more bio cleavage-resistant bond, an ether bond (named UPEI-104). We then compared the stability of UPEI-104 to the original parent compound UPEI-100 in human plasma as well as liver microsomes. Our results demonstrated that both UPEI-100 and UPEI-104 could be detected in human plasma for over 120 min; however, only UPEI-104 was detectable for an average of 7 min following incubation with human liver microsomes. This increased stability did not affect the biological activity of UPEI-104 as measured using our tMCAO model. Our results suggest that combining compounds using an ether bond can improve stability while maintaining biological activity. Full article

(This article belongs to the Special Issue Neuroprotection against Ischemic Brain Injury)

Open AccessArticle The Role of Citicoline in Neuroprotection and Neurorepair in Ischemic Stroke

by José Álvarez-Sabín and Gustavo C. Román

Brain Sci. 2013, 3(3), 1395-1414; doi:10.3390/brainsci3031395

Received: 16 July 2013 / Revised: 10 August 2013 / Accepted: 14 August 2013 / Published: 23 September 2013

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Abstract

Advances in acute stroke therapy resulting from thrombolytic treatment, endovascular procedures, and stroke units have improved significantly stroke survival and prognosis; however, for the large majority of patients lacking access to advanced therapies stroke mortality and residual morbidity remain high and many patients

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Advances in acute stroke therapy resulting from thrombolytic treatment, endovascular procedures, and stroke units have improved significantly stroke survival and prognosis; however, for the large majority of patients lacking access to advanced therapies stroke mortality and residual morbidity remain high and many patients become incapacitated by motor and cognitive deficits, with loss of independence in activities of daily living. Therefore, over the past several years, research has been directed to limit the brain lesions produced by acute ischemia (neuroprotection) and to increase the recovery, plasticity and neuroregenerative processes that complement rehabilitation and enhance the possibility of recovery and return to normal functions (neurorepair). Citicoline has therapeutic effects at several stages of the ischemic cascade in acute ischemic stroke and has demonstrated efficiency in a multiplicity of animal models of acute stroke. Long-term treatment with citicoline is safe and effective, improving post-stroke cognitive decline and enhancing patients’ functional recovery. Prolonged citicoline administration at optimal doses has been demonstrated to be remarkably well tolerated and to enhance endogenous mechanisms of neurogenesis and neurorepair contributing to physical therapy and rehabilitation. Full article

(This article belongs to the Special Issue Neuroprotection against Ischemic Brain Injury)

Open AccessArticle Genetic Deletion of Prostacyclin IP Receptor Exacerbates Transient Global Cerebral Ischemia in Aging Mice

by Hania Shakil and Sofiyan Saleem

Brain Sci. 2013, 3(3), 1095-1108; doi:10.3390/brainsci3031095

Received: 5 May 2013 / Revised: 18 June 2013 / Accepted: 27 June 2013 / Published: 22 July 2013

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Abstract

Transient global cerebral ischemia causes delayed neuronal death in the hippocampal CA1 region. It also induces an up regulation of cyclooxygenase 2 (COX-2), which generates several metabolites of arachidonic acid, known as prostanoids, including Prostaglandin I₂ (PGI₂). The present study

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Transient global cerebral ischemia causes delayed neuronal death in the hippocampal CA1 region. It also induces an up regulation of cyclooxygenase 2 (COX-2), which generates several metabolites of arachidonic acid, known as prostanoids, including Prostaglandin I₂ (PGI₂). The present study investigated whether the PGI2 IP receptor plays an important role in brain injury after global cerebral ischemia in aged mice. Adult young (2–3 months) and aged (12–15 months) male C57Bl/6 wild-type (WT) or IP receptor knockout (IP KO) mice underwent a 12 min bilateral common carotid artery occlusion (BCCAO) or a sham surgery. Behavior tests (neurologic deficit and T-maze) were performed 3 and 7 days after BCCAO. After seven days of reperfusion, the numbers of cells positive for markers of neurons, astrocytes, microglia, myeloperoxidase (MPO) and phosphorylated CREB (p-CREB) were evaluated immunohistochemically. Interestingly, in young and aged IP KO ischemic mice, there was a significant increase (p < 0.01) in cognitive deficit, hippocampal CA1 pyramidal neuron death, microglia and MPO activation, while p-CREB was reduced as compared to their corresponding WT controls. These data suggest that following ischemia, IP receptor deletion contributes to memory and cognitive deficits regulated by the CREB pathway and that treatment with IP receptor agonists could be a useful target to prevent harmful consequences. Full article

