Biomedical subjects

Keun-Hwa Jung

Publications and source records attributed to Keun-Hwa Jung.

At least 19 recordsLinked to original sources

PubMed2025

Prediction of personalized antiseizure medications response based on clinical signatures in epilepsy.

Despite the increasing number of available antiseizure medications (ASMs), optimal medical therapy is still a process of trial and error. We aimed to predict the responsiveness of various ASMs based on initial tests using artificial intelligence. The study consisted of 2586 patients fulfilling the following criteria: (1) first visit to the epileptologists from 2008 to 2017, (2) a diagnosis of epilepsy, and 3) ≥ three years of follow-up duration. The clinical characteristics, ASM history, seizure frequency, laboratory, EEG, and MRI results, were collected. Machine algorithms were utilized to predict the responsiveness of specific regimens. Valproate showed the highest area under curve (AUC), 0.636. The AUCs of levetiracetam, oxcarbazepine, and lamotrigine were 0.614, 0.633, and 0.674. The AUCs of common dual regimens were 0.543 for levetiracetam + oxcarbazepine, 0.454 for levetiracetam + valproate, and 0.583 for levetiracetam + lamotrigine. Levetiracetam + carbamazepine showed the highest AUC, 0.686. In Shapley Additive exPlanations analysis, seizure type significantly impacted prediction performance for valproate responsiveness, and onset age and disease duration for lamotrigine. The prediction performances for the response based on initial data differ according to ASMs. An enormous dataset from a multicenter would improve the prediction power of ASM responsiveness in the future.

Humans↗

PubMed2006

Pharmacological induction of heat shock protein exerts neuroprotective effects in experimental intracerebral hemorrhage.

Heat shock proteins (HSPs) are reported to reduce inflammation and apoptosis in a variety of brain insults. Geranylgeranylacetone (GGA), developed as an antiulcer in Japan, has been known to induce HSP70 and to exert cytoprotective effects. In this study, we investigated whether GGA, as a specific HSP inducer, exerts therapeutic effects in experimentally induced intracerebral hemorrhage (ICH). ICH was induced with male Sprague-Dawley rats via the collagenase infusion. GGA (800 mg/kg) was administered via oral tube according to various schedules of treatment. The treatment with GGA, beginning before the induction of ICH and continuing until day 3, showed the reduction of brain water content and the increased level of HSP70 protein, as compared to the treatment with vehicle, although GGA started after the induction of ICH or administered as a single dose before ICH failed to up-regulate HSP70 and to reduce brain edema. The rats treated with GGA exhibited better functional recovery than those treated with vehicle. In the pre- and post- treatment group, inflammatory cells and cell death in the perihematomal regions were found to have been decreased. The treatment of GGA inhibited the mRNA expression of MMP-9, uPA, IL-6 and MIP-1, with concomitant increment of eNOS and phosphorylated STAT3 and Akt after ICH. We demonstrated that GGA induced a reduction in the brain edema along with marked inhibitory effects on inflammation and cell death after ICH.

Analysis of Variance↗

PubMed2006

Combined neuroprotective effects of celecoxib and memantine in experimental intracerebral hemorrhage.

Memantine, a N-methyl-D-aspartate (NMDA) receptor antagonist, inhibits hematoma expansion and celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, reduces perihematomal inflammation in intracerebral hemorrhage. We examined whether the combination treatment has additive effects in experimental intracerebral hemorrhage (ICH). ICH was induced using stereotaxic infusion of collagenase into brains of adult rats. After the induction of ICH, rats were treated with intraperitoneal injection of memantine (20 mg/kg), celecoxib (20 mg/kg) or both agents. Only vehicles were administrated in rats of the control group. Results showed that the combination treatment of memantine and celecoxib reduced both hematoma volume and brain edema. Combination treatment also induced the better functional recovery with further attenuation of cerebral inflammation and apoptosis compared to the control group. When compared to the single agent groups, the combination treatment showed better effects in neuroprotection and anti-inflammation. These results suggest the feasible combined application of memantine and celecoxib in ICH treatment.

