Three-Dimensional Analysis of Mouse Habenula Subnuclei Reveals Reduced Volume and Gene Expression in the Lipopolysaccharide-mediated Depression Model

The habenula (Hb) is small but important brain structure, anatomically and functionally links the forebrain with the midbrain to modulate various neuropsychiatric functions associated with drug addiction and emotion-associated dysfunctions. Several reports suggested that the dysfunction of Hb-related functions affected the Hb structurally and functionally. However, the technical limitation has awaited the solid conclusion of whether Hb change due to depression is likely to occur in certain subnuclei of the Hb. To probe this possibility, we developed 3-dimensional reconstruction methods for the high-resolution volumetric analysis of Hb and the mRNA levels at the given volume in normal or lipopolysaccharide (LPS)-mediated mouse model of depression. Notably, we discovered that the volume reduction was prominent in medial Hb but not in lateral Hb after LPS treatments. On the other hand, the RNA expression levels of known Hb regional markers such as Tac1 (dorsal part of medial Hb), ChAT (ventral part of medial Hb), and Tacr1 (medial and lateral Hb) were all decreased in all Hb subnuclei in LPS-injected mice. Accordingly, accurate volumetry with marker labeling was not feasible. Collectively, these established 3D analyses of mouse Hb successfully and precisely determine the volume-based changes of small brain structure, which should be applicable in a wider range of mouse models or pathological specimens.

Gait Ignition Failure in JNPL3 Human Tau-mutant Mice

Cognitive impairments and motor dysfunction are commonly observed behavioral phenotypes in genetic animal models of neurodegenerative diseases. JNPL3 transgenic mice expressing human P301L-mutant tau display motor disturbances with age- and gene dose-dependent development of neurofibrillary tangles, suggesting that tau pathology causes neurodegeneration associated with motor behavioral abnormalities. Although gait ignition failure (GIF), a syndrome marked by difficulty in initiating locomotion, has been described in patients with certain forms of tauopathies, transgenic mouse models mirroring human GIF syndrome have yet to be reported. Using the open field and balance beam tests, here we discovered that JNPL3 homozygous mice exhibit a marked delay of movement initiation. The elevated plus maze excluded the possibility that hesitation to start in JNPL3 mice was caused by enhanced levels of anxiety. Considering the normal gait ignition in rTg4510 mice expressing the same mutant tau in the forebrain, GIF in JNPL3 mice seems to arise from abnormal tau deposition in the hindbrain areas involved in locomotor initiation. Accordingly, immunohistochemistry revealed highly phosphorylated paired helical filament tau in JNPL3 brainstem areas associated with gait initiation. Together, these findings demonstrate a novel behavioral phenotype of impaired gait initiation in JNPL3 mice and underscore the value of this mouse line as a tool to study the neural mechanisms and potential treatments for human GIF syndrome.

Human Neural Stem Cells: Translational Research for Neonatal Hypoxic-Ischemic Brain Injury

Neonatal hypoxic-ischemic (HI) brain injury is a major cause of neonatal mortality and long-term neurodevelopmental disabilities. Although promising neuroprotective interventions have been studied, the current management of HI brain injury has been limited to supportive measures and induced hypothermia. In addition to engrafting, migrating toward the damage sites and differentiating into multiple lineages, multipotent neural stem/progenitor cells (NSPCs) also provide trophic/immunomodulatory factors and integrate into the host neurons upon implantation into an HI-injured brain. However, NSPC-based therapies have shown poor cell survival and integration, poor differentiation or restricted differentiation into the glial lineages. Furthermore, to achieve full functional recovery following brain injury, the optimization of cell therapy is needed to recapitulate the precise migration of stem cells to the region of interest and the neural rewiring present in the brain microenvironment. Therefore, the efficacy of NSPCs in the treatment of CNS injury is currently insufficient. Human NSPCs (hNSPCs) were isolated from the forebrain of an aborted fetus at 13 weeks of gestation with full parental consent and the approval of the Institutional Review Board of the Yonsei University College of Medicine. Here, to enhance the regenerative ability of hNSPCs in HI brain injury, cells were either pretreated with pharmacological agents or engineered to serve as vehicles for gene delivery. Furthermore, when combined with a poly (glycolic acid)-based synthetic scaffold, hNSPCs provide a more versatile treatment for neonatal HI brain injury. Finally, hNSPCs transfected with zinc-doped ferrite magnetic nanoparticles for controlling both cell migration and differentiation offer a simple and smart tool for cell-based therapies.