(This article belongs to the Special Issue Neuroprotection against Ischemic Brain Injury)

Open AccessArticle Neuroprotective Role of Nerve Growth Factor in Hypoxic-Ischemic Brain Injury

by Claudia Fantacci, Domenico Capozzi, Pietro Ferrara and Antonio Chiaretti

Brain Sci. 2013, 3(3), 1013-1022; doi:10.3390/brainsci3031013

Received: 17 May 2013 / Revised: 2 June 2013 / Accepted: 7 June 2013 / Published: 25 June 2013

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Abstract

Hypoxic-ischemic brain injuries (HIBI) in childhood are frequently associated with poor clinical and neurological outcome. Unfortunately, there is currently no effective therapy to restore neuronal loss and to determine substantial clinical improvement. Several neurotrophins, such as Nerve Growth Factor (NGF), Brain-Derived Neurotrophic Factor

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Hypoxic-ischemic brain injuries (HIBI) in childhood are frequently associated with poor clinical and neurological outcome. Unfortunately, there is currently no effective therapy to restore neuronal loss and to determine substantial clinical improvement. Several neurotrophins, such as Nerve Growth Factor (NGF), Brain-Derived Neurotrophic Factor (BDNF), and Glial Derived Neurotrophic Factor (GDNF), play a key role in the development, differentiation, and survival of the neurons of the peripheral and central nervous system. Experimental animal studies demonstrated their neuroprotective role in HIBI, while only a few studies examined the neuroprotective mechanisms in patients with severe HIBI. We report two cases of children with HIBI and prolonged comatose state who showed a significant improvement after intraventricular NGF administration characterized by amelioration of electroencephalogram (EEG) and cerebral perfusion at single-photon emission computed tomography (SPECT). The improvement in motor and cognitive functions of these children could be related to the neuroprotective role exerted by NGF in residual viable cholinergic neurons, leading to the restoration of neuronal networks in the damaged brain. Full article

(This article belongs to the Special Issue Neuroprotection against Ischemic Brain Injury)

Open AccessArticle The Protective Effect of Glibenclamide in a Model of Hemorrhagic Encephalopathy of Prematurity

by Cigdem Tosun, Michael T. Koltz, David B. Kurland, Hina Ijaz, Melda Gurakar, Gary Schwartzbauer, Turhan Coksaygan, Svetlana Ivanova, Volodymyr Gerzanich and J. Marc Simard

Brain Sci. 2013, 3(1), 215-238; doi:10.3390/brainsci3010215

Received: 6 January 2013 / Revised: 21 February 2013 / Accepted: 22 February 2013 / Published: 7 March 2013

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Abstract

We studied a model of hemorrhagic encephalopathy of prematurity (EP) that closely recapitulates findings in humans with hemorrhagic EP. This model involves tandem insults of 20 min intrauterine ischemia (IUI) plus an episode of elevated venous pressure induced by intraperitoneal glycerol on post-natal

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We studied a model of hemorrhagic encephalopathy of prematurity (EP) that closely recapitulates findings in humans with hemorrhagic EP. This model involves tandem insults of 20 min intrauterine ischemia (IUI) plus an episode of elevated venous pressure induced by intraperitoneal glycerol on post-natal day (P) 0. We examined Sur1 expression, which is upregulated after focal ischemia but has not been studied after brief global ischemia including IUI. We found that 20 min IUI resulted in robust upregulation of Sur1 in periventricular microvessels and tissues. We studied tandem insult pups from untreated or vehicle-treated dams (TI-CTR), and tandem insult pups from dams administered a low-dose, non-hypoglycemogenic infusion of the Sur1 blocker, glibenclamide, for 1 week after IUI (TI-GLIB). Compared to pups from the TI-CTR group, pups from the TI-GLIB group had significantly fewer and less severe hemorrhages on P1, performed significantly better on the beam walk and accelerating Rotarod on P35 and in tests of thigmotaxis and rapid learning on P35–49, and had significantly greater body and brain weights at P52. We conclude that low-dose glibenclamide administered to the mother at the end of pregnancy protects pups subjected to IUI from post-natal events of elevated venous pressure and its consequences. Full article