Animals↗

PubMed2006

Pharmacological Induction of Ischemic Tolerance by Glutamate Transporter-1 (EAAT2) Upregulation.

BACKGROUND AND PURPOSE: Astrocytic glutamate transporter protein, GLT-1 (EAAT2), recovers extracellular glutamate and ensures that neurons are protected from excess stimulation. Recently, beta-lactam antibiotics, like ceftriaxone (CTX), were reported to induce the upregulation of GLT-1. Here, we investigated ischemic tolerance induction by CTX in an experimental model of focal cerebral ischemia. METHODS: CTX (200 mg/kg per day, IP) was administered for 5 consecutive days before transient focal ischemia, which was induced by intraluminal thread occlusion of the middle cerebral artery for 90 minutes or permanently. RESULTS: Repeated CTX injections enhanced GLT-1 mRNA and protein expressions after 3 and 5 days of treatment, respectively. CTX-pretreated animals showed a reduction in infarct volume by 58% (reperfusion) and 39% (permanent), compared with the vehicle-pretreated animals at 24 hours postischemia (P<0.01). Lower doses of CTX (20 mg/kg per day and 100 mg/kg per day) reduced infarct volumes to a lesser degree. The injection of GLT-1 inhibitor (dihydrokainate) at 30 minutes before ischemia ameliorated the effect of CTX pretreatment. However, CTX administration at 30 minutes after ischemia produced no significant reduction in infarct volume. CTX reduced the levels of proinflammatory cytokines (tumor necrosis factor-alpha, FasL), matrix metalloproteinase (MMP)-9, and activated caspase-9 (P<0.01). In addition, CTX-pretreated animals showed better functional recovery at day 1 to week 5 after ischemia (P<0.05). CONCLUSIONS: This study presents evidence that CTX induces ischemic tolerance in focal cerebral ischemia and that this is mediated by GLT-1 upregulation.

Animals↗

PubMed2006

Early intravenous infusion of sodium nitrite protects brain against in vivo ischemia-reperfusion injury.

BACKGROUND AND PURPOSE: The rate of nitric oxide (NO) generation from nitrite is linearly dependent on reductions in oxygen and pH levels. Recently, nitrite-derived NO has been reported to exert a profound protection against liver and heart ischemia-reperfusion injury. In this study, we hypothesized that nitrite would be reduced to NO in the ischemic brain and exert NO-dependent neuroprotective effects. METHODS: Cerebral ischemia-reperfusion injury was induced by intraluminal thread occlusion of middle cerebral artery in the adult male rats. Solutions of sodium nitrite were infused intravenously at the time of reperfusion. Sodium nitrate and carboxy-PTIO (30 minutes before ischemic surgery), a direct NO scavenger, were infused for comparisons. RESULTS: Nitrite reduced infarction volume and enhanced local cerebral blood flow and functional recovery. The effects were observed at concentrations of 48 nmol and 480 nmol, but not at 4800 nmol nitrite and 480 nmol nitrate. The neuroprotective effects of nitrite were inhibited completely by the carboxy-PTIO. The 480 nmol nitrite attenuated dihydroethidium activity, 3-nitrotyrosine formation, and lipid peroxidation in the ischemic brain. CONCLUSIONS: Nitrite exerted profound neuroprotective effects with antioxidant properties in the ischemic brains. These results suggest that nitrite, as a biological storage reserve of NO, may be a novel therapeutic agent in the setting of acute stroke.

Animals↗

PubMed2006

Memantine reduces striatal cell death with decreasing calpain level in 3-nitropropionic model of Huntington's disease.

Huntington's disease has an increase in the activated calpain, which is enhanced by the NMDA receptor activation. We investigated the neuroprotective effect of memantine in 3-nitropropionic acid (3NP)-induced striatal degeneration model. Either memantine (20 mg/kg/day) or PBS was intraperitoneally administered for five days with 3NP continuous infusion. In the memantine-treated group, the striatal lesion volume, the number of TUNEL+ cells, and Fluoro-Jade C+ degenerating neurons were all decreased. Memantine increased Bcl-xl and decreased Bax level. Memantine also exerted an inhibitory effect on the micro-calpain level and decreased the huntingtin proteolytic fragments. Those rats treated with memantine showed less degree of weight loss at 5 days. Subsequently, memantine was found to have neuroprotective effects and save striatal cells with decreasing calpain levels in the 3NP model of Huntington's disease.