Neurobiological Functions of the Period Circadian Clock 2 Gene, Per2

Most organisms have adapted to a circadian rhythm that follows a roughly 24-hour cycle, which is modulated by both internal (clock-related genes) and external (environment) factors. In such organisms, the central nervous system (CNS) is influenced by the circadian rhythm of individual cells. Furthermore, the period circadian clock 2 (Per2) gene is an important component of the circadian clock, which modulates the circadian rhythm. Per2 is mainly expressed in the suprachiasmatic nucleus (SCN) of the hypothalamus as well as other brain areas, including the midbrain and forebrain. This indicates that Per2 may affect various neurobiological activities such as sleeping, depression, and addiction. In this review, we focus on the neurobiological functions of Per2, which could help to better understand its roles in the CNS.

A Group of Descending Glutamatergic Neurons Activated by Stress in Corticolimbic Regions Project to the Nucleus Accumbens

The nucleus accumbens (NAc) is the major component of the ventral striatum that regulates stress-induced depression. The NAc receives dopaminergic inputs from the ventral tegmental area (VTA), and the role of VTA-NAc neurons in stress response has been recently characterized. The NAc also receives glutamatergic inputs from various forebrain structures including the prelimbic cortex (PL), basolateral amygdala (BLA), and ventral hippocampus (vHIP), whereas the role of those glutamatergic afferents in stress response remains underscored. In the present study, we investigated the extent to which descending glutamatergic neurons activated by stress in the PL, BLA, and vHIP project to the NAc. To specifically label the input neurons into the NAc, fluorescent-tagged cholera toxin subunit B (CTB), which can be used as a retrograde neuronal tracer, was injected into the NAc. After two weeks, the mice were placed under restraint for 1 h. Subsequent histological analyses indicated that CTB-positive cells were detected in 170~680 cells/mm² in the PL, BLA, and vHIP, and those CTB-positive cells were mostly glutamatergic. In the PL, BLA, and vHIP regions analyzed, stress-induced c-Fos expression was found in 20~100 cells/mm². Among the CTB-positive cells, 2.6% in the PL, 4.2% in the BLA, and 1.1% in the vHIP were co-labeled by c-Fos, whereas among c-Fos-positive cells, 7.7% in the PL, 19.8% in the BLA, and 8.5% in the vHIP were co-labeled with CTB. These results suggest that the NAc receives a significant but differing proportion of glutamatergic inputs from the PL, BLA, and vHIP in stress response.

Abnormal Effective Connectivity of the Anterior Forebrain Regions in Disorders of Consciousness / 神经科学通报·英文版

A number of studies have indicated that disorders of consciousness result from multifocal injuries as well as from the impaired functional and anatomical connectivity between various anterior forebrain regions. However, the specific causal mechanism linking these regions remains unclear. In this study, we used spectral dynamic causal modeling to assess how the effective connections (ECs) between various regions differ between individuals. Next, we used connectome-based predictive modeling to evaluate the performance of the ECs in predicting the clinical scores of DOC patients. We found increased ECs from the striatum to the globus pallidus as well as from the globus pallidus to the posterior cingulate cortex, and decreased ECs from the globus pallidus to the thalamus and from the medial prefrontal cortex to the striatum in DOC patients as compared to healthy controls. Prediction of the patients' outcome was effective using the negative ECs as features. In summary, the present study highlights a key role of the thalamo-basal ganglia-cortical loop in DOCs and supports the anterior forebrain mesocircuit hypothesis. Furthermore, EC could be potentially used to assess the consciousness level.

