1.Morphological Analysis of Short and Long Term Changes after Ligation of Unilateral Common Carotid Artery in Gerbils.
Jee Hyang JEONG ; Hea Soo KOO ; Kyung Gyu CHOI
Journal of the Korean Neurological Association 1999;17(4):561-567
BACKGROUND: The ligation of the unilateral common carotid artery (CCA) in the gerbil has been known as an ischemic animal model showing various changes including selective neuronal necrosis as well as infarction. This study was performed to analyze the short and long term morphological changes of transient unilateral forebrain ischemia with special attention to astroglial proliferation. METHODS: 67 mongolian gerbils were subjected to 2 hr, 3 hr, 4 hr, or 5 hr of forebrain ischemia by the unilateral CCA ligation method. Each of the ischemic groups were examined after a 1 day, 3 day, or 7 day period of reperfusion. Long term reperfusion groups consisted of 2, 3, and 4 weeks of reperfusion after 5hr of unilateral CCA ligation. Morphological changes were analyzed by H-E staining and an immunohistochemical reaction with GFAP antibody. RESULTS: The ligation of the unilateral CCA, induced unilateral hemispheric infarction in 14 gerbils, selective neuronal necrosis (SNN) involving caudate in 1 gerbil, and delayed neuronal necrosis (DND) of the hippocampal CA1 neurons in 2 gerbils. Infarction was most frequent in 1 day reperfusion groups and did not show any differences according to the duration of ischemia. The GFAP reaction was strongly positive in the center of infarction at a 1 day period and negative at a 3 & 7 day period. The surrounding brain parenchyme progressively revealed increased positive reactions. Gerbils with SNN and DND showed moderately or markedly increased GFAP positive reactions in the unilateral caudate, thalamus, and hippocampus, whereas no apparent changes were shown by a H-E stain. CONCLUSIONS: Reactive astrogliosis is a stereotyped reaction of ischemic brain injury and is a more sensitive parameter than neuronal changes.
Brain
;
Brain Injuries
;
Carotid Artery, Common*
;
Gerbillinae*
;
Hippocampus
;
Infarction
;
Ischemia
;
Ligation*
;
Models, Animal
;
Necrosis
;
Neurons
;
Prosencephalon
;
Reperfusion
;
Thalamus
2.Expression of Cytokines in Radiation Injured Brain at Acute Phase.
Jang Bo LEE ; Min Ho KIM ; Yong Gu CHUNG ; Jung Yul PARK
Journal of Korean Neurosurgical Society 2007;42(3):200-204
OBJECTIVE: Radiation therapy is an important treatment for brain tumor. However, serious complications such as radiation necrosis can occur and it may be secondary to the expression of acute phase genes, like cytokines. In particular, inflammatory cytokines (IL-1beta, TNF-alpha) and other immunomodulatory cytokines (TNF-alpha, TGF-beta1) might be changed after irradiation (high single dose irradiation). Although it has been reported that IL-1 level is remarkably elevated within 8 week after the irradiation to the rat brain, the change of cytokines levels at acute phase (within 24 hours) has not been reported. In the present study, we examined TNF-alpha, TGF-beta1, and IL-1beta levels in acute phase to clarify the early effect of cytokines on the radiation-induced brain damage. METHODS: Fifty Sprague-Dawley rats were used and these were divided into irradiation group and control group. After a burr-hole trephination on the right parietal area using a drill, a single 10 Gy was irradiated at the trephined site. Their forebrains were extirpated at 30 min, 2 hr, 8 hr, 12 hr and 24 hr, respectively and examined for the expression of TNF-alpha, TGF-beta1 and IL-1beta. RESULTS: The expression of TNF-alpha and TGF-beta1 were decreased until 12 hr after irradiation but elevated thereafter. The expression of IL-1 was peak at 8 hr and then decreased until 12 hr but elevated after this time window. The present study indicated that expression of cytokines (TNF-alpha, TGF-beta1 and IL-1beta) were increased at 24 hr after the irradiation to the rat brain. IL-1beta level, on the other hand, reached peak at 8 hr after radiation injury. CONCLUSION: These findings indicate that IL-1, among various cytokines, may have a more important role in the inflammatory reaction by radiation injury at acute phase and provide some clues for better understanding of the pathogenesis of radiation injury.
Animals
;
Brain Injuries
;
Brain Neoplasms
;
Brain*
;
Cytokines*
;
Hand
;
Interleukin-1
;
Necrosis
;
Prosencephalon
;
Rabeprazole
;
Radiation Injuries
;
Rats
;
Rats, Sprague-Dawley
;
Transforming Growth Factor beta1
;
Trephining
;
Tumor Necrosis Factor-alpha
3.Expression of Cytokines in Radiation Injured Brain at Acute Phase.