Animals↗

PubMed2006

Cyclooxygenase-2 inhibitor, celecoxib, inhibits the altered hippocampal neurogenesis with attenuation of spontaneous recurrent seizures following pilocarpine-induced status epilepticus.

Recent evidences suggest key roles of abnormal neurogenesis and astrogliosis in the pathogenesis of epilepsy. Alterations in the microenvironment of the stem cell, such as microglial activation and cyclooxygenase-2 induction may cause ectopic neurogenesis or astrogliosis. Here, we examined if inflammatory blockade with celecoxib, a selective cyclooxygenase-2 inhibitor, could modulate the altered microenvironment in the epileptic rat brain. Celecoxib attenuated the likelihood of developing spontaneous recurrent seizures after pilocarpine-induced prolonged seizure. During the latent period, celecoxib prevented neuronal death and microglia activation in the hilus and CA1 and inhibited the generation of ectopic granule cells in the hilus and new glia in CA1. The direct inhibition of precursor cells by celecoxib was further demonstrated in human neural stem cells culture. These findings raise the evidence of COX-2 induction to act importantly on epileptogenesis and suggest a potential therapeutic role for COX-2 inhibitors in chronic epilepsy.

Animals↗

PubMed2006

Quantification of human neural stem cell engraftments in rat brains using ERV-3 real-time PCR.

Few sensitive and reliable methods have been available for quantifying the number of transplanted human neural stem cells (hNSC) in the animal brain. To develop an accurate method for quantifying the number of hNSC incorporated in rat brain, we performed real-time PCR on hNSC-transplanted rat brains using a target sequence for ERV-3, which is an endogenous retrovirus present with a known copy number in all human cells, but not present in rodent cells. A standard curve was developed for known amount of different mixes of hNSC and rat fibroblasts, and test samples were prepared by manually incorporating variable, predefined numbers of hNSCs into rat brains. A cerebral rat hemisphere injected with 10(7) hNSC revealed 1.125% chimerism. Moreover, a linear correlation was found between hNSC numbers injected and their concentrations in the rat brain. In conclusion, the developed quantitative ERV-3 assay enables a simple, fast, and reproducible detection and quantitation of hNSC numbers in the rat brain.

Animals↗

PubMed2006

Peroxisome proliferator-activated receptor-gamma-agonist, rosiglitazone, promotes angiogenesis after focal cerebral ischemia.

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist, rosiglitazone, not only improves insulin resistance in patients with type II diabetes but also exerts a broad spectrum protective effects in variable animal models of neurologic or cardiovascular diseases. We studied the effect of rosiglitazone on angiogenesis and neurological recovery after focal cerebral ischemia. Rosiglitazone (3 mg/kg or 0.3 mg/kg, p.o.) was administered for 7 days prior to and 3 days after the induction of focal ischemia (total 10 days) in adult rats. The rosiglitazone-treated group showed the enhanced neurologic improvement, the reduced infarction volume compared to the ischemia-vehicle group with dose dependency, and the reduced hemispheric atrophy. Rosiglitazone treatment reduced TUNEL(+)/activated caspase-3(+) cells, MPO(+)/Ox-42(+) inflammatory cell infiltrations, caspase-3 activity, and Bax(+) cells, as compared to the ischemia-vehicle group. The vascular surface area, the vascular branch points, the vascular length, and the number of BrdU(+) endothelial cells were significantly increased in the rosiglitazone group compared with the ischemia-vehicle group. Rosiglitazone increased eNOS expression around the ischemic margin with downregulation of FasL. Here, we show that rosiglitazone treatment enhances angiogenesis and functional recovery with dose-dependent induction of ischemic tolerance.

