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Brain Sci., Volume 3, Issue 3 (September 2013), Pages 1013-1416

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Editorial

Jump to: Research, Review

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
[...] Read more.
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

Jump to: Editorial, Review

Open AccessArticle Neuroprotective Role of Nerve Growth Factor in Hypoxic-Ischemic Brain Injury
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
[...] Read more.
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 Psychophysical Estimates of Frequency Discrimination: More than Just Limitations of Auditory Processing
Brain Sci. 2013, 3(3), 1023-1042; doi:10.3390/brainsci3031023
Received: 14 April 2013 / Revised: 20 May 2013 / Accepted: 14 June 2013 / Published: 5 July 2013
Cited by 3 | PDF Full-text (359 KB) | HTML Full-text | XML Full-text
Abstract
Efficient auditory processing is hypothesized to support language and literacy development. However, behavioral tasks used to assess this hypothesis need to be robust to non-auditory specific individual differences. This study compared frequency discrimination abilities in a heterogeneous sample of adults using two different
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Efficient auditory processing is hypothesized to support language and literacy development. However, behavioral tasks used to assess this hypothesis need to be robust to non-auditory specific individual differences. This study compared frequency discrimination abilities in a heterogeneous sample of adults using two different psychoacoustic task designs, referred to here as: 2I_6A_X and 3I_2AFC designs. The role of individual differences in nonverbal IQ (NVIQ), socioeconomic status (SES) and musical experience in predicting frequency discrimination thresholds on each task were assessed using multiple regression analyses. The 2I_6A_X task was more cognitively demanding and hence more susceptible to differences specifically in SES and musical training. Performance on this task did not, however, relate to nonword repetition ability (a measure of language learning capacity). The 3I_2AFC task, by contrast, was only susceptible to musical training. Moreover, thresholds measured using it predicted some variance in nonword repetition performance. This design thus seems suitable for use in studies addressing questions regarding the role of auditory processing in supporting language and literacy development. Full article
(This article belongs to the Special Issue Brain and Language)
Open AccessArticle Reading the Wrong Way with the Right Hemisphere
Brain Sci. 2013, 3(3), 1060-1075; doi:10.3390/brainsci3031060
Received: 26 April 2013 / Revised: 4 June 2013 / Accepted: 8 July 2013 / Published: 17 July 2013
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Abstract
Reading is a complex process, drawing on a variety of brain functions in order to link symbols to words and concepts. The three major brain areas linked to reading and phonological analysis include the left temporoparietal region, the left occipitotemporal region and the
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Reading is a complex process, drawing on a variety of brain functions in order to link symbols to words and concepts. The three major brain areas linked to reading and phonological analysis include the left temporoparietal region, the left occipitotemporal region and the inferior frontal gyrus. Decreased activation of the left posterior language system in dyslexia is well documented but there is relatively limited attention given to the role of the right hemisphere. The current study investigated differences in right and left hemisphere activation between individuals with dyslexia and non-impaired readers in lexical decision tasks (regular words, irregular words, pseudowords) during functional Magnetic Resonance Imaging (fMRI). Results revealed the expected hypo-activation in the left posterior areas in those with dyslexia but also areas of overactivation in the right hemisphere. During pseudoword decisions, for example, adults with dyslexia showed more right inferior occipital gyrus activation than controls. In general the increased activation of left-hemisphere language areas found in response to both regular and pseudowords was absent in dyslexics. Laterality indices showed that while controls showed left lateralised activation of the temporal lobe during lexical decision making, dyslexic readers showed right activation. Findings will inform theories of reading and will have implications for the design of reading interventions. Full article
(This article belongs to the Special Issue Brain and Language)
Open AccessArticle Effects of Ethanol Exposure during Distinct Periods of Brain Development on Hippocampal Synaptic Plasticity
Brain Sci. 2013, 3(3), 1076-1094; doi:10.3390/brainsci3031076
Received: 15 May 2013 / Revised: 15 June 2013 / Accepted: 29 June 2013 / Published: 19 July 2013