Jang Bo LEE ; Min Ho KIM ; Yong Gu CHUNG ; Jung Yul PARK
Journal of Korean Neurosurgical Society 2007;42(3):200-204
OBJECTIVE: Radiation therapy is an important treatment for brain tumor. However, serious complications such as radiation necrosis can occur and it may be secondary to the expression of acute phase genes, like cytokines. In particular, inflammatory cytokines (IL-1beta, TNF-alpha) and other immunomodulatory cytokines (TNF-alpha, TGF-beta1) might be changed after irradiation (high single dose irradiation). Although it has been reported that IL-1 level is remarkably elevated within 8 week after the irradiation to the rat brain, the change of cytokines levels at acute phase (within 24 hours) has not been reported. In the present study, we examined TNF-alpha, TGF-beta1, and IL-1beta levels in acute phase to clarify the early effect of cytokines on the radiation-induced brain damage. METHODS: Fifty Sprague-Dawley rats were used and these were divided into irradiation group and control group. After a burr-hole trephination on the right parietal area using a drill, a single 10 Gy was irradiated at the trephined site. Their forebrains were extirpated at 30 min, 2 hr, 8 hr, 12 hr and 24 hr, respectively and examined for the expression of TNF-alpha, TGF-beta1 and IL-1beta. RESULTS: The expression of TNF-alpha and TGF-beta1 were decreased until 12 hr after irradiation but elevated thereafter. The expression of IL-1 was peak at 8 hr and then decreased until 12 hr but elevated after this time window. The present study indicated that expression of cytokines (TNF-alpha, TGF-beta1 and IL-1beta) were increased at 24 hr after the irradiation to the rat brain. IL-1beta level, on the other hand, reached peak at 8 hr after radiation injury. CONCLUSION: These findings indicate that IL-1, among various cytokines, may have a more important role in the inflammatory reaction by radiation injury at acute phase and provide some clues for better understanding of the pathogenesis of radiation injury.
Animals
;
Brain Injuries
;
Brain Neoplasms
;
Brain*
;
Cytokines*
;
Hand
;
Interleukin-1
;
Necrosis
;
Prosencephalon
;
Rabeprazole
;
Radiation Injuries
;
Rats
;
Rats, Sprague-Dawley
;
Transforming Growth Factor beta1
;
Trephining
;
Tumor Necrosis Factor-alpha
4.Effectiveness of propofol pretreatment on the extent of deranged cerebral mitochondrial oxidative enzyme system after incomplete forebrain ischemia/reperfusion in rats .
Younsuk LEE ; Choonkun CHUNG ; Yong Seok OH
Journal of Korean Medical Science 2000;15(6):627-630
It has been suggested that propofol has the protective effect on cerebral ischemia-reperfusion injury. The aim of this study is to evaluate the effect of propofol pretreatment on incomplete forebrain ischemia-reperfusion injury in rats. Thirty Sprague-Dawley rats were anesthetized with isoflurane in oxygen and randomly allocated into propofol group (n=13) and saline group (n=17). In propofol group, propofol was pretreated in a step-down scheme before inducing forebrain ischemia by occlusion of both common carotid arteries and arterial hypotension. After ischemia (20 min) and reperfusion (30 min), rats were decapitated. Brain was sliced to obtain coronal slices of 4-12 mm from frontal pole, which were reacted with 2% 2,3,5-triphenyl-2H-tetrazolium chloride (TTC) for 10 min to differentiate the damaged tissues from normal tissues. Median (interquartile range) values of the average percent infarct area were 0.0 (8.6)% and 20.1 (41.2)% in propofol and saline groups, respectively. There was significant difference between the groups. In conclusion, propofol may have a protective effect on incomplete forebrain ischemia-reperfusion injury.
Animal
;
Brain Ischemia/prevention & control*
;
Brain Ischemia/pathology
;
Cerebral Infarction/prevention & control
;
Cerebral Infarction/pathology
;
Disease Models, Animal
;
Free Radical Scavengers/pharmacology*
;
Mitochondria/enzymology*
;
Neuroprotective Agents/pharmacology*
;
Oxidative Phosphorylation
;
Propofol/pharmacology*
;
Prosencephalon/metabolism
;
Prosencephalon/injuries
;
Prosencephalon/drug effects*
;
Rats
;
Rats, Sprague-Dawley
;
Reperfusion Injury/prevention & control*
;
Reperfusion Injury/pathology
;
Tetrazolium Salts
5.The effects of desflurane on delayed neuronal injury after transient forebrain ischemia in the rat.