Animals↗

PubMed2006

Granulocyte colony-stimulating factor stimulates neurogenesis via vascular endothelial growth factor with STAT activation.

The adult brain harbors multipotent stem cells, which reside in specialized niches that support self-renewal. Granulocyte colony-stimulating factor (G-CSF) induces bone marrow stem cells proliferation and mobilization from their niche, and activates endothelial cell proliferation, which might help to establish a vascular niche for neural stem cells (NSCs). Here, we show that G-CSF induced receptor-mediated proliferation and differentiation of neural precursors in human NSCs cultures and in adult rat brain in vivo. In human NSCs cultures, G-CSF activated STAT3 and 5, and increased VEGF and its receptor, VEGFR2 (Flk-1) expression, and VEGFR2 tyrosine kinase inhibitor blocked the neurogenesis stimulated by G-CSF. G-CSF also activated endothelial cell proliferation in adult rat brain in vivo. Our results indicate that G-CSF stimulates neurogenesis through reciprocal interaction with VEGF and STAT activation.

Brain↗

PubMed2006

Memantine reduces hematoma expansion in experimental intracerebral hemorrhage, resulting in functional improvement.

Glutamate is accumulated in abundance during the early period of experimental hematoma, and the activation of N-methyl-D-aspartate (NMDA) receptors by glutamate can result in an influx of calcium and neuronal death in cases of intracerebral hemorrhage (ICH). Memantine, which is known to be a moderate-affinity, uncompetitive, NMDA receptor antagonist, was investigated with regard to its ability to block the glutamate overstimulation and tissue plasminogen activator (tPA)/urokinase plasminogen activator (uPA)/matrix metalloproteinase (MMP)-9 modulation in experimental ICH. Intracerebral hemorrhage was induced via the infusion of collagenase into the left basal ganglia of adult rats. Either memantine (20 mg/kg/day) or PBS was intraperitoneally administered 30 min after the induction of ICH, and, at daily intervals afterwards, for either 3 or 14 days. Hemorrhage volume decreased by 47% in the memantine group, as compared with the ICH-only group. In the memantine group, the numbers of TUNEL+, myeloperoxidase (MPO)+, and OX42+ cells decreased in the periphery of the hematoma. Memantine resulted in an upregulation of bcl-2 expression and an inhibition of caspase-3 activation. Memantine also exerted a profound inhibitory effect on the upregulation of tPA/uPA mRNA, and finally decreased the MMP-9 level in the hemorrhagic brain. In modified limb-placing test, the memantine-treated rats exhibited lower scores initially, and recovered more quickly and thoroughly throughout the 35 days of the study. Here, we show that memantine causes a reduction of hematoma expansion, coupled with an inhibitory effect on the tPA/uPA and MMP-9 level. Subsequently, memantine was found to reduce inflammatory infiltration and apoptosis, and was also determined to induce functional recovery after ICH.

Animals↗

PubMed2006

Erythropoietin reduces perihematomal inflammation and cell death with eNOS and STAT3 activations in experimental intracerebral hemorrhage.

Erythropoietin (EPO), a pleiotropic cytokine involved in erythropoiesis, is tissue-protective in ischemic, traumatic, toxic and inflammatory injuries. In this study, we investigated the effect of EPO in experimental intracerebral hemorrhage (ICH). Two hours after inducing ICH via the stereotaxic infusion of collagenase, recombinant human EPO (500 or 5000 IU/kg, ICH + EPO group) or PBS (ICH + vehicle group) was administered intraperitoneally, then once daily afterwards for 1 or 3 days. ICH + EPO showed the better functional recovery in both rotarod and modified limb placing tests. The brain water content was decreased in ICH + EPO dose-dependently, as compared with ICH + vehicle. The effect of EPO on the brain water content was inhibited by N(omega)-Nitro-L-arginine methyl ester hydrochloride (L-NAME, 10 mg/kg). Mean hemorrhage volume was also decreased in ICH + EPO. EPO reduced the numbers of TUNEL +, myeloperoxidase + or OX-42 + cells in the perihematomal area. In addition, EPO reduced the mRNA level of TNF-alpha, Fas and Fas-L, as well as the activities of caspase-8, 9 and 3. EPO treatment showed up-regulations of endothelial nitric oxide synthase (eNOS) and p-eNOS, pAkt, pSTAT3 and pERK levels. These data suggests that EPO treatment in ICH induces better functional recovery with reducing perihematomal inflammation and apoptosis, coupled with activations of eNOS, STAT3 and ERK.