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Abstract
Fetal alcohol spectrum disorders occur when a mother drinks during pregnancy and can greatly influence synaptic plasticity and cognition in the offspring. In this study we determined whether there are periods during brain development that are more susceptible to the effects of ethanol
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Fetal alcohol spectrum disorders occur when a mother drinks during pregnancy and can greatly influence synaptic plasticity and cognition in the offspring. In this study we determined whether there are periods during brain development that are more susceptible to the effects of ethanol exposure on hippocampal synaptic plasticity. In particular, we evaluated how the ability to elicit long-term potentiation (LTP) in the hippocampal dentate gyrus (DG) was affected in young adult rats that were exposed to ethanol during either the 1st, 2nd, or 3rd trimester equivalent. As expected, the effects of ethanol on young adult DG LTP were less severe when exposure was limited to a particular trimester equivalent when compared to exposure throughout gestation. In males, ethanol exposure during the 1st, 2nd or 3rd trimester equivalent did not significantly reduce LTP in the DG. In females, ethanol exposure during either the 1st or 2nd trimester equivalents did not impact LTP in early adulthood, but following exposure during the 3rd trimester equivalent alone, LTP was significantly increased in the female DG. These results further exemplify the disparate effects between the ability to elicit LTP in the male and female brain following perinatal ethanol exposure (PNEE). Full article
(This article belongs to the Special Issue Ethanol Neurotoxicity)
Open AccessArticle Genetic Deletion of Prostacyclin IP Receptor Exacerbates Transient Global Cerebral Ischemia in Aging Mice
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 Developmental Neurotoxicity of Alcohol and Anesthetic Drugs Is Augmented by Co-Exposure to Caffeine
Brain Sci. 2013, 3(3), 1128-1152; doi:10.3390/brainsci3031128
Received: 22 April 2013 / Revised: 6 July 2013 / Accepted: 11 July 2013 / Published: 30 July 2013
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Abstract
Anesthetic and anti-epileptic drugs used in pediatric and obstetric medicine and several drugs, including alcohol, that are abused by pregnant women, trigger widespread neuroapoptosis in the developing brain of several animal species, including non-human primates. Caffeine (CAF) is often administered to premature infants
[...] Read more.
Anesthetic and anti-epileptic drugs used in pediatric and obstetric medicine and several drugs, including alcohol, that are abused by pregnant women, trigger widespread neuroapoptosis in the developing brain of several animal species, including non-human primates. Caffeine (CAF) is often administered to premature infants to stimulate respiration, and these infants are also exposed simultaneously to anesthetic drugs for procedural sedation and/or surgical procedures. Pregnant women who abuse alcohol or other apoptogenic drugs also may heavily consume CAF. We administered CAF to infant mice alone or in combination with alcohol, phencyclidine, diazepam, midazolam, ketamine, or isoflurane, which are drugs of abuse and/or drugs frequently used in pediatric medicine, and found that CAF weakly triggers neuroapoptosis by itself and markedly potentiates the neuroapoptogenic action of each of these other drugs. Exposure of infant mice to CAF + phencyclidine resulted in long-term impairment in behavioral domains relevant to attention deficit/hyperactivity disorder, whereas exposure to CAF + diazepam resulted in long-term learning/memory impairment. At doses used in these experiments, these behavioral impairments either did not occur or were substantially less pronounced in mice exposed to CAF alone or to phencyclidine or diazepam alone. CAF currently enjoys the reputation of being highly beneficial and safe for use in neonatal medicine. Our data suggest the need to consider whether CAF may have harmful as well as beneficial effects on the developing brain, and the need for research aimed at understanding the full advantage of its beneficial effects while avoiding its potentially harmful effects. Full article
(This article belongs to the Special Issue Ethanol Neurotoxicity)
Open AccessArticle Neural Correlates of Processing Passive Sentences
Brain Sci. 2013, 3(3), 1198-1214; doi:10.3390/brainsci3031198
Received: 27 May 2013 / Revised: 16 July 2013 / Accepted: 19 July 2013 / Published: 2 August 2013
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Abstract
Previous research has shown that comprehension of complex sentences involving wh-movement (e.g., object-relative clauses) elicits activation in the left inferior frontal gyrus (IFG) and left posterior temporal cortex. However, relatively little is known about the neural correlates of processing passive sentences, which
