The Effect of Combination Treatment of Melatonin and Hypothermia on Hypoxic-Ischemic Brain Injury in Neonatal Rats

PURPOSE: Melatonin is a naturally occurring hormone produced by the pineal gland. Melatonin has many pharmacological effects in different tissues or organs. Melatonin is especially known to have antioxidant and neuroprotective effects. Hypothermia is a therapeutic tool against hypoxia-ischemia (HI) of the brain. This study examines the effect of combined therapy using melatonin and hypothermia in neonatal rats with HI. METHODS: Seven-day old rats were subjected to HI and randomized into four groups : vehicle, melatonin alone, vehicle and hypothermia, and melatonin and hypothermia. Melatonin (30 mg/kg) was intraperitoneally administered in two doses: immediately following HI, and 24 h later. Hypothermia consisted of whole-body cooling (3 hours, 27degrees C). Sham-treated animals not subjected to HI were also studied. P10, P14, and P35 rats were sacrificed for experiments. RESULTS: Vehicle-treated P10 rats increased in brain infarction compared to controls in TTC staining study. And also, P35 rats decreased in brain volume of injured hemisphere in H&E stain. Melatonin or hypothermia alone did not show any protective effect against HI. However, a combination of melatonin and hypothermia effectively reduced the brain injury. In addition, the results of in situ zymography, TUNEL assay and immunofluorescence studies showed that neuroprotective effects were achieved only with combined therapy. CONCLUSION: Melatonin may contribute to synergistic effects to neuroprotection of hypothermia on brain damage after HI.

Effects of Single Treatment of Anti-Dementia Drugs on Sleep-Wake Patterns in Rats

We studied the effects of acetylcholinesterase inhibitors, donepezil and galantamine, and an N-methyl-D-aspartate (NMDA) receptor blocker, memantine, on sleep-wake architecture in rats. Screw electrodes were chronically implanted into the frontal and parietal cortex for the electroencephalography (EEG). EEG was recorded with a bio-potential amplifier for 8 h from 09:30 to 17:30. Vibration was recorded to monitor animal activity with a vibration measuring device. Sleep-wake states such as wake (W), slow-wave sleep (S) and paradoxical or rapid eye movement sleep (P), were scored every 10 sec by an experimenter. We measured mean episode duration and number of episode to determine which factor sleep disturbance was attributed to. Donepezil and memantine showed a significant increase in total W duration and decreases in total S and P duration and delta activity. Memantine showed increases in sleep latency and motor activity. Changes of S and P duration in memantine were attributed from changes of mean episode duration. Galantamine had little effect on sleep architecture. From these results, it is showed that galantamine may be an anti-dementia drug that does not cause sleep disturbances and memantine may be a drug that causes severe sleep disturbance.

Apoptosis and upregulation of TNF-alpha and TRAIL receptor 1 (DR4) in the pathogenesis of food protein-induced enterocolitis syndrome / 소아과

PURPOSE: Expression levels of tumor necrosis factor (TNF)-alpha expression on the mucosa of the small intestine is increased in patients with villous atrophy in food protein-induced enterocolitis syndrome (FPIES). TNF-alpha has been reported to induce apoptotic cell death in the epithelial cells. We studied the TNF family and TNF-receptor family apoptosis on the duodenal mucosa to investigate their roles in the pathogenesis of FPIES. METHODS: Fifteen infants diagnosed as having FPIES using standard oral challenge test and 5 controls were included. Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining was performed to identify the apoptotic cell death bodies. Immunohistochemical staining of TNF-alpha, Fas ligand (FasL) for TNF family and TNF-related apoptosis-including ligand (TRAIL) receptor 1 (DR4), TRAIL receptor 2 (DR5), and Fas for TNF-receptor family were performed to determine the apoptotic mechanisms. RESULTS: TUNEL+ was significantly more highly expressed in the duodenal mucosa of FPIES patients than in controls (P=0.043). TNF-alpha (P=0.0001) and DR4 (P=0.003) were significantly more highly expressed in FPIES patients than in controls. Expression levels of FasL, Fas, and DR5 were low in both groups and were not significantly different between the 2 groups. CONCLUSION: These results suggest that FPIES pathogenesis is induced by apoptosis, and that TNF-alpha expression and DR4 pathway may have an important role in apoptosis.