(This article belongs to the Special Issue Neuroprotection against Ischemic Brain Injury)

Open AccessArticle Therapeutic Effect of Caffeine Treatment Immediately Following Neonatal Hypoxic-Ischemic Injury on Spatial Memory in Male Rats

by Michelle Alexander, Amanda L. Smith, Ted S. Rosenkrantz and R. Holly Fitch

Brain Sci. 2013, 3(1), 177-190; doi:10.3390/brainsci3010177

Received: 22 December 2012 / Revised: 16 February 2013 / Accepted: 21 February 2013 / Published: 5 March 2013

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Abstract

Hypoxia Ischemia (HI) refers to the disruption of blood and/or oxygen delivery to the brain. Term infants suffering perinatal complications that result in decreased blood flow and/or oxygen delivery to the brain are at risk for HI. Among a variety of developmental delays

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Hypoxia Ischemia (HI) refers to the disruption of blood and/or oxygen delivery to the brain. Term infants suffering perinatal complications that result in decreased blood flow and/or oxygen delivery to the brain are at risk for HI. Among a variety of developmental delays in this population, HI injured infants demonstrate subsequent memory deficits. The Rice-Vannucci rodent HI model can be used to explore behavioral deficits following early HI events, as well as possible therapeutic agents to help reduce deleterious outcomes. Caffeine is an adenosine receptor antagonist that has recently shown promising results as a therapeutic agent following HI injury. The current study sought to investigate the therapeutic benefit of caffeine following early HI injury in male rats. On post-natal day (P) 7, HI injury was induced (cauterization of the right common carotid artery, followed by two hours of 8% oxygen). Male sham animals received only a midline incision with no manipulation of the artery followed by room air exposure for two hours. Subsets of HI and sham animals then received either an intraperitoneal (i.p.) injection of caffeine (10 mg/kg), or vehicle (sterile saline) immediately following hypoxia. All animals later underwent testing on the Morris Water Maze (MWM) from P90 to P95. Results show that HI injured animals (with no caffeine treatment) displayed significant deficits on the MWM task relative to shams. These deficits were attenuated by caffeine treatment when given immediately following the induction of HI. We also found a reduction in right cortical volume (ipsilateral to injury) in HI saline animals as compared to shams, while right cortical volume in the HI caffeine treated animals was intermediate. These findings suggest that caffeine is a potential therapeutic agent that could be used in HI injured infants to reduce brain injury and preserve subsequent cognitive function. Full article

(This article belongs to the Special Issue Neuroprotection against Ischemic Brain Injury)

Review

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Open AccessReview Growth Factors for the Treatment of Ischemic Brain Injury (Growth Factor Treatment)

by Amara Larpthaveesarp, Donna M. Ferriero and Fernando F. Gonzalez

Brain Sci. 2015, 5(2), 165-177; doi:10.3390/brainsci5020165

Received: 13 March 2015 / Revised: 13 April 2015 / Accepted: 21 April 2015 / Published: 30 April 2015

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Abstract

In recent years, growth factor therapy has emerged as a potential treatment for ischemic brain injury. The efficacy of therapies that either directly introduce or stimulate local production of growth factors and their receptors in damaged brain tissue has been tested in a

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In recent years, growth factor therapy has emerged as a potential treatment for ischemic brain injury. The efficacy of therapies that either directly introduce or stimulate local production of growth factors and their receptors in damaged brain tissue has been tested in a multitude of models for different Central Nervous System (CNS) diseases. These growth factors include erythropoietin (EPO), vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), and insulin-like growth factor (IGF-1), among others. Despite the promise shown in animal models, the particular growth factors that should be used to maximize both brain protection and repair, and the therapeutic critical period, are not well defined. We will review current pre-clinical and clinical evidence for growth factor therapies in treating different causes of brain injury, as well as issues to be addressed prior to application in humans. Full article

(This article belongs to the Special Issue Neuroprotection against Ischemic Brain Injury)

Open AccessReview Molecular Dissection of Cyclosporin A’s Neuroprotective Effect Reveals Potential Therapeutics for Ischemic Brain Injury

by Minoru Kawakami

Brain Sci. 2013, 3(3), 1325-1356; doi:10.3390/brainsci3031325

Received: 23 June 2013 / Revised: 30 July 2013 / Accepted: 14 August 2013 / Published: 5 September 2013

