• The Korean Journal of Physiology and Pharmacology
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• v.22 no.6
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• pp.679-688
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• 2018

Autism spectrum disorders (ASDs) are neurodevelopmental disorders that share behavioral features, the results of numerous studies have suggested that the underlying causes of ASDs are multifactorial. Behavioral and/or neurobiological analyses of ASDs have been performed extensively using a valid model of prenatal exposure to valproic acid (VPA). Abnormal synapse formation resulting from altered neurite outgrowth in neural progenitor cells (NPCs) during embryonic brain development has been observed in both the VPA model and ASD subjects. Although several mechanisms have been suggested, the actual mechanism underlying enhanced neurite outgrowth remains unclear. In this study, we found that VPA enhanced the expression of brain-derived neurotrophic factor (BDNF), particularly mature BDNF (mBDNF), through dual mechanisms. VPA increased the mRNA and protein expression of BDNF by suppressing the nuclear expression of methyl-CpG-binding protein 2 (MeCP2), which is a transcriptional repressor of BDNF. In addition, VPA promoted the expression and activity of the tissue plasminogen activator (tPA), which induces BDNF maturation through proteolytic cleavage. Trichostatin A and sodium butyrate also enhanced tPA activity, but tPA activity was not induced by valpromide, which is a VPA analog that does not induce histone acetylation, indicating that histone acetylation activity was required for tPA regulation. VPA-mediated regulation of BDNF, MeCP2, and tPA was not observed in astrocytes or neurons. Therefore, these results suggested that VPA-induced mBDNF upregulation was associated with the dysregulation of MeCP2 and tPA in developing cortical NPCs.

• Journal of Korean Neurosurgical Society
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• v.42 no.4
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• pp.337-341
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• 2007

Objective : Repeated administration of mannitol in the setting of large hemispheric infarction is a controversial and poorly defined therapeutic intervention. This study was performed to examine the effects of multiple-dose mannitol on a brain edema after large hemispheric infarction. Methods : A middle cerebral artery was occluded with the rat suture model for 6 hours and reperfused in 22 rats. The rats were randomly assigned to either control (n=10) or the mannitol-treated group (n=12) in which intravenous mannitol infusions (0.8 g/kg) were performed six times every four hours. After staining a brain slice with 2,3,5-triphenyltetrazolium chloride, the weight of hemispheres, infarcted (IH) and contralateral (CH), and the IH/CH weight ratio were examined, and then hemispheric accumulation of mannitol was photometrically evaluated based on formation of NADH catalyzed by mannitol dehydrogenase. Results : Mannitol administration produced changes in body weight of $-7.6{\pm}1.1%$, increased plasma osmolality to $312{\pm}8\;mOsm/L$. It remarkably increased weight of IH ($0.77{\pm}0.06\;gm$ versus $0.68{\pm}0.03\;gm$ : p<0.01) and the IH/CH weight ratio ($1.23{\pm}0.07$ versus $1.12{\pm}0.05$ : p<0.01). The photometric absorption at 340 nm of the cerebral tissue in the mannitol-treated group was increased to $0.375{\pm}0.071$ and $0.239{\pm}0.051$ in the IH and CH, respectively from $0.167{\pm}0.082$ and $0.162{\pm}0.091$ in the IH and CH of the control group (p<0.01). Conclusion : Multiple-dose mannitol is likely to aggravate cerebral edema due to parenchymal accumulation of mannitol in the infarcted brain tissue.