The Effect of Delayed Administration of Green Tea Polyphenol, (-)-pigallocatechin-3-gallate, on the Change of Putrescine Level and Hippocampal Neuronal Cell Damage after Transient Global Ischemia in Gerbil

OBJECTIVE: T(-)-Epigallocatechin gallate(EGCG) `a green tea polyphenol' is a potent antioxidant and known to reduce the free radical-induced lipid peroxidation. In our previous study, systemic administration of EGCG immediately after ischemia has been shown to inhibit the hippocampal neuronal damage in the gerbil model of global ischemia. Polyamines, especially putrescine(PU) is thought to be important in the generation of brain edema and neuronal cell damage associated with various types of excitotoxic neuronal injury. We investigate the effects of delayed administration of EGCG on the changes in polyamine levels and neuronal damage after transient global ischemia in gerbils. METHODS: To produce transient global ischemia, both common carotid arteries were occluded for 3 min with micro-clips. The gerbils were treated with EGCG(50mg/kg, i.p.) immediately or 2hr after ischemia. Putrescine levels were examined in the cerebral cortex and hippocampus 24 hours after ischemia using high performance liquid chromatography. RESULTS: PU levels in the cerebral cortex and hippocampus were increased significantly after the ischemia. The administrations of EGCG immediately after the ischemia attenuated the ischemia-induced increase of PU level, however, 2 hr delayed EGCG administration did not reduce the increase of PU level. EGCG administered immediately or 2 hr after ischemia significantly reduced neuronal damage in the hippocampal CA1 region, respectively. CONCLUSION: These findings suggest that EGCG may has a promise in the management of stroke.

Effect of Ibuprofen on the Changes of Polyamine Level and Neuronal Cell Damage after Transient Global Ischemia in Gerbil

BACKGROUND: In brain ischemia, increased arachidonic acid metabolism can play important roles in neuronal dam-age. Ibuprofen was reported to have a protective role against neuronal damage in focal brain ischemia and reperfusion. The present study was designed to investigate whether ibuprofen can inhibit the global ischemia-induced neuronal dam-age and changes of polyamine (PA) level which is known to related to the neuronal damage, breakdown of blood brain barrier, and brain edema. METHODS: Male Mongolian gerbils were used in this study. Transient global ischemia was induced by occlusion of bilateral common carotid arteries for 3 min with microclips. Ibuprofen was administered imme-diately after ischemia. The animals were sacrificed one day after ischemia for PA measurement and sacrificed 5 days after ischemia for histological evaluation. Histological examination was performed by counting surviving neuronal cells in one mm of CA1 area in dorsal hippocampus. RESULTS: Cerebral cortex and hippocampal putrescine(PU) levels in vehicle-treated ischemic group significantly increased comparing to sham-operated animals and the increase of PU was attenuated by ibuprofen administration (50 mg/kg). Hippocampal spermine level decreased significantly after ischemia. Hippocampal neuronal cell damage in CA1 area was markedly observed in vehicle-treated animals compared to sham operated animals. Ibuprofen administration at the dose of 50 mg/kg significantly inhibited hippocampal CA1 neuronal damage compared to vehicle-treated animals. CONCLUSIONS: Ibuprofen attenuates PA response following transient glob-al ischemia and may have putative neuroprotective effect against neuronal damage induced by global ischemia.

Effect of Melatonin on Brain Polyamine Contents and Hippocampal Neuronal Damage after Transient Global Ischemia in Mongolian Gerbil / 대한뇌혈관학회지

OBJECTIVES: This study was designed to examine whether melatonin has a neuroprotective effect against hippocampal neuronal damage following transient global ischemia in a gerbil. Polyamine is known to play a role in the pathophysiology of ischemic neuronal damage, we evaluated the influences of melatonin on the polyamine level as well as histology. MATERIAL AND METHODS: Male Mongolian gerbils (60-80 g) were used in this study. Transient global ischemia was induced by occlusion of the bilateral common carotid arteries for 3 min with microclips. Melatonin was administered immediately after occlusion. The animals were decapitated 24 h after the occlusion for polyamine measurement by a high performance liquid chromatography (HPLC) and 4 days after the occlusion for histological evaluation (hematoxylin and eosin staining). A histological examination was performed by a blinded investigator. RESULTS: The hippocampal putrescine level increased compared to sham-operated animals and the increase of putrescine was attenuated by 20 mg/kg melatonin administration. Spermidine and spermine levels didn't show significant changes after ischemia. Hippocampal neuronal damage in the CA1 region was markedly observed in vehicle-treated animals compared to sham-operated animals. Melatonin administration (10 or 20 mg/kg) significantly inhibited hippocampal CA1 neuronal damage after ischemia compared to corresponding vehicle-treated animals (p<0.05 and p<0.01, respectively). CONCLUSION: Melatonin attenuates the putrescine level after transient global ischemia and may have putative neuroprotective effects against global ischemia induced neuronal damage.