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Previous research has shown that comprehension of complex sentences involving wh-movement (e.g., object-relative clauses) elicits activation in the left inferior frontal gyrus (IFG) and left posterior temporal cortex. However, relatively little is known about the neural correlates of processing passive sentences, which differ from other complex sentences in terms of representation (i.e., noun phrase (NP)-movement) and processing (i.e., the time course of syntactic reanalysis). In the present study, 27 adults (14 younger and 13 older) listened to passive and active sentences and performed a sentence-picture verification task using functional Magnetic Resonance Imaging (fMRI). Passive sentences, relative to active sentences, elicited greater activation in bilateral IFG and left temporo-occipital regions. Participant age did not significantly affect patterns of activation. Consistent with previous research, activation in left temporo-occipital cortex likely reflects thematic reanalysis processes, whereas, activation in the left IFG supports processing of complex syntax (i.e., NP-movement). Right IFG activation may reflect syntactic reanalysis processing demands associated with the sentence-picture verification task. Full article
(This article belongs to the Special Issue Brain and Language)
Open AccessArticle The Neural Correlates of Abstract and Concrete Words: Evidence from Brain-Damaged Patients
Brain Sci. 2013, 3(3), 1229-1243; doi:10.3390/brainsci3031229
Received: 31 May 2013 / Revised: 19 July 2013 / Accepted: 22 July 2013 / Published: 7 August 2013
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Abstract
Neuropsychological and activation studies on the neural correlates of abstract and concrete words have produced contrasting results. The present study explores the anatomical substrates of abstract/concrete words in 22 brain-damaged patients with a single vascular lesion either in the right or left hemisphere.
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Neuropsychological and activation studies on the neural correlates of abstract and concrete words have produced contrasting results. The present study explores the anatomical substrates of abstract/concrete words in 22 brain-damaged patients with a single vascular lesion either in the right or left hemisphere. One hundred and twenty (60 concrete and 60 abstract) noun triplets were used for a semantic similarity judgment task. We found a significant interaction in word type × group since left temporal brain-damaged patients performed significantly better with concrete than abstract words. Lesion mapping of patients with predominant temporal damage showed that the left superior and middle temporal gyri and the insula were the areas of major overlapping, while the anterior portion of the left temporal lobe was generally spared. Errors on abstract words mainly concerned (although at a non-significant level) semantically associate targets, while in the case of concrete words, coordinate targets were significantly more impaired than associate ones. Our results suggest that the left superior and middle temporal gyri and the insula are crucial regions in processing abstract words. They also confirm the hypothesis of a semantic similarity vs. associative organization of concrete and abstract concepts. Full article
(This article belongs to the Special Issue Brain and Language)
Open AccessArticle Representation of Linguistic Information Determines Its Susceptibility to Memory Interference
Brain Sci. 2013, 3(3), 1244-1260; doi:10.3390/brainsci3031244
Received: 17 May 2013 / Revised: 18 July 2013 / Accepted: 30 July 2013 / Published: 8 August 2013
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Abstract
We used the dual-task paradigm to infer how linguistic information is represented in the brain by indexing its susceptibility to retrieval interference. We measured recognition memory, in bilingual Chinese-English, and monolingual English speakers. Participants were visually presented with simplified Chinese characters under full
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We used the dual-task paradigm to infer how linguistic information is represented in the brain by indexing its susceptibility to retrieval interference. We measured recognition memory, in bilingual Chinese-English, and monolingual English speakers. Participants were visually presented with simplified Chinese characters under full attention, and later asked to recognize them while simultaneously engaging in distracting tasks that required either phonological or visuo-spatial processing of auditorily presented letters. Chinese speakers showed significantly greater memory interference from the visuo-spatial than phonological distracting task, a pattern that was not present in the English group. Such a pattern suggests that retrieval of simplified Chinese characters differentially requires visuo-spatial processing resources in Chinese speakers; these are compromised under dual-task conditions when such resources are otherwise engaged in a distracting task. In a secondary analysis, we showed the complementary pattern in a group of English speakers, whose memory for English words was disrupted to a greater degree from the phonological than visuo-spatial distracting task. Together, these results suggest the mode of representation of linguistic information can be indexed behaviorally by susceptibility to retrieval interference that occurs when representations overlap with resources required in a competing task. Full article