• Journal of Korean Neurosurgical Society
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• v.63 no.2
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• pp.163-170
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• 2020

Objective : Milk fat globule-epidermal growth factor VIII (MFG-E8) may play a key role in inflammatory responses and has the potential to function as a neuroprotective agent for ameliorating brain injury in cerebral infarction. This study aimed to determine the role of MFG-E8 in brain injury in the subacute phase of cerebral ischemia in a rat model. Methods : Focal cerebral ischemia was induced in rats by occluding the middle cerebral artery with the modified intraluminal filament technique. Twenty-four hours after ischemia induction, rats were randomly assigned to two groups and treated with either recombinant human MFG-E8 or saline. Functional outcomes were assessed using the modified Neurological Severity Score (mNSS), and infarct volumes were evaluated using histology. Anti-inflammation, angiogenesis, and neurogenesis were assessed using immunohistochemistry with antibodies against ionized calcium-binding adapter molecule 1 (Iba-1), rat endothelial cell antigen-1 (RECA-1), and bromodeoxyuridine (BrdU)/doublecortin (DCX), respectively. Results : Our results showed that intravenous MFG-E8 treatment did not reduce the infarct volume; however, the mNSS test revealed that neurobehavioral deficits were significantly improved in the MFG-E8-treated group than in the vehicle group. Immunofluorescence staining revealed a significantly lower number of Iba-1-positive cells and higher number of RECA-1 in the periinfarcted brain region, and significantly higher numbers of BrdU- and DCX-positive cells in the subventricular zone in the MFG-E8-treated group than in the vehicle group. Conclusion : Our findings suggest that MFG-E8 improves neurological function by suppressing inflammation and enhancing angiogenesis and neuronal proliferation in the subacute phase of cerebral infarction.

• Investigative Magnetic Resonance Imaging
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• v.19 no.3
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• pp.168-177
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• 2015

Purpose: Brain surface intensity model (BSIM)-based cortical thickness analysis does not require complicated 3D segmentation of brain gray/white matters. Instead, this technique uses the local intensity profile to compute cortical thickness. The aim of the present study was to evaluate intra-rater and inter-rater reliability of BSIM-based cortical thickness analysis using images from elderly participants. Materials and Methods: Fifteen healthy elderly participants (ages, 55-84 years) were included in this study. High-resolution 3D T1-spoiled gradient recalled-echo (SPGR) images were obtained using 3T MRI. BSIM-based processing steps included an inhomogeneity correction, intensity normalization, skull stripping, atlas registration, extraction of intensity profiles, and calculation of cortical thickness. Processing steps were automatic, with the exception of semiautomatic skull stripping. Individual cortical thicknesses were compared to a database indicating mean cortical thickness of healthy adults, in order to produce Z-score thinning maps. Intra-class correlation coefficients (ICCs) were calculated in order to evaluate inter-rater and intra-rater reliabilities. Results: ICCs for intra-rater reliability were excellent, ranging from 0.751-0.940 in brain regions except the right occipital, left anterior cingulate, and left and right cerebellum (ICCs = 0.65-0.741). Although ICCs for inter-rater reliability were fair to excellent in most regions, poor inter-rater correlations were observed for the cingulate and occipital regions. Processing time, including manual skull stripping, was $17.07{\pm}3.43min$. Z-score maps for all participants indicated that cortical thicknesses were not significantly different from those in the comparison databases of healthy adults. Conclusion: BSIM-based cortical thickness measurements provide acceptable intra-rater and inter-rater reliability. We therefore suggest BSIM-based cortical thickness analysis as an adjunct clinical tool to detect cortical atrophy.

• Science of Emotion and Sensibility
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• v.8 no.2
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• pp.155-160
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• 2005

The aim of this study was to examine the effects of aqua-acupuncture a mixture of bos taurus domesticus and selenarctos thiberanus, and bos taurus domesticus, selenarctos thiberanus and Moschus moschiferus on an animal model of arthritic pain. Under halothane anesthesia, arthritic pain was induced by the injection of $2\%$ carrageenan into the left knee joint cavity of male Sprague-Dawley rats. The responses of afferents to a movement cycle were recorded before and after aqua-acupuncture. The aqua-acupuncture at acupoints reduced neural responses to noxious movement stimulation. Aqua-acupuncture at Zusanli inhibited neural responses of articular afferents to noxious stimulation more than at Hegu. These results indicate that aqua-acupuncture of a mixture of bos taurus domesticus and selenarctos thiberanus, and bos taurus domesticus, selenarctos thiberanus and Moschus moschiferusmay provide a potent strategy in relieving arthritic pain.