Jeong Han LEE ; Osun KWON ; Jae Young KWON
Korean Journal of Anesthesiology 2009;57(2):195-202
BACKGROUND: Volatile anesthetics have been shown protective against focal or global cerebral ischemia in animal models. However isoflurane failed to provide persistent protection because of late onset of apoptosis after ischemia. The aim of this study was to elucidate the effects of desflurane on delayed neuronal damage after forebrain ischemia. METHODS: Rats were divided into 2 groups and anesthetized with desflurane or isoflurane. Forebrain ischemia was produced by both induced hypotension and 10 minutes of common carotid artery clamping. After 2 days and 2 weeks, rats were killed under anesthesia and brains were removed for Western blot analysis of Bcl-2, Bax, and caspase 3 expression and histopathologic study. RESULTS: The apoptotic cell numbers in hippocampal CA1 area were increased after 2 weeks, and there was no significant difference between groups. There was no significant difference in caspase 3 expression between groups. The Bax/Bcl-2 ratio was increased at 2 weeks after ischemia, and there was no significant difference between group. CONCLUSIONS: The data indicate that desflurane also delays but does not prevent the neuronal injury caused by ischemia. Desflurane reduced the development of apoptosis early after ischemia but did not prevent it at later stages of post-ischemic recovery.
Anesthesia
;
Anesthetics
;
Animals
;
Apoptosis
;
Blotting, Western
;
Brain
;
Brain Injuries
;
Brain Ischemia
;
Carotid Artery, Common
;
Caspase 3
;
Cell Count
;
Constriction
;
Hypotension
;
Ischemia
;
Isoflurane
;
Models, Animal
;
Neurons
;
Prosencephalon
;
Rats
6.Prolonged Ischemic Cerebral Infarct in the Rat after Middle Cerebral Artery Occlusion: Part 1:Evolution and Time Course of the Infarction.
Chun Kun PARK ; Chul Ku JUNG ; Dal Soo KIM ; Moon Chan KIM ; Joon Ki KANG
Journal of Korean Neurosurgical Society 1989;18(4):505-514
Although evolution and time course of ischemic brain infarct should be a matter of interest to investigators in the research of brain ischemia as well as traumatic brain injury, few papers have ever been reported. Authors observed quantitatively sequential changes of infarct size and regional cerebral blood flow(rCBF) to assess the evolution of focal ischemic brain infarct in the rat following left MCAO. Fifteen rats, weighting 250 g to 370 g, were used in this experiment. The experiment animals were divided into three groups: 6, 24 and 48 hours groups(HG) after MCAO. The rCBF of bilateral caudate nuclei was measured by hydrogen clearance methods. Areas of brain infarction were delineated by tripheny-tetrazolium chloride(TTC) at the preselected 8 coronal levels of forebrain. The areas of brain damage were drawn on scale diagrams(x4 actual size) of forebrain and measured by a plannimeter. In the experimental groups, just after MCAO, rCBF of the ipsilateral caudate nucleus was reduced to 29.4+/-6.5 to 24.5+/-7.9 ml/100 g/min from the basal value of around 117 to 121 ml/100 g/min and showed a tendency of getting more reduced to 19.4+/-7.6 ml/100 g/min by 48 hours. The rCBF of the contralateral caudate nucleus was maintained in the basal value throughout the experiment. Comparing the total amounts of ischemic damage of 48 HG to those of 5 and 24 HG, the infarction size was significantly increased in cerebral hemisphere as well as cerebral cortex and caudate nucleus(p<0.05). But there was not any significant difference between 6 and 24 HG. The experiment provides evidence for the evolution of focal ischemic brain infarct without any further change of decreased rCBF. The data suggest that it is desirable to observe the change of pathologic findings by not less then 48 hours following the arterial occlusion in the study of ischemic brain infarction in the rat, particularly as long as ischemic damage is delineated by TTC.
Animals
;
Brain
;
Brain Infarction
;
Brain Injuries
;
Brain Ischemia
;
Caudate Nucleus
;
Cerebral Cortex
;
Cerebrum
;
Humans
;
Hydrogen
;
Infarction*
;
Infarction, Middle Cerebral Artery*
;
Middle Cerebral Artery*
;
Prosencephalon
;
Rats*
;
Research Personnel
7.Therapeutic Application of Neural Stem Cells for Neonatal Hypoxic-ischemic Brain Injury.
Kook In PARK ; Kyoyeon GOO ; Kwangsoo JUNG ; Miri KIM ; Il Sun KIM ; Seokhwan YUN ; Il Shin LEE ; Jeong Eun SHIN ; Ha Yang YU ; Ho Seon EUN ; Jung Eun KIM ; Ran NAMGUNG ; Chul LEE
Neonatal Medicine 2013;20(3):343-353
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.