(This article belongs to the Special Issue Brain and Language)
Figures

Open AccessArticle Working Memory Capacity, Inhibitory Control and the Role of L2 Proficiency in Aging L1 Dutch Speakers of Near-Native L2 English
Brain Sci. 2013, 3(3), 1261-1281; doi:10.3390/brainsci3031261
Received: 1 June 2013 / Revised: 17 July 2013 / Accepted: 26 July 2013 / Published: 19 August 2013
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Abstract
This paper examines the intricate relationship between working memory (WM) capacity and inhibitory control as a function of both L2 proficiency and age. In both its design and research questions, this study closely follows Gass & Lee’s work, where both L1 and L2
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This paper examines the intricate relationship between working memory (WM) capacity and inhibitory control as a function of both L2 proficiency and age. In both its design and research questions, this study closely follows Gass & Lee’s work, where both L1 and L2 Reading Span Tasks (as measures of WM capacity) and L1 and L2 Stroop interference tasks (to measure inhibitory control) were administered. In this study, the test battery is augmented by both an L1 and L2 C-test of overall language proficiency. Participants were 63 L1 Dutch speakers of L2 English, who had been immersed in an L2 environment for a considerable amount of time. Their data were set off against those of 54 monolingual Dutch speakers and 56 monolingual English speakers. At the time of testing, all the bilingual participants had a near-native command of English and their L1 and L2 WM scores were not found to be significantly different. However, discrepancies did occur in Stroop test scores of inhibition, where the bilinguals performed better in their L2 English than L1 Dutch. These main effects often contradicted the results found in Gass & Lee’s study, who examined less proficient L2 learners. An aging effect was furthermore found: older subjects consistently performed more poorly on WM and inhibition tasks than their younger peers. These results can shed light on how individual factors like WM capacity and inhibitory control interact in successful late bilinguals and how these dynamics shift with advanced age. Full article
(This article belongs to the Special Issue Brain and Language)
Open AccessArticle Altered Intrinsic Functional Connectivity in Language-Related Brain Regions in Association with Verbal Memory Performance in Euthymic Bipolar Patients
Brain Sci. 2013, 3(3), 1357-1373; doi:10.3390/brainsci3031357
Received: 5 August 2013 / Revised: 29 August 2013 / Accepted: 2 September 2013 / Published: 12 September 2013
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Abstract
Potential abnormalities in the structure and function of the temporal lobes have been studied much less in bipolar disorder than in schizophrenia. This may not be justified because language-related symptoms, such as pressured speech and flight of ideas, and cognitive deficits in the
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Potential abnormalities in the structure and function of the temporal lobes have been studied much less in bipolar disorder than in schizophrenia. This may not be justified because language-related symptoms, such as pressured speech and flight of ideas, and cognitive deficits in the domain of verbal memory are amongst the hallmark of bipolar disorder (BD), and contribution of temporal lobe dysfunction is therefore likely. In the current study, we examined resting-state functional connectivity (FC) between the auditory cortex (Heschl’s gyrus [HG], planum temporale [PT]) and whole brain using seed correlation analysis in n = 21 BD euthymic patients and n = 20 matched healthy controls and associated it with verbal memory performance. In comparison to controls BD patients showed decreased functional connectivity between Heschl’s gyrus and planum temporale and the left superior and middle temporal gyrus. Additionally, fronto-temporal functional connectivity with the right inferior frontal/precentral gyrus and the insula was increased in patients. Verbal episodic memory deficits in the investigated sample of BD patients and language-related symptoms might therefore be associated with a diminished FC within the auditory/temporal gyrus and a compensatory fronto-temporal pathway. Full article
(This article belongs to the Special Issue Brain and Language)
Figures

Open AccessArticle Damage to Myelin and Oligodendrocytes: A Role in Chronic Outcomes Following Traumatic Brain Injury?