Aberrant growth of the anterior cranial base relevant to severe midface hypoplasia of Apert syndrome / 대한악안면성형재건외과학회지

BACKGROUND: A 9-year-old male showed severe defects in midface structures, which resulted in maxillary hypoplasia, ocular hypertelorism, relative mandibular prognathism, and syndactyly. He had been diagnosed as having Apert syndrome and received a surgery of frontal calvaria distraction osteotomy to treat the steep forehead at 6 months old, and a surgery of digital separation to treat severe syndactyly of both hands at 6 years old. Nevertheless, he still showed a turribrachycephalic cranial profile with proptosis, a horizontal groove above supraorbital ridge, and a short nose with bulbous tip. METHODS: Fundamental aberrant growth may be associated with the cranial base structure in radiological observation. RESULTS: The Apert syndrome patient had a shorter and thinner nasal septum in panthomogram, PA view, and Waters’ view; shorter zygomatico-maxillary width (83.5 mm) in Waters’ view; shorter length between the sella and nasion (63.7 mm) on cephalogram; and bigger zygomatic axis angle of the cranial base (118.2°) in basal cranial view than a normal 9-year-old male (94.8 mm, 72.5 mm, 98.1°, respectively). On the other hand, the Apert syndrome patient showed interdigitating calcification of coronal suture similar to that of a normal 30-year-old male in a skull PA view. CONCLUSION: Taken together, the Apert syndrome patient, 9 years old, showed retarded growth of the anterior cranial base affecting severe midface hypoplasia, which resulted in a hypoplastic nasal septum axis, retruded zygomatic axes, and retarded growth of the maxilla and palate even after frontal calvaria distraction osteotomy 8 years ago. Therefore, it was suggested that the severe midface hypoplasia and dysostotic facial profile of the present Apert syndrome case are closely relevant to the aberrant growth of the anterior cranial base supporting the whole oro-facial and forebrain development.

Transient forebrain ischemia induces impairment in cognitive performance prior to extensive neuronal cell death in Mongolian gerbil (Meriones unguiculatus)

In Mongolian gerbils, bilateral common carotid artery occlusion (BCCAO) for several minutes induces ischemia, due to an incomplete circle of Willis, resulting in delayed neuronal cell death in the Cornet d'Ammon 1 (CA1) region of the hippocampus. Neuronal cell death in the hippocampus and changes in behavior were examined after BCCAO was performed for 5 min in the gerbils. One day after BCCAO, the pyramidal neurons of the CA1 region of the hippocampus showed degenerative changes (clumped chromatin in nuclei). At 5 and 10 days after BCCAO, extensive neuronal cell death was observed in the hippocampal CA1 region. Cognitive performance was evaluated by using the radial maze and passive avoidance tests. In the radial maze test, which examines win-stay performance, the number of errors was significantly higher in ischemic gerbils than in sham-operated gerbils on days 1 and 2 post-operation. In the passive avoidance test, the latency and freezing times were significantly shorter in ischemic gerbils than in sham-operated gerbils on the days 1, 2, and 4–6 post-operation. These results indicate that transient forebrain ischemia impairs cognitive performance, even immediately after the ischemic insult when there are only subtle signs of neuronal cell death.

Chronic cerebral hypoperfusion and plasticity of the posterior cerebral artery following permanent bilateral common carotid artery occlusion