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Abstract

After the onset of brain ischemia, a series of events leads ultimately to the death of neurons. Many molecules can be pharmacologically targeted to protect neurons during these events, which include glutamate release, glutamate receptor activation, excitotoxicity, Ca²⁺ influx into cells, mitochondrial

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After the onset of brain ischemia, a series of events leads ultimately to the death of neurons. Many molecules can be pharmacologically targeted to protect neurons during these events, which include glutamate release, glutamate receptor activation, excitotoxicity, Ca²⁺ influx into cells, mitochondrial dysfunction, activation of intracellular enzymes, free radical production, nitric oxide production, and inflammation. There have been a number of attempts to develop neuroprotectants for brain ischemia, but many of these attempts have failed. It was reported that cyclosporin A (CsA) dramatically ameliorates neuronal cell damage during ischemia. Some researchers consider ischemic cell death as a unique process that is distinct from both apoptosis and necrosis, and suggested that mitochondrial dysfunction and Δψ collapse are key steps for ischemic cell death. It was also suggested that CsA has a unique neuroprotective effect that is related to mitochondrial dysfunction. Here, I will exhibit examples of neuroprotectants that are now being developed or in clinical trials, and will discuss previous researches about the mechanism underlying the unique CsA action. I will then introduce the results of our cDNA subtraction experiment with or without CsA administration in the rat brain, along with our hypothesis about the mechanism underlying CsA’s effect on transcriptional regulation. Full article

(This article belongs to the Special Issue Neuroprotection against Ischemic Brain Injury)

► Figures

Open AccessReview Cannabinoids: Well-Suited Candidates for the Treatment of Perinatal Brain Injury

by David Fernández-López, Ignacio Lizasoain, Maria Ángeles Moro and José Martínez-Orgado

Brain Sci. 2013, 3(3), 1043-1059; doi:10.3390/brainsci3031043

Received: 16 April 2013 / Revised: 14 May 2013 / Accepted: 26 June 2013 / Published: 10 July 2013

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Abstract

Perinatal brain injury can be induced by a number of different damaging events occurring during or shortly after birth, including neonatal asphyxia, neonatal hypoxia-ischemia and stroke-induced focal ischemia. Typical manifestations of these conditions are the presence of glutamate excitoxicity, neuroinflammation and oxidative stress,

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Perinatal brain injury can be induced by a number of different damaging events occurring during or shortly after birth, including neonatal asphyxia, neonatal hypoxia-ischemia and stroke-induced focal ischemia. Typical manifestations of these conditions are the presence of glutamate excitoxicity, neuroinflammation and oxidative stress, the combination of which can potentially result in apoptotic-necrotic cell death, generation of brain lesions and long-lasting functional impairment. In spite of the high incidence of perinatal brain injury, the number of clinical interventions available for the treatment of the affected newborn babies is extremely limited. Hence, there is a dramatic need to develop new effective therapies aimed to prevent acute brain damage and enhance the endogenous mechanisms of long-term brain repair. The endocannabinoid system is an endogenous neuromodulatory system involved in the control of multiple central and peripheral functions. An early responder to neuronal injury, the endocannabinoid system has been described as an endogenous neuroprotective system that once activated can prevent glutamate excitotoxicity, intracellular calcium accumulation, activation of cell death pathways, microglia activation, neurovascular reactivity and infiltration of circulating leukocytes across the blood-brain barrier. The modulation of the endocannabinoid system has proven to be an effective neuroprotective strategy to prevent and reduce neonatal brain injury in different animal models and species. Also, the beneficial role of the endocannabinoid system on the control of the endogenous repairing responses (neurogenesis and white matter restoration) to neonatal brain injury has been described in independent studies. This review addresses the particular effects of several drugs that modulate the activity of the endocannabinoid system on the progression of different manifestations of perinatal brain injury during both the acute and chronic recovery phases using rodent and non-rodent animal models, and will provide a complete description of the known mechanisms that mediate such effects. Full article

(This article belongs to the Special Issue Neuroprotection against Ischemic Brain Injury)

Open AccessReview Neuroprotective Mechanisms of Taurine against Ischemic Stroke

by Janet Menzie, Howard Prentice and Jang-Yen Wu

Brain Sci. 2013, 3(2), 877-907; doi:10.3390/brainsci3020877

Received: 15 February 2013 / Revised: 14 May 2013 / Accepted: 17 May 2013 / Published: 3 June 2013