Brain Sci. 2013, 3(3), 1374-1394; doi:10.3390/brainsci3031374
Received: 6 May 2013 / Revised: 23 August 2013 / Accepted: 2 September 2013 / Published: 16 September 2013
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Abstract
There is increasing evidence in the experimental and clinical traumatic brain injury (TBI) literature that loss of central myelinated nerve fibers continues over the chronic post-traumatic phase after injury. However, the biomechanism(s) of continued loss of axons is obscure. Stretch-injury to optic nerve
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There is increasing evidence in the experimental and clinical traumatic brain injury (TBI) literature that loss of central myelinated nerve fibers continues over the chronic post-traumatic phase after injury. However, the biomechanism(s) of continued loss of axons is obscure. Stretch-injury to optic nerve fibers in adult guinea-pigs was used to test the hypothesis that damage to the myelin sheath and oligodendrocytes of the optic nerve fibers may contribute to, or facilitate, the continuance of axonal loss. Myelin dislocations occur within internodal myelin of larger axons within 1–2 h of TBI. The myelin dislocations contain elevated levels of free calcium. The volume of myelin dislocations increase with greater survival and are associated with disruption of the axonal cytoskeleton leading to secondary axotomy. Waves of Ca2+ depolarization or spreading depression extend from the initial locus injury for perhaps hundreds of microns after TBI. As astrocytes and oligodendrocytes are connected via gap junctions, it is hypothesized that spreading depression results in depolarization of central glia, disrupt axonal ionic homeostasis, injure axonal mitochondria and allow the onset of axonal degeneration throughout an increasing volume of brain tissue; and contribute toward post-traumatic continued loss of white matter. Full article
(This article belongs to the Special Issue Myelin Repair)
Open AccessArticle The Role of Citicoline in Neuroprotection and Neurorepair in Ischemic Stroke
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)

Review

Jump to: Editorial, Research

Open AccessReview Cannabinoids: Well-Suited Candidates for the Treatment of Perinatal Brain Injury
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,
[...] Read more.
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 Astrocyte Regulation of CNS Inflammation and Remyelination
Brain Sci. 2013, 3(3), 1109-1127; doi:10.3390/brainsci3031109
Received: 15 May 2013 / Revised: 12 July 2013 / Accepted: 12 July 2013 / Published: 22 July 2013
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Abstract
Astrocytes regulate fundamentally important functions to maintain central nervous system (CNS) homeostasis. Altered astrocytic function is now recognized as a primary contributing factor to an increasing number of neurological diseases. In this review, we provide an overview of our rapidly developing understanding of
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Astrocytes regulate fundamentally important functions to maintain central nervous system (CNS) homeostasis. Altered astrocytic function is now recognized as a primary contributing factor to an increasing number of neurological diseases. In this review, we provide an overview of our rapidly developing understanding of the basal and inflammatory functions of astrocytes as mediators of CNS responsiveness to inflammation and injury. Specifically, we elaborate on ways that astrocytes actively participate in the pathogenesis of demyelinating diseases of the CNS through their immunomodulatory roles as CNS antigen presenting cells, modulators of blood brain barrier function and as a source of chemokines and cytokines. We also outline how changes in the extracellular matrix can modulate astrocytes phenotypically, resulting in dysregulation of astrocytic responses during inflammatory injury. We also relate recent studies describing newly identified roles for astrocytes in leukodystrophies. Finally, we describe recent advances in how adapting this increasing breadth of knowledge on astrocytes has fostered new ways of thinking about human diseases, which offer potential to modulate astrocytic heterogeneity and plasticity towards therapeutic gain. In summary, recent studies have provided improved insight in a wide variety of neuroinflammatory and demyelinating diseases, and future research on astrocyte pathophysiology is expected to provide new perspectives on these diseases, for which new treatment modalities are increasingly necessary. Full article
(This article belongs to the Special Issue Myelin Repair)
Open AccessReview Drug-Induced Apoptosis: Mechanism by which Alcohol and Many Other Drugs Can Disrupt Brain Development