Vascular dementia (VaD) is a group of heterogeneous diseases with the common feature of cerebral hypoperfusion. To identify key factors contributing to VaD pathophysiology, we performed a detailed comparison of Wistar and Sprague–Dawley (SD) rats subjected to permanent bilateral common carotid artery occlusion (BCCAo). Eight-week old male Wistar and SD rats underwent BCCAo, followed by a reference memory test using a five-radial arm maze with tactile cues. Continuous monitoring of cerebral blood flow (CBF) was performed with a laser Doppler perfusion imaging (LDPI) system. A separate cohort of animals was sacrificed for evaluation of the brain vasculature and white matter damage after BCCAo. We found reference memory impairment in Wistar rats, but not in SD rats. Moreover, our LDPI system revealed that Wistar rats had significant hypoperfusion in the brain region supplied by the posterior cerebral artery (PCA). Furthermore, Wistar rats showed more profound CBF reduction in the forebrain region than did SD rats. Post-mortem analysis of brain vasculature demonstrated greater PCA plasticity at all time points after BCCAo in Wistar rats. Finally, we confirmed white matter rarefaction that was only observed in Wistar rats. Our studies show a comprehensive and dynamic CBF status after BCCAo in Wistar rats in addition to severe PCA dolichoectasia, which correlated well with white matter lesion and memory decline.

The neuroprotective mechanism of ampicillin in a mouse model of transient forebrain ischemia

Ampicillin, a beta-lactam antibiotic, dose-dependently protects neurons against ischemic brain injury. The present study was performed to investigate the neuroprotective mechanism of ampicillin in a mouse model of transient global forebrain ischemia. Male C57BL/6 mice were anesthetized with halothane and subjected to bilateral common carotid artery occlusion for 40 min. Before transient forebrain ischemia, ampicillin (200 mg/kg, intraperitoneally [i.p.]) or penicillin G (6,000 U/kg or 20,000 U/kg, i.p.) was administered daily for 5 days. The pretreatment with ampicillin but not with penicillin G signifi cantly attenuated neuronal damage in the hippocampal CA1 subfield. Mechanistically, the increased activity of matrix metalloproteinases (MMPs) following forebrain ischemia was also attenuated by ampicillin treatment. In addition, the ampicillin treatment reversed increased immunoreactivities to glial fibrillary acidic protein and isolectin B4, markers of astrocytes and microglia, respectively. Furthermore, the ampicillin treatment significantly increased the level of glutamate transporter-1, and dihydrokainic acid (DHK, 10 mg/kg, i.p.), an inhibitor of glutamate transporter-1 (GLT-1), reversed the neuroprotective effect of ampicillin. Taken together, these data indicate that ampicillin provides neuroprotection against ischemia-reperfusion brain injury, possibly through inducing the GLT-1 protein and inhibiting the activity of MMP in the mouse hippocampus.

Agmatine protection against chlorpromazine-induced forebrain cortex injury in rats

This study was conducted to investigate whether agmatine (AGM) provides protection against oxidative stress induced by treatment with chlorpromazine (CPZ) in Wistar rats. In addition, the role of reactive oxygen species and efficiency of antioxidant protection in the brain homogenates of forebrain cortexes prepared 48 h after treatment were investigated. Chlorpromazine was applied intraperitoneally (i.p.) in single dose of 38.7 mg/kg body weight (BW) The second group was treated with both CPZ and AGM (75 mg/kg BW). The control group was treated with 0.9% saline solution in the same manner. All tested compounds were administered i.p. in a single dose. Rats were sacrificed by decapitation 48 h after treatment Treatment with AGM significantly attenuated the oxidative stress parameters and restored antioxidant capacity in the forebrain cortex. The data indicated that i.p. administered AGM exerted antioxidant action in CPZ-treated animals. Moreover, reactive astrocytes and microglia may contribute to secondary nerve-cell damage and participate in the balance of destructive vs. protective actions involved in the pathogenesis after poisoning.

Association between respiratory and postural adaptations and self-perception of school-aged children with mouth breathing in relation to their quality of life