• Biomolecules & Therapeutics
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• v.15 no.3
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• pp.169-174
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• 2007

In the present study, we investigated the neuroprotective effects of standardized Ginkgo biloba extract (GBB) (total terpene trilactones, 13 ${\pm}$ 3%; biflavone, 4.5 ${\pm}$ 1.5%; flavonol glycoside, < 8%; proanthocyanidine, under detection limit) on ischemia-reperfusion-induced brain injury in the rats. Ischemia was induced by the intraluminal occlusion of the right middle cerebral artery for 2 h and reperfusion was continued for 22 h. GBB was orally administered, promptly prior to reperfusion and 2 h after. Total infarction volume in the ipsilateral hemispheres of ischemia-reperfusion rats were significantly reduced by treatment with GBB in a dose-dependent manner (P<0.05). The therapeutic time window of GBB was 3 h in this ischemia-reperfusion rat model. Furthermore, GBB also significantly inhibited increased neutrophil infiltration of ischemic brain tissue, as estimated by myeloperoxidase activity. These findings suggest that GBB plays a crucial protective role in ischemia-induced brain injury, in part, via inhibition of neutrophil infiltration, and suggest that this GBB could serve as a neuroprotective agent following transient focal ischemic brain injury.

• Preventive Nutrition and Food Science
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• v.16 no.3
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• pp.217-223
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• 2011

Ischemic stroke constitutes about 80% of all stroke incidences. It is characterized by brain cell death in a region where cerebral arteries supplying blood are occluded. Under these ischemic conditions, apoptosis is responsible for the cell death, at least in part. Goat's-beard (Aruncus dioicus var. kamtschaticus) is a perennial plant that grows naturally in the alpine regions of Korea. In the present study, we first determined whether water extract of goat's-beard (HY1646) and some of its fractions prepared by partitioning with organic solvents could improve the viability of human hepatocellular carcinoma cells (HepG2) cultured under hypoxic condition by blocking apoptotic pathways. Based on the in vitro findings, we subsequently investigated whether HY1646 and the ethyl acetate fraction (EA) selected from cell culture-based screening could attenuate brain injury in a rat middle cerebral artery occlusion (MCAO) model of ischemia (2 hr), followed by 22 hours of reperfusion. The cell number was sustained close to that initially plated in the presence of HY1646 even after 24 hr of cell culture under hypoxic condition (3% $O_2$), at which time the cell number reached almost zero in the absence of HY1646. This improvement in cell viability was attributed to the delay in apoptosis, identified by the formation of DNA ladder in gel electrophoresis. Of fractions soluble in hexane, ethyl acetate (EA) and butanol, EA was chosen for the animal experiments because EA demonstrated the best cell viability at the lowest concentration (10 ${\mu}g$/mL). HY1646 (200 mg/kg) and EA (10 and 20 mg/kg) significantly reduced infarct size, an index of brain injury, by 16.6, 40.0 and 61.0%, respectively, as assessed by 2,3,5-triphenyl tetrazolium chloride staining. The findings suggest that prophylactic intake of goat's beard might be beneficial for preventing ischemic stroke.

• Journal of Ginseng Research
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• v.42 no.3
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• pp.379-388
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• 2018

Background: Ginsenosides are the main ingredients of Korean Red Ginseng. They have extensively been studied for their beneficial value in neurodegenerative diseases such as Parkinson's disease (PD). However, the multitarget effects of Korean Red Ginseng extract (KRGE) with various components are unclear. Methods: We investigated the multitarget activities of KRGE on neurological dysfunction and neurotoxicity in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. KRGE (37.5 mg/ kg/day, 75 mg/kg/day, or 150 mg/kg/day, per os (p.o.)) was given daily before or after MPTP intoxication. Results: Pretreatment with 150 mg/kg/day KRGE produced the greatest positive effect on motor dysfunction as assessed using rotarod, pole, and nesting tests, and on the survival rate. KRGE displayed a wide therapeutic time window. These effects were related to reductions in the loss of tyrosine hydroxylase-immunoreactive dopaminergic neurons, apoptosis, microglial activation, and activation of inflammatory factors in the substantia nigra pars compacta and/or striatum after MPTP intoxication. In addition, pretreatment with KRGE activated the nuclear factor erythroid 2-related factor 2 pathways and inhibited phosphorylation of the mitogen-activated protein kinases and nuclear factor-kappa B signaling pathways, as well as blocked the alteration of blood-brain barrier integrity. Conclusion: These results suggest that KRGE may effectively reduce MPTP-induced neurotoxicity with a wide therapeutic time window through multitarget effects including antiapoptosis, antiinflammation, antioxidant, and maintenance of blood-brain barrier integrity. KRGE has potential as a multitarget drug or functional food for safe preventive and therapeutic strategies for PD.