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Abstract

Ischemic stroke exhibits a multiplicity of pathophysiological mechanisms. To address the diverse pathophysiological mechanisms observed in ischemic stroke investigators seek to find therapeutic strategies that are multifaceted in their action by either investigating multipotential compounds or by using a combination of compounds. Taurine,

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Ischemic stroke exhibits a multiplicity of pathophysiological mechanisms. To address the diverse pathophysiological mechanisms observed in ischemic stroke investigators seek to find therapeutic strategies that are multifaceted in their action by either investigating multipotential compounds or by using a combination of compounds. Taurine, an endogenous amino acid, exhibits a plethora of physiological functions. It exhibits antioxidative properties, stabilizes membrane, functions as an osmoregulator, modulates ionic movements, reduces the level of pro-inflammators, regulates intracellular calcium concentration; all of which contributes to its neuroprotective effect. Data are accumulating that show the neuroprotective mechanisms of taurine against stroke pathophysiology. In this review, we describe the neuroprotective mechanisms employed by taurine against ischemic stroke and its use in clinical trial for ischemic stroke. Full article

(This article belongs to the Special Issue Neuroprotection against Ischemic Brain Injury)

Open AccessReview Neural Repair and Neuroprotection with Stem Cells in Ischemic Stroke

by Laura L. Stone, Andy Grande and Walter C. Low

Brain Sci. 2013, 3(2), 599-614; doi:10.3390/brainsci3020599

Received: 31 January 2013 / Revised: 12 April 2013 / Accepted: 12 April 2013 / Published: 23 April 2013

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Abstract

Stem cells have been touted as a potential source of cells for repair in regenerative medicine. When transplanted into the central nervous system, stem cells have been shown to differentiate into neurons and glia. Recent studies, however, have also revealed neuroprotective properties of

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Stem cells have been touted as a potential source of cells for repair in regenerative medicine. When transplanted into the central nervous system, stem cells have been shown to differentiate into neurons and glia. Recent studies, however, have also revealed neuroprotective properties of stem cells. These studies suggest that various types of stem cells are able to protect against the loss of neurons in conditions of ischemic brain injury. In this article, we discuss the use of stem cells for ischemic stroke and the parameters under which neuroprotection can occur in the translation of stem cell therapy to the clinical setting. Full article

(This article belongs to the Special Issue Neuroprotection against Ischemic Brain Injury)

Open AccessReview NADPH Oxidase as a Therapeutic Target for Neuroprotection against Ischaemic Stroke: Future Perspectives

by Sarah K. McCann and Carli L. Roulston

Brain Sci. 2013, 3(2), 561-598; doi:10.3390/brainsci3020561

Received: 31 January 2013 / Revised: 14 March 2013 / Accepted: 20 March 2013 / Published: 22 April 2013

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Abstract

Oxidative stress caused by an excess of reactive oxygen species (ROS) is known to contribute to stroke injury, particularly during reperfusion, and antioxidants targeting this process have resulted in improved outcomes experimentally. Unfortunately these improvements have not been successfully translated to the clinical

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Oxidative stress caused by an excess of reactive oxygen species (ROS) is known to contribute to stroke injury, particularly during reperfusion, and antioxidants targeting this process have resulted in improved outcomes experimentally. Unfortunately these improvements have not been successfully translated to the clinical setting. Targeting the source of oxidative stress may provide a superior therapeutic approach. The NADPH oxidases are a family of enzymes dedicated solely to ROS production and pre-clinical animal studies targeting NADPH oxidases have shown promising results. However there are multiple factors that need to be considered for future drug development: There are several homologues of the catalytic subunit of NADPH oxidase. All have differing physiological roles and may contribute differentially to oxidative damage after stroke. Additionally, the role of ROS in brain repair is largely unexplored, which should be taken into consideration when developing drugs that inhibit specific NADPH oxidases after injury. This article focuses on the current knowledge regarding NADPH oxidase after stroke including in vivo genetic and inhibitor studies. The caution required when interpreting reports of positive outcomes after NADPH oxidase inhibition is also discussed, as effects on long term recovery are yet to be investigated and are likely to affect successful clinical translation. Full article

(This article belongs to the Special Issue Neuroprotection against Ischemic Brain Injury)