Effect of Melatonin on the Changes of Hippocampal Polyamine Content and Neuronal Damage Following Transient Global Ischemia in Mongolian Gerbil: a Study of the Differences of Pre- and Post-ischemic Treatment / 대한마취과학회지

BACKGROUND: We designed this study to examine whether melatonin has a neuroprotective effect against hippocampal neuronal damage following transient global ischemia in a gerbil. Because polyamine is known to participate in the process of ischemic neuronal damage, we examined the influence of melatonin on the polyamine level as well as histology. In particular, we examined the difference between pre- and post-ischemic treatments of melatonin by using the above mentioned parameters. METHODS: Male Mongolian gerbils (60 - 80 g) were used in this study. Transient global ischemia was induced by occlusion of the bilateral common carotid arteries for 3 min with microclips. Melatonin was administered 1 h before or 1 h after occlusion. The animals were dissected 4 days after the occlusion for polyamine measurement by a high performance liquid chromatography (HPLC) and histological evaluation (hematoxylin and eosin staining). A histological examination was performed by a blinded investigator. RESULTS: The hippocampal putrescine (PU) level increased compared to sham-operated animals and the increase of PU was attenuated by melatonin administration (pre- or post-ischemic treatment). Spermidine (SD) and spermine (SM) levels didn't show significant changes after ischemia. Hippocampal neuronal damage in the CA1 region was markedly observed in vehicle-treated animals compared to sham- operated animals. Both pre- and post-ischemic melatonin administration significantly inhibited hippocampal CA1 neuronal damage compared to corresponding vehicle-treated animals (P < 0.01, respectively). CONCLUSIONS: Melatonin attenuates the polyamine response following transient global ischemia and may have putative neuroprotective effects against global ischemia-induced neuronal damage. There is no difference in neuroprotective effects of melatonin between pre- & post-ischemic treatments.

Effect of Melatonin Administration on the Immobilization Stress-induced Polyamine Responses in Brain and Gastrointestinal Tract / 대한정신약물학회지

OBJECTIVE: The present study was designed to identify the acute and chronic immobilization stress-induced polyamine (putrescine) responses and their modulation by administration of melatonin in brain regions (frontal cortex and hippocampus) and gastrointestinal tract regions (GIT, gastric mucosa and duodenal mucosa). METHOD: For immobilization stress (3 or 14 days), rats (250-300 g, male Sprague-Dawley rats) were placed in restrainers once daily, for 3 h. Melatonin (10 mg/kg, i.p.) was administered once daily immediately after stress. Rats were sacrificed 2 h after the final application of stress for the measurement of putrescine levels. RESULTS: The putrescine levels of frontal cortex, hippocampus, gastric mucosa and duodenal mucosa were significantly increased by acute stress (p<0.05, p<0.05, p<0.0005 and p<0.01, respectively). The putrescine levels of frontal cortex and duodenal mucosa were significantly increased by chronic stress (p<0.05, respectively). In chronic stress group, animals showed adaptation tendency. The changes of putrescine level in gastric and duodenal mucosa induced by chronic stress were significantly lower than those by acute stress (p<0.05, respectively). The putrescine responses to acute stress in frontal cortex, hippocampus, gastric mucosa and duodenal mucosa were attenuated by administration of melatonin (p<0.01, p<0.05, p<0.05 and p<0.05, respectively). The putrescine response to chronic stress in frontal cortex was attenuated by melatonin administration (p<0.05, respectively). CONCLUSION: The results suggested that putrescine may play a role in stress response of brain regions (frontal cortex and hippocampus) and GIT regions (gastric and duodenal mucosa). Melatonin can inhibit the stress-induced putrescine responses in the brain and GIT.

Effect of sedative dose of propofol on neuronal damage after transient forebrain ischemia in Mongolian gerbils

This study investigated whether propofol, an intravenous, non-barbiturate anesthetic, could reduce brain damage following global forebrain ischemia. Transient global ischemia was induced in gerbils by occlusion of bilateral carotid arteries for 3 min. Propofol (50 mg/kg) was administered intraperitoneally 30 min before, immediately after, and at 1 h, 2 h, 6 h after occlusion. Thereafter, propofol was administered twice daily for three days. Treated animals were processed in parallel with ischemic animals receiving 10% intralipid as a vehicle or with sham-operated controls. In histologic findings, counts of viable neurons were made in the pyramidal cell layer of the hippocampal CA1 area 4 days after ischemia. The number of viable neurons in the pyramidal cell layer of CA1 area was similar in animals treated with a vehicle or a subanesthetic dose of propofol. In terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling (TUNEL) assay, semiquantitative analysis of dark-brown neuronal cells was made in the hippocampal CA1 area. There was no significant difference in the degree of TUNEL staining in the hippocampal CA1 area between vehicle-treated and propofol-treated animals. These results show that subanesthetic dose of propofol does not reduce delayed neuronal cell death following transient global ischemia in Mongolian gerbils.