Brain Sci. 2013, 3(3), 1153-1181; doi:10.3390/brainsci3031153
Received: 25 May 2013 / Revised: 8 July 2013 / Accepted: 11 July 2013 / Published: 31 July 2013
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Abstract
Maternal ingestion of alcohol during pregnancy can cause a disability syndrome termed Fetal Alcohol Spectrum Disorder (FASD), which may include craniofacial malformations, structural pathology in the brain, and a variety of long-term neuropsychiatric disturbances. There is compelling evidence that exposure to alcohol during
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Maternal ingestion of alcohol during pregnancy can cause a disability syndrome termed Fetal Alcohol Spectrum Disorder (FASD), which may include craniofacial malformations, structural pathology in the brain, and a variety of long-term neuropsychiatric disturbances. There is compelling evidence that exposure to alcohol during early embryogenesis (4th week of gestation) can cause excessive death of cell populations that are essential for normal development of the face and brain. While this can explain craniofacial malformations and certain structural brain anomalies that sometimes accompany FASD, in many cases these features are absent, and the FASD syndrome manifests primarily as neurobehavioral disorders. It is not clear from the literature how alcohol causes these latter manifestations. In this review we will describe a growing body of evidence documenting that alcohol triggers widespread apoptotic death of neurons and oligodendroglia (OLs) in the developing brain when administered to animals, including non-human primates, during a period equivalent to the human third trimester of gestation. This cell death reaction is associated with brain changes, including overall or regional reductions in brain mass, and long-term neurobehavioral disturbances. We will also review evidence that many drugs used in pediatric and obstetric medicine, including general anesthetics (GAs) and anti-epileptics (AEDs), mimic alcohol in triggering widespread apoptotic death of neurons and OLs in the third trimester-equivalent animal brain, and that human children exposed to GAs during early infancy, or to AEDs during the third trimester of gestation, have a significantly increased incidence of FASD-like neurobehavioral disturbances. These findings provide evidence that exposure of the developing human brain to GAs in early infancy, or to alcohol or AEDs in late gestation, can cause FASD-like neurodevelopmental disability syndromes. We propose that the mechanism by which alcohol, GAs and AEDs produce neurobehavioral deficit syndromes is by triggering apoptotic death and deletion of neurons and OLs (or their precursors) from the developing brain. Therefore, there is a need for research aimed at deciphering mechanisms by which these agents trip the apoptosis trigger, the ultimate goal being to learn how to prevent these agents from causing neurodevelopmental disabilities. Full article
(This article belongs to the Special Issue Ethanol Neurotoxicity)
Open AccessReview Repair of the Peripheral Nerve—Remyelination that Works
Brain Sci. 2013, 3(3), 1182-1197; doi:10.3390/brainsci3031182
Received: 24 June 2013 / Revised: 7 July 2013 / Accepted: 19 July 2013 / Published: 2 August 2013
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Abstract
In this review we summarize the events known to occur after an injury in the peripheral nervous system. We have focused on the Schwann cells, as they are the most important cells for the repair process and facilitate axonal outgrowth. The environment created
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In this review we summarize the events known to occur after an injury in the peripheral nervous system. We have focused on the Schwann cells, as they are the most important cells for the repair process and facilitate axonal outgrowth. The environment created by this cell type is essential for the outcome of the repair process. The review starts with a description of the current state of knowledge about the initial events after injury, followed by Wallerian degeneration, and subsequent regeneration. The importance of surgical repair, carried out as soon as possible to increase the chances of a good outcome, is emphasized throughout the review. The review concludes by describing the target re-innervation, which today is one of the most serious problems for nerve regeneration. It is clear, compiling this data, that even though regeneration of the peripheral nervous system is possible, more research in this area is needed in order to perfect the outcome. Full article
(This article belongs to the Special Issue Myelin Repair)