Open AccessReview Stroke Neuroprotection: Targeting Mitochondria

by Lora Talley Watts, Reginald Lloyd, Richard Justin Garling and Timothy Duong

Brain Sci. 2013, 3(2), 540-560; doi:10.3390/brainsci3020540

Received: 8 March 2013 / Revised: 8 April 2013 / Accepted: 9 April 2013 / Published: 19 April 2013

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Abstract

Stroke is the fourth leading cause of death and the leading cause of long-term disability in the United States. Blood flow deficit results in an expanding infarct core with a time-sensitive peri-infarct penumbra that is considered salvageable and is the primary target for

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Stroke is the fourth leading cause of death and the leading cause of long-term disability in the United States. Blood flow deficit results in an expanding infarct core with a time-sensitive peri-infarct penumbra that is considered salvageable and is the primary target for treatment strategies. The only current FDA-approved drug for treating ischemic stroke is recombinant tissue plasminogen activator (rt-PA). However, this treatment is limited to within 4.5 h of stroke onset in a small subset of patients. The goal of this review is to focus on mitochondrial-dependent therapeutic agents that could provide neuroprotection following stroke. Dysfunctional mitochondria are linked to neurodegeneration in many disease processes including stroke. The mechanisms reviewed include: (1) increasing ATP production by purinergic receptor stimulation, (2) decreasing the production of ROS by superoxide dismutase, or (3) increasing antioxidant defenses by methylene blue, and their benefits in providing neuroprotection following a stroke. Full article

(This article belongs to the Special Issue Neuroprotection against Ischemic Brain Injury)

Open AccessReview Endovascular Thrombectomy Following Acute Ischemic Stroke: A Single-Center Case Series and Critical Review of the Literature

by Eric Sussman, Christopher Kellner, Michael McDowell, Peter Yang, Eric Nelson, Sophie Greenberg, Daniel Sahlein, Sean Lavine, Philip Meyers and E. Sander Connolly

Brain Sci. 2013, 3(2), 521-539; doi:10.3390/brainsci3020521

Received: 14 February 2013 / Revised: 26 March 2013 / Accepted: 28 March 2013 / Published: 12 April 2013

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Abstract

Acute ischemic stroke (AIS) due to thrombo-embolic occlusion in the cerebral vasculature is a major cause of morbidity and mortality in the United States and throughout the world. Although the prognosis is poor for many patients with AIS, a variety of strategies and

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Acute ischemic stroke (AIS) due to thrombo-embolic occlusion in the cerebral vasculature is a major cause of morbidity and mortality in the United States and throughout the world. Although the prognosis is poor for many patients with AIS, a variety of strategies and devices are now available for achieving recanalization in patients with this disease. Here, we review the treatment options for cerebrovascular thromboembolic occlusion with a focus on the evolution of strategies and devices that are utilized for achieving endovascular clot extraction. In order to demonstrate the progression of this treatment strategy over the past decade, we will also present a single-center case series of AIS patients treated with endovascular thrombectomy. Full article

(This article belongs to the Special Issue Neuroprotection against Ischemic Brain Injury)

Open AccessReview Non-Coding RNAs as Potential Neuroprotectants against Ischemic Brain Injury

by Prameet Kaur, Fujia Liu, Jun Rong Tan, Kai Ying Lim, Sugunavathi Sepramaniam, Dwi Setyowati Karolina, Arunmozhiarasi Armugam and Kandiah Jeyaseelan

Brain Sci. 2013, 3(1), 360-395; doi:10.3390/brainsci3010360

Received: 28 December 2012 / Revised: 19 February 2013 / Accepted: 6 March 2013 / Published: 20 March 2013

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Abstract

Over the past decade, scientific discoveries have highlighted new roles for a unique class of non-coding RNAs. Transcribed from the genome, these non-coding RNAs have been implicated in determining the biological complexity seen in mammals by acting as transcriptional and translational regulators. Non-coding