Objective: To investigate the respiratory and postural adaptations associated with mouth and nasal breathing and to evaluate the associations of such adaptations in mouth breathers' self-perceived quality of life. Method: Cross-sectional study with mouth breathers (initial n=116 and final n=48) and nasal breathers (initial n=131 and final n=24) from elementary school, aged between 7 and 14 years. Chest expansion, using cirtometry, the breathing pattern and the use of accessory muscles, by means of clinical evaluations and photogrammetry, and flexibility tests were evaluated in both groups. Subsequently, the mouth breathers were asked to complete the quality of life questionnaire. Statistical tests: Chi-square, odds ratio, Mann-Whitney, and binomial tests were first applied followed by logistic regressions. Results: Thoracic breathing (p=0.04), using of accessory muscles (p=0.03) and reductions in flexibility (p=0.001) increased the chances of an individual being a mouth breather when compared to nasal breathers. Subsequently, using of accessory muscles decreased the chances of snoring among mouth breathers (p=0.03); the presence of shoulder asymmetry reduced the chances of experiencing quiet sleep (p=0.05) and increased the chances of coughing or being tired when playing or running (p=0.008). Finally, forward head position reduced the chances of waking up at night (p=0.04) and experiencing shortness of breath (p=0.05). Conclusions: Respiratory and postural adaptations increased the chances of individuals persisting with mouth breathing. Additionally, these adaptations could be associated with mouth breathers' self-perceived quality of life. .

The Centrifugal Influence on Gustatory Neurons in the Nucleus of the Solitary Tract

Neuronal activities of taste-responsive cells in the nucleus of the solitary tract (NST) are affected by various physiological factors, such as blood glucose level or sodium imbalance. These phenomena suggest that NST taste neurons are under the influence of neural substrates that regulate nutritional homeostasis. In this study, we reviewed a series of in vivo electrophysiological investigations that demonstrate that forebrain nuclei, such as the lateral hypothalamus or central nucleus of the amygdala, send descending projections and modulate neuronal activity of gustatory neurons in the NST. These centrifugal modulations may mediate plasticity of taste response in the NST under different physiological conditions.

Comparison of teratogenecity induced by nano- and micro-sized particles of zinc oxide in cultured mouse embryos / 대한수의학회지

The increasing uses of zinc oxide nanoparticles (nZnO) in industrial and personal care products raise possible danger of using nZnO in human. To determine whether ZnO induces size-dependent anomalies during embryonic organogenesis, mouse embryos on embryonic day 8.5 were cultured for 2 days under 50, 100, and 150 microg of nZnO (< 100 nm) or micro-sized ZnO (mZnO; 80 +/- 25 microm), after which the morphological changes, cumulative quantity of Zn particles, and expressions of antioxidant and apoptotic genes were investigated. Although embryos exposed to 50 microg of ZnO exhibited no defects on organogenesis, embryos exposed to over 100 microg of ZnO showed increasing anomalies. Embryos treated with 150 microg of nZnO revealed significant changes in Zn absorption level and morphological parameters including yolk sac diameter, head length, flexion, hindbrain, forebrain, branchial bars, maxillary process, mandibular process, forelimb, and total score compared to the same dose of mZnO-treated embryos. Furthermore, CuZn-superoxide dismutase, cytoplasmic glutathione peroxidase (GPx) and phospholipid hydroperoxidase GPx mRNA levels were significantly decreased, but caspase-3 mRNA level was greatly increased in nZnO-treated embryos as compared to normal control embryos. These findings indicate that nZnO has severer teratogenic effects than mZnO in developing embryos.

Comparison of neuroprotective effects of Melissa officinalis total extract and its acidic and non-acidic fractions against a beta-Induced toxicity

Alzheimer's disease [AD] is a neurodegenerative disease that was characterized with deposit of beta amyloid [A beta] aggregate in senile plaque. Oxidative damage to neurons and loss of cholinergic neurons in forebrain region are observed in this disease. Melissa officinalis is a medicinal plant from Lamiaceae family, used traditionally in the treatment of cognitive disorders. It has cholinomimetic and potent antioxidant activity. In the present study, we investigated the possible neuroprotective effects of total ethanolic extract, acidic and nonacidic fraction of Melissa officinalis on A beta-induced cytotoxicity and oxidative stress in PC12 cells and also measured their in-vitro anticholinesterase activity. PC12 cells were incubated with the extract and fractions prior to the incubation with A beta and cell toxicity was assessed by MTT assay. In addition, productions of reactive oxygen species [ROS], Malondialdehyde [MDA] as a biomarker of lipid peroxidation and glutathione peroxidase activity were measured. Pretreatment of cells with total extract and acidic fraction [not non-acidic fraction] had protective effect against A beta-induced oxidative changes and cell death. In concentrations in which both total extracts of an acidic fraction showed neuroprotective effects, inhibition of cholinesterase activity was not significant. Then, the protective effects of Melissa officinalis total extract and acidic fraction were not attributed to their anticholinesterase activity. Acidic fraction showed more potent protective effect compared to the total extract, leading to the fact that polyphenolic compounds and terpenoic acids are the most effective components in the total extract concentrated in this fraction