Effect of lithium on the Polyamine Response in Brain after Stress / 대한정신약물학회지

OBJECTIVE: The present study was designed to identify the stress-induced polyamine (PA) response and its modulation by chronic treatment of lithium in brain (hippocampus) and periphery (liver). METHOD: For immobilization stress, rats (230-250 g, male) were placed in restrainer once daily, for 3h. All biochemical measurements were done 5h after the beginning of immobilization stress application. Stress application was done for 5 days and, after a resting interval of 7 days, rats were subjected to an additional stress. Additional groups were subjected to same stress schedule, but during the 7 day interval, one group received once daily injections of 2.5 mmol/kg lithium chloride subcutaneously, and other received saline. RESULTS: The putrescine (PU) level was increased after each stress episode. After cessation of the intermittent stress period, an additional stress 7 days later led again to an increase in PU level in brain but not in liver. The later increase in PU level was blocked by lithium treatment during the intervening 7 day interval between stressors. CONCLUSION: The results suggest that long-term lithium treatment can inhibit an overreactive PA response in brain. So, maladjustment of a stress induced PA response may be a factor to the affective illness and can be target of lithium.

Vestibular dysfunction in patients with idiopathic parkinson's disease

BACKGROUND AND OBJECTIVES: Qualitative oculomotor abnormalities have been reported in parkinsonian patients for many years, but conflicting results have been obtained. This study was performed to evaluate the correlation between the severity of the disease and the abnormalities of the ocular movements in idiopathic parkinson's disease. METHODS: We gave the vestibular function tests in patients with idiopathic parkinson's disease and normal controls. Eye movement recordings were made with automated electronystagmography and rotation test was performed. A total of 46 patients (mean age : 61.2+/-6.7) and 24 controls (mean age : 60.5+/-4.3) were studied. The severity of the disease was divided into two groups by modified Hoehn & Yahr staging ; H-Y stage 1 and 2 as a mild group and stage 3 and 4 as a severe group. RESULTS: Saccadic latency and accuracy, pursuitic gain and velocity, vestibulo-ocular reflex (VOR) suppression by vision were significantly altered in patients, whereas mean velocity of optokinetic nystagmus (OKN) and VOR gain in darkness were normal. Alteration of saccadic latency and accuracy, pursuitic gain and velocity, VOR suppression by vision were profound in the severe group compared with a mild group and controls, but the above parameters did not differ between a mild group and controls. In a hemiparkinson's group, saccadic latency and accuracy, pursuitic gain, OKN mean velocity and gain was not different between the both sides. CONCLUSION: The results indicate that severe Parkinson's disease damages nigrostriatal or other specific pathways which were involved in the regulation of the saccadic, pursuitic and pursuitic-mediated visual fixation system. In a hemiparkinson's group asymmetric damage of dopaminergic innervation which was involved in the regulation of ocular movements was not found.

A study of subjective symptoms and life styles among long term computer users

BACKGROUND: The effect of Video Display Terminals(VDT) Syndrome is well documented. The purpose of this study is to examine the difference in systemic subjective symptoms between long term users of computers with that of the general population and to help plan to avoid the risk of developing Video Display Terminal Syndrome. METHOD: Data was collected for this study between August 1996 and February 1997. Two groups consisting of seventy(70) long term computer users(Exposed Subjects) and fifty nine(59) non users (Non Exposed Subjects), were selected for the survey. Data was gathered from the exposed subjects through their response to the survey questionnaire posted on the internet requiring detailed responses concerning ten systemic subjective symptoms that were experienced as a result of the long term exposure to VDT. Data was gathered from the non exposed subjects through written responses to the questionnaire. RESULTS: Among the more significant difference was the experience of ocular symptoms among the exposed group. The exposed group experienced in descending order eleven items of ocular symptoms. Congestion, strain, decreased visual acuity, ocular pain, and dryness. Among seven items of lifestyle, the exposed group characteristically exercised less(P<0.05) and did more home activity (P<0.05), characteristically lead healthier life than the non exposed group. Participation in exercise differed most among the groups. The exposed group participating in moderate exercise scored 517+/-551.6 compared to the non exposed group which exercised very vigorously(p<0.05). In comparison of subjective symptom and life styles per daily exposure time(over 8,10,16 hours daily) there was significant difference between 8 and 10hour exposers only in the stress item(P<0.05). In the exposure group there were less cardiovascular symptoms(P<0.05) due to more art activity(P<0.05), more cardiovascular symptoms and less sleep activity(P<0.001) and more ocular symptoms(P<0.05) due to higher levels of stress. CONCLUSIONS: By exercising, exposers can decrease the respiratory symptoms, and by seeking methods that enable efficient management of work time, the subjects can benefit from the reduced work time, and by seeking methods so that one receive less stress and can resolve them they can reduce their ocular symptoms, sleep problems, cardiovascular symptoms. And in their spare time, the subjects can be recommended to involve in art activity for each person, through PC indirectly. Designing the development of cyber gallery, museum, literature room, concert can reduce the oecur-rence rate of cardiovascular symptoms.