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Over the past decade, scientific discoveries have highlighted new roles for a unique class of non-coding RNAs. Transcribed from the genome, these non-coding RNAs have been implicated in determining the biological complexity seen in mammals by acting as transcriptional and translational regulators. Non-coding RNAs, which can be sub-classified into long non-coding RNAs, microRNAs, PIWI-interacting RNAs and several others, are widely expressed in the nervous system with roles in neurogenesis, development and maintenance of the neuronal phenotype. Perturbations of these non-coding transcripts have been observed in ischemic preconditioning as well as ischemic brain injury with characterization of the mechanisms by which they confer toxicity. Their dysregulation may also confer pathogenic conditions in neurovascular diseases. A better understanding of their expression patterns and functions has uncovered the potential use of these riboregulators as neuroprotectants to antagonize the detrimental molecular events taking place upon ischemic-reperfusion injury. In this review, we discuss the various roles of non-coding RNAs in brain development and their mechanisms of gene regulation in relation to ischemic brain injury. We will also address the future directions and open questions for identifying promising non-coding RNAs that could eventually serve as potential neuroprotectants against ischemic brain injury. Full article

(This article belongs to the Special Issue Neuroprotection against Ischemic Brain Injury)

Open AccessReview The Role of Ghrelin in Neuroprotection after Ischemic Brain Injury

by Sarah J. Spencer, Alyson A. Miller and Zane B. Andrews

Brain Sci. 2013, 3(1), 344-359; doi:10.3390/brainsci3010344

Received: 10 December 2012 / Revised: 19 February 2013 / Accepted: 7 March 2013 / Published: 19 March 2013

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Abstract

Ghrelin, a gastrointestinal peptide with a major role in regulating feeding and metabolism, has recently been investigated for its neuroprotective effects. In this review we discuss pre-clinical evidence suggesting ghrelin may be a useful therapeutic in protecting the brain against injury after ischemic

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Ghrelin, a gastrointestinal peptide with a major role in regulating feeding and metabolism, has recently been investigated for its neuroprotective effects. In this review we discuss pre-clinical evidence suggesting ghrelin may be a useful therapeutic in protecting the brain against injury after ischemic stroke. Specifically, we will discuss evidence showing ghrelin administration can improve neuronal cell survival in animal models of focal cerebral ischemia, as well as rescue memory deficits. We will also discuss its proposed mechanisms of action, including anti-apoptotic and anti-inflammatory effects, and suggest ghrelin treatment may be a useful intervention after stroke in the clinic. Full article

(This article belongs to the Special Issue Neuroprotection against Ischemic Brain Injury)

Open AccessReview Stem Cell Transplantation for Neuroprotection in Stroke

by Kazutaka Shinozuka, Travis Dailey, Naoki Tajiri, Hiroto Ishikawa, Yuji Kaneko and Cesar V. Borlongan

Brain Sci. 2013, 3(1), 239-261; doi:10.3390/brainsci3010239

Received: 7 December 2012 / Revised: 22 February 2013 / Accepted: 26 February 2013 / Published: 7 March 2013

Cited by 12 | PDF Full-text (245 KB) | HTML Full-text | XML Full-text

Abstract

Stem cell-based therapies for stroke have expanded substantially over the last decade. The diversity of embryonic and adult tissue sources provides researchers with the ability to harvest an ample supply of stem cells. However, the optimal conditions of stem cell use are still

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Stem cell-based therapies for stroke have expanded substantially over the last decade. The diversity of embryonic and adult tissue sources provides researchers with the ability to harvest an ample supply of stem cells. However, the optimal conditions of stem cell use are still being determined. Along this line of the need for optimization studies, we discuss studies that demonstrate effective dose, timing, and route of stem cells. We recognize that stem cell derivations also provide uniquely individual difficulties and limitations in their therapeutic applications. This review will outline the current knowledge, including benefits and challenges, of the many current sources of stem cells for stroke therapy. Full article

(This article belongs to the Special Issue Neuroprotection against Ischemic Brain Injury)

Open AccessReview Neuroprotective Therapies after Perinatal Hypoxic-Ischemic Brain Injury

by Felipe Goñi de Cerio, Idoia Lara-Celador, Antonia Alvarez and Enrique Hilario

Brain Sci. 2013, 3(1), 191-214; doi:10.3390/brainsci3010191

Received: 7 January 2013 / Revised: 13 February 2013 / Accepted: 22 February 2013 / Published: 5 March 2013

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Abstract

Hypoxic-ischemic (HI) brain injury is one of the main causes of disabilities in term-born infants. It is the result of a deprivation of oxygen and glucose in the neural tissue. As one of the most important causes of brain damage in the newborn