• Molecules and Cells
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• v.39 no.4
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• pp.337-344
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• 2016

Intravenous administration of mesenchymal stem cells (IV-MSC) protects the ischemic rat brain in a stroke model, but the molecular mechanism underlying its therapeutic effect is unclear. We compared genomic profiles using the mRNA microarray technique in a rodent stroke model. Rats were treated with $1{\times}10^6$ IV-MSC or saline (sham group) 2 h after transient middle cerebral artery occlusion (MCAo). mRNA microarray was conducted 72 h after MCAo using brain tissue from normal rats (normal group) and the sham and MSC groups. Predicted pathway analysis was performed in differentially expressed genes (DEGs), and functional tests and immunohistochemistry for inflammation-related proteins were performed. We identified 857 DEGs between the sham and normal groups, with the majority of them (88.7%) upregulated in sham group. Predicted pathway analysis revealed that cerebral ischemia activated 10 signaling pathways mainly related to inflammation and cell cycle. IV-MSC attenuated the numbers of dysregulated genes in cerebral ischemia (118 DEGs between the MSC and normal groups). In addition, a total of 218 transcripts were differentially expressed between the MSC and sham groups, and most of them (175/218 DEGs, 80.2%) were downregulated in the MSC group. IV-MSC reduced the number of Iba-$1^+$ cells in the peri-infarct area, reduced the overall infarct size, and improved functional deficits in MCAo rats. In conclusion, transcriptome analysis revealed that IV-MSC attenuated postischemic genomic alterations in the ischemic brain. Amelioration of dysregulated inflammation- and cell cycle-related gene expression in the host brain is one of the molecular mechanisms of IV-MSC therapy for cerebral ischemia.

• Biomolecules & Therapeutics
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• v.29 no.2
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• pp.144-153
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• 2021

Astrocytes play various important roles such as maintaining brain homeostasis, supporting neurons, and secreting inflammatory mediators to protect the brain cells. In aged subjects, astrocytes show diversely changed phenotypes and dysfunctions. But, the study of aged astrocytes or astrocytes from aged subjects is not yet sufficient to provide a comprehensive understanding of their important processes in the regulation of brain function. In this study, we induced an in vitro aged astrocyte model through late passage cultivation of rat primary cultured astrocytes. Astrocytes were cultured until passage 7 (P7) as late passage astrocytes and compared with passage 1 (P1) astrocytes as early passage astrocytes to confirm the differences in phenotypes and the effects of serial passage. In this study, we confirmed the morphological, molecular, and functional changes of late passage astrocytes showing aging phenotypes through SA-β-gal staining and measurement of nuclear size. We also observed a reduced expression of inflammatory mediators including IL-1β, IL-6, TNFα, iNOS, and COX2, as well as dysregulation of wound-healing, phagocytosis, and mitochondrial functions such as mitochondrial membrane potential and mitochondrial oxygen consumption rate. Culture-conditioned media obtained from P1 astrocytes promoted neurite outgrowth in immature primary cultures of rat cortices, which is significantly reduced when we treated the immature neurons with the culture media obtained from P7 astrocytes. These results suggest that late passage astrocytes show senescent astrocyte phenotypes with functional defects, which makes it a suitable model for the study of the role of astrocyte senescence on the modulation of normal and pathological brain aging.