Open AccessReview Reprogramming Cells for Brain Repair
Brain Sci. 2013, 3(3), 1215-1228; doi:10.3390/brainsci3031215
Received: 13 June 2013 / Revised: 27 July 2013 / Accepted: 30 July 2013 / Published: 6 August 2013
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Abstract
At present there are no clinical therapies that can repair traumatic brain injury, spinal cord injury or degenerative brain disease. While redundancy and rewiring of surviving circuits can recover some lost function, the brain and spinal column lack sufficient endogenous stem cells to
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At present there are no clinical therapies that can repair traumatic brain injury, spinal cord injury or degenerative brain disease. While redundancy and rewiring of surviving circuits can recover some lost function, the brain and spinal column lack sufficient endogenous stem cells to replace lost neurons or their supporting glia. In contrast, pre-clinical studies have demonstrated that exogenous transplants can have remarkable efficacy for brain repair in animal models. Mesenchymal stromal cells (MSCs) can provide paracrine factors that repair damage caused by ischemic injury, and oligodendrocyte progenitor cell (OPC) grafts give dramatic functional recovery from spinal cord injury. These studies have progressed to clinical trials, including human embryonic stem cell (hESC)-derived OPCs for spinal cord repair. However, ESC-derived allografts are less than optimal, and we need to identify a more appropriate donor graft population. The cell reprogramming field has developed the ability to trans-differentiate somatic cells into distinct cell types, a technology that has the potential to generate autologous neurons and glia which address the histocompatibility concerns of allografts and the tumorigenicity concerns of ESC-derived grafts. Further clarifying how cell reprogramming works may lead to more efficient direct reprogram approaches, and possibly in vivo reprogramming, in order to promote brain and spinal cord repair. Full article
(This article belongs to the Special Issue Myelin Repair)
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Open AccessReview Myelin Recovery in Multiple Sclerosis: The Challenge of Remyelination
Brain Sci. 2013, 3(3), 1282-1324; doi:10.3390/brainsci3031282
Received: 8 July 2013 / Revised: 12 August 2013 / Accepted: 12 August 2013 / Published: 28 August 2013
Cited by 11 | PDF Full-text (1599 KB) | HTML Full-text | XML Full-text
Abstract
Multiple sclerosis (MS) is the most common demyelinating and an autoimmune disease of the central nervous system characterized by immune-mediated myelin and axonal damage, and chronic axonal loss attributable to the absence of myelin sheaths. T cell subsets (Th1, Th2, Th17, CD8+
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Multiple sclerosis (MS) is the most common demyelinating and an autoimmune disease of the central nervous system characterized by immune-mediated myelin and axonal damage, and chronic axonal loss attributable to the absence of myelin sheaths. T cell subsets (Th1, Th2, Th17, CD8+, NKT, CD4+CD25+ T regulatory cells) and B cells are involved in this disorder, thus new MS therapies seek damage prevention by resetting multiple components of the immune system. The currently approved therapies are immunoregulatory and reduce the number and rate of lesion formation but are only partially effective. This review summarizes current understanding of the processes at issue: myelination, demyelination and remyelination—with emphasis upon myelin composition/ architecture and oligodendrocyte maturation and differentiation. The translational options target oligodendrocyte protection and myelin repair in animal models and assess their relevance in human. Remyelination may be enhanced by signals that promote myelin formation and repair. The crucial question of why remyelination fails is approached is several ways by examining the role in remyelination of available MS medications and avenues being actively pursued to promote remyelination including: (i) cytokine-based immune-intervention (targeting calpain inhibition), (ii) antigen-based immunomodulation (targeting glycolipid-reactive iNKT cells and sphingoid mediated inflammation) and (iii) recombinant monoclonal antibodies-induced remyelination. Full article
(This article belongs to the Special Issue Myelin Repair)
Open AccessReview Molecular Dissection of Cyclosporin A’s Neuroprotective Effect Reveals Potential Therapeutics for Ischemic Brain Injury
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
Cited by 3 | PDF Full-text (391 KB) | HTML Full-text | XML Full-text
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)
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