Application of confocal simultaneous scanner unit in the study of forebrain neurodevelopment in zebrafish / 生理学报

With the application of the photoconversion technology of genetically expressed fluorescent proteins in biologic field, more powerful confocal imaging ability was demanded. The aim of the present study was to establish an experimental model employing confocal simultaneous scanner unit for simultaneous laser stimulation and imaging, taking study of forebrain neurodevelopment in zebrafish as an example. In the present study, 36-48-hour-old Tg(lhx5:kaede) zebrafish embryos were mounted with 1.2% low melting temperature agarose. The forebrain neurons marked with kaede were observed using the simultaneous scanner unit of confocal microscopy. The 405 nm laser was used to stimulate the region of interest (ROI), while 488 and 559 nm lasers were used to acquire images at the same time. The photoconversion state of kaede protein was then reviewed, and the projecting pattern of neurons stimulated by the ultraviolet laser was examined. The results showed that, the fluorescence of stimulated kaede turned from green to red, and the photoconversion of kaede demonstrated anterior dorsal telencephalon (ADt) neurons projected axons ventrally into the anterior commissure (AC) and supraoptic tract (SOT). These results suggest the confocal simultaneous scanner unit meets the demand of the photoconversion experiment. The application of confocal simultaneous scanning technology in examining Tg(lhx5:kaede) zebrafish embryos affords an ideal experimental model in neurodevelopment study.

Influence of acute ethanol intoxication on neuronal apoptosis and Bcl-2 protein expression after severe traumatic brain injury in rats / 中华创伤杂志(英文版)

<p><b>OBJECTIVE</b>To study the influence and mechanism of acute ethanol intoxication (AEI) on rat neuronal apoptosis after severe traumatic brain injury (TBI).</p><p><b>METHODS</b>Ninety-six Sprague-Dawley rats were randomly divided into four groups: normal control, AEI-only, TBI-only and TBI+AEI (n equal to 24 for each). Severe TBI model was developed according to Feeney's method. Rats in TBI+AEI group were firstly subjected to AEI, and then suffered head trauma. In each group, animals were sacrificed at 6 h, 24 h, 72 h, and 168 h after TBI. The level of neuronal apoptosis and the expression of Bcl-2 protein were determined by TUNEL assay and immunohistochemical method, respectively.</p><p><b>RESULTS</b>Apoptotic cells mainly distributed in the cortex and white matter around the damaged area. Neuronal apoptosis significantly increased at 6 h after trauma and peaked at 72 h. Both the level of neuronal apoptosis and expression of Bcl-2 protein in TBI-only group and TBI+AEI group were higher than those in control group (P less than 0.05). Compared with TBI-only group, the two indexes were much higher in TBI+AEI group at all time points (P less than 0.05).</p><p><b>CONCLUSION</b>Our findings suggest that AEI can increase neuronal apoptosis after severe TBI.</p>

Characterization of nestin expression in astrocytes in the rat hippocampal CA1 region following transient forebrain ischemia / 대한해부학회지