Aborted Fetus
;
Biocompatible Materials
;
Brain
;
Brain Injuries
;
Cell Lineage
;
Central Nervous System
;
Ethics Committees, Research
;
Genetic Therapy
;
Humans
;
Nervous System Diseases
;
Neural Stem Cells
;
Neurites
;
Neurons
;
Pregnancy
;
Prosencephalon
;
Tissue Therapy
;
Transplants
8.Changes in Gene Expression during Brain Ischemia and the Effect of Pretreatment of BN52021 (PAF Antagonist).
Sang Ook NAM ; Su Young KIM ; Jin Sup JUNG
Journal of the Korean Child Neurology Society 1998;6(1):29-38
BACKGROUND: This study was undertaken to determine temporal changes in expression of various genes and the effect of platelet-activating factor antagonist on their expression. SUBJECTS AND METHODS: The changes in expression of various genes including interleukin-1, iNOS, TNF-alpha, ICAM-1, cPLA2, GLUT1, BDNF and Bcl-X according to time were examined using reverse-transcription polymerase chain reaction(RT-PCR) by checking at various time points after induction of middle cerebral artery(MCA) occlusion in the thrombotic and embolic models of stroke of Sprague-Dawley rats. We also examined the effect of pretreatment of a PAF antagonist, BN52021 on the expression of the same genes by RT-PCR and by in situ hybridization technique. RESULTS: The expressions of BDNF, IL-1, GLUT1, iNOS, cPLA2 and TNF-alpha were increased in ischemic brain tissue. However, the temporal profiles of their expression were variable; the peak expression was observed after 1 hour reperfusion in TNF-alpha, after 4 hours in IL-1, cPLA2 and BDNF and after 24 hours in GLUT1 and iNOS. Pretreatment of a PAF antagonist, BN52021, significantly inhibited the ischemia-induced expression of TNF-alpha, cPLA2 and iNOS without affecting the expression of the BDNF and GLUT1. In situ hybridization showed that cPLA2 expression induced by transient forebrain ischemia in dentate gyrus was ameliorated by the pretreatment of BN52021. CONCLUSION: This result indicates that BN52021, PAF antagonist, specifically inhibits expression of certain genes, which may be related to its protective effect on ischemic brain injury.
Brain Injuries
;
Brain Ischemia*
;
Brain*
;
Brain-Derived Neurotrophic Factor
;
Dentate Gyrus
;
Gene Expression*
;
In Situ Hybridization
;
Intercellular Adhesion Molecule-1
;
Interleukin-1
;
Ischemia
;
Prosencephalon
;
Rats, Sprague-Dawley
;
Reperfusion
;
Stroke
;
Tumor Necrosis Factor-alpha
9.Influence of acute ethanol intoxication on neuronal apoptosis and Bcl-2 protein expression after severe traumatic brain injury in rats.
Min HE ; Wei-Guo LIU ; Liang WEN ; Hang-Gen DU ; Li-Chun YIN ; Li CHEN
Chinese Journal of Traumatology 2013;16(3):136-139
OBJECTIVETo study the influence and mechanism of acute ethanol intoxication (AEI) on rat neuronal apoptosis after severe traumatic brain injury (TBI).
METHODSNinety-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.
RESULTSApoptotic 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).
CONCLUSIONOur findings suggest that AEI can increase neuronal apoptosis after severe TBI.
Animals ; Apoptosis ; drug effects ; Brain Injuries ; Cerebral Cortex ; cytology ; Disease Models, Animal ; Ethanol ; poisoning ; Immunohistochemistry ; In Situ Nick-End Labeling ; Male ; Neurons ; physiology ; Prosencephalon ; cytology ; Proto-Oncogene Proteins c-bcl-2 ; metabolism ; Rats ; Rats, Sprague-Dawley
10.The neuroprotective mechanism of ampicillin in a mouse model of transient forebrain ischemia.
Kyung Eon LEE ; Kyung Ok CHO ; Yun Sik CHOI ; Seong Yun KIM
The Korean Journal of Physiology and Pharmacology 2016;20(2):185-192
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.
Ampicillin*
;
Animals
;
Astrocytes
;
Brain Injuries
;
Carotid Artery, Common
;
Glial Fibrillary Acidic Protein
;
Glutamic Acid
;
Halothane
;
Hippocampus
;
Humans
;
Ischemia*
;
Lectins
;
Male
;
Matrix Metalloproteinases
;
Mice*
;
Microglia
;
Neurons
;
Neuroprotective Agents
;
Penicillin G
;
Prosencephalon*