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Hypoxic-ischemic (HI) brain injury is one of the main causes of disabilities in term-born infants. It is the result of a deprivation of oxygen and glucose in the neural tissue. As one of the most important causes of brain damage in the newborn period, the neonatal HI event is a devastating condition that can lead to long-term neurological deficits or even death. The pattern of this injury occurs in two phases, the first one is a primary energy failure related to the HI event and the second phase is an energy failure that takes place some hours later. Injuries that occur in response to these events are often manifested as severe cognitive and motor disturbances over time. Due to difficulties regarding the early diagnosis and treatment of HI injury, there is an increasing need to find effective therapies as new opportunities for the reduction of brain damage and its long term effects. Some of these therapies are focused on prevention of the production of reactive oxygen species, anti-inflammatory effects, anti-apoptotic interventions and in a later stage, the stimulation of neurotrophic properties in the neonatal brain which could be targeted to promote neuronal and oligodendrocyte regeneration. Full article

(This article belongs to the Special Issue Neuroprotection against Ischemic Brain Injury)

Open AccessReview The Role of Substance P in Ischaemic Brain Injury

by Renée J. Turner and Robert Vink

Brain Sci. 2013, 3(1), 123-142; doi:10.3390/brainsci3010123

Received: 5 January 2013 / Revised: 23 January 2013 / Accepted: 23 January 2013 / Published: 30 January 2013

Cited by 5 | PDF Full-text (1627 KB) | HTML Full-text | XML Full-text

Abstract

Stroke is a leading cause of death, disability and dementia worldwide. Despite extensive pre-clinical investigation, few therapeutic treatment options are available to patients, meaning that death, severe disability and the requirement for long-term rehabilitation are common outcomes. Cell loss and tissue injury following

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Stroke is a leading cause of death, disability and dementia worldwide. Despite extensive pre-clinical investigation, few therapeutic treatment options are available to patients, meaning that death, severe disability and the requirement for long-term rehabilitation are common outcomes. Cell loss and tissue injury following stroke occurs through a number of diverse secondary injury pathways, whose delayed nature provides an opportunity for pharmacological intervention. Amongst these secondary injury factors, increased blood-brain barrier permeability and cerebral oedema are well-documented complications of cerebral ischaemia, whose severity has been shown to be associated with final outcome. Whilst the mechanisms of increased blood-brain barrier permeability and cerebral oedema are largely unknown, recent evidence suggests that the neuropeptide substance P (SP) plays a central role. The aim of this review is to examine the role of SP in ischaemic stroke and report on the potential utility of NK1 tachykinin receptor antagonists as therapeutic agents. Full article

(This article belongs to the Special Issue Neuroprotection against Ischemic Brain Injury)

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Open AccessConcept Paper A Program for Solving the Brain Ischemia Problem

by Donald J. DeGracia

Brain Sci. 2013, 3(2), 460-503; doi:10.3390/brainsci3020460

Received: 15 January 2013 / Revised: 23 March 2013 / Accepted: 26 March 2013 / Published: 8 April 2013

Cited by 2 | PDF Full-text (3273 KB) | HTML Full-text | XML Full-text

Abstract

Our recently described nonlinear dynamical model of cell injury is here applied to the problems of brain ischemia and neuroprotection. We discuss measurement of global brain ischemia injury dynamics by time course analysis. Solutions to proposed experiments are simulated using hypothetical values for

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Our recently described nonlinear dynamical model of cell injury is here applied to the problems of brain ischemia and neuroprotection. We discuss measurement of global brain ischemia injury dynamics by time course analysis. Solutions to proposed experiments are simulated using hypothetical values for the model parameters. The solutions solve the global brain ischemia problem in terms of “master bifurcation diagrams” that show all possible outcomes for arbitrary durations of all lethal cerebral blood flow (CBF) decrements. The global ischemia master bifurcation diagrams: (1) can map to a single focal ischemia insult, and (2) reveal all CBF decrements susceptible to neuroprotection. We simulate measuring a neuroprotectant by time course analysis, which revealed emergent nonlinear effects that set dynamical limits on neuroprotection. Using over-simplified stroke geometry, we calculate a theoretical maximum protection of approximately 50% recovery. We also calculate what is likely to be obtained in practice and obtain 38% recovery; a number close to that often reported in the literature. The hypothetical examples studied here illustrate the use of the nonlinear cell injury model as a fresh avenue of approach that has the potential, not only to solve the brain ischemia problem, but also to advance the technology of neuroprotection. Full article

(This article belongs to the Special Issue Neuroprotection against Ischemic Brain Injury)

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