Recent studies have suggested that nestin facilitates cellular structural remodeling in vasculature-associated cells in response to ischemic injury. The current study was designed to investigate the potential role of post-ischemic nestin expression in parenchymal astrocytes. With this aim, we characterized ischemia-induced nestin expression in the CA1 hippocampal region, an area that undergoes a delayed neuronal death, followed by a lack of neuronal generation after transient forebrain ischemia. Virtually all of the nestin-positive cells in the ischemic CA1 hippocampus were reactive astrocytes. However, induction of nestin expression did not correlate simply with astrogliosis, but rather showed characteristic time- and strata-dependent expression patterns. Nestin induction in astrocytes of the pyramidal cell layer was rapid and transient, while a long-lasting induction of nestin was observed in astrocytes located in the CA1 dendritic subfields, such as the stratum oriens and radiatum, until at least day 28 after ischemia. There was no detectable expression in the stratum lacunosum moleculare despite the evident astroglial reaction. Almost all of the nestin-positive cells also expressed a transcription factor for neural/glial progenitors, i.e., Sox-2 or Sox-9, and some cells were also positive for Ki-67. However, all of the nestin-positive astrocytes expressed the calcium-binding protein S100beta, which is known to be expressed in a distinct, post-mitotic astrocyte population. Thus, our data indicate that in the ischemic CA1 hippocampus, nestin expression was induced in astroglia that were becoming reactive, but not in a progenitor/stem cell population, suggesting that nestin may allow for the structural remodeling of these cells in response to ischemic injury.

Therapeutic Application of Neural Stem Cells for Neonatal Hypoxic-ischemic Brain Injury

Neural stem cells (NSCs) are characterized by a capacity for self-renewal, differentiation into multiple neural cell lineages, and migration toward damaged sites in the central nervous system (CNS). NSCs expanded in culture could be implanted into the brain where they integrate into host neural circuitry and stably express foreign genes. It hence appears that transplantation of NSCs has been proposed as a promising therapeutic strategy in neurological disorders. During hypoxic-ischemic (HI) brain injury, factors are transiently elaborated to which NSCs respond by migrating to degenerating regions and differentiating towards replacement of dying neural cells. In addition, NSCs serve as vehicles for gene delivery and appear capable of simultaneous neural cell replacement and gene therapy (e.g. with factors that might enhance neuronal differentiation, neurites outgrowth, proper connectivity, neuroprotection, and/or immunomodulatory substances). When combined with certain synthetic biomaterials, NSCs may be even more effective in 'engineering' the damaged CNS towards reconstitution. Human NSCs were isolated from the forebrain of an aborted fetus at 13 weeks of gestation and were grown as neurospheres in cultures. After the characterization of human NSCs in preclinical testing and the approval of the IRB, a clinical trial of the transplantation of human NSCs into patients with severe perinatal HI brain injury has been performed. The existing data from these clinical trials have shown to be safe, well tolerated, and of neurologically-some benefits. Therefore, long-term and large scale multicenter clinical study is required to determine its precise therapeutic effect and safety.

The neuroprotective effect of combining sevoflurane and remote ischemic preconditioning in forebrain ischemia model

BACKGROUND: The aim of this study was to investigate the combining effects of sevoflurane and remote ischemic preconditioning (RIPC) on cell death of pyramidal neurons in the CA1 hippocampus induced by transient global cerebral ischemia in rats. METHODS: Twenty rats were assigned to one of two groups; sevoflurane group and combination of sevoflurane and RIPC group. RIPC was performed by occluding the bilateral femoral arteries for 10 min 3 times in an interval of 10 min. Ischemia was induced by a bilateral common carotid artery occlusion plus hemorrhagic hypotension (26-30 mmHg) and was maintained for 8 min. Histologic outcomes were measured at 7 days after ischemia in CA1 pyramidal cells of the rat hippocampus. RESULTS: The combination group contained significantly more viable cells in the hippocampal CA1 area than sevoflurane group (71% vs. 46%, P = 0.03). The mean percentage of apoptotic cells was significantly reduced in the combination group compared to sevoflurane group (11% vs. 41%, P = 0.014). CONCLUSIONS: A combination of sevoflurane and RIPC can offer additional neuroprotective effects after transient global cerebral ischemia in rats.