Animals↗

PubMed2005

G-CSF protects human cerebral hybrid neurons against in vitro ischemia.

Granulocyte colony-stimulating factor (G-CSF) protects neurons against experimental focal cerebral ischemia. However, its neuroprotective effect on human brain is unknown. We sought to determine whether G-CSF can protect the human cerebral neurons in vitro. Human cerebral-neuroblastoma hybrid cell line (A1) was exposed to oxygen and glucose deprivation with or without G-CSF. G-CSF promoted cell survival and decreased cytotoxicity effectively at 25 ng/ml. G-CSF reduced early apoptotic (annexin V+/PI-), and late apoptotic or necrotic (annexin V+/PI+) cells, and decreased active caspase-3 immunoreactivity. G-CSF could protect human cerebral neurons following in vitro ischemia.

Blotting, Western↗

PubMed2005

Combined treatment of vascular endothelial growth factor and human neural stem cells in experimental focal cerebral ischemia.

Recent studies have indicated the beneficial effects of vascular endothelial growth factor (VEGF), and transplanted neural stem cells (NSCs) in cerebral ischemia. We investigated the effects of the combined administration of NSCs and VEGF on focal cerebral ischemia in adult rats. Four groups (n = 12, respectively)--group 1 (ischemia-only), group 2 (ischemia + VEGF), group 3 (ischemia + NSCs) and group 4 (ischemia + NSCs + VEGF)--were compared. Human NSCs (HB1.F3), labeled with Lac Z+ or PKH26, were given intravenously 24h after surgery (5 x 10(6) cells). At 48 h after surgery, recombinant human VEGF (50 microg/kg) was infused intravenously (1 microg/(kg min)). Behavioral tests using the modified limb placing and rotarod tests were performed every week following ischemia. Immunohistochemistry for endothelial barrier antigen (EBA), VEGF and Nissl staining were performed at day 35 after ischemia. Group 4 showed better behavioral recovery at 7, 14 and 28 days than group 3 (p = 0.020, 0.005 and 0.043, respectively). These functional recoveries were correlated with enhanced EBA immunoreactivities at day 35 after ischemia, especially in the ipsilesional striatum. Group 4 showed lesser degree of brain atrophy in cortex and striatum, when compared with other groups. The distribution of VEGF was not co-localized with NSCs. Our results suggest that VEGF may act synergistically on NSC-transplanted, ischemic brain via a pro-angiogenic effect.

Animals↗

PubMed2005

Granulocyte colony-stimulating factor enhances angiogenesis after focal cerebral ischemia.

Granulocyte colony-stimulating factor (G-CSF) is a neuroprotective agent and activates endothelial proliferation and bone marrow stem cell mobilization. We studied the effect of G-CSF on angiogenesis and neurological recovery after focal cerebral ischemia. After the induction of transient focal ischemia in rats, G-CSF (50 micro/day, i.p.) or PBS was administered for 3 days. We evaluated the functional recovery, infarct volume, inflammatory infiltration, blood-brain barrier (BBB) disruption, hemispheric atrophy, protein expressions of endothelial nitric oxide synthase (eNOS) and angiopoietins, and the therapeutic time window of G-CSF administration. We then analyzed endothelial cell proliferation, the vascular surface area, the number of branch points, and the vascular length. G-CSF treatment improved behavioral recovery and reduced the infarct volume, the inflammatory infiltration, the BBB disruption, and the hemispheric atrophy. G-CSF injection, starting at 2 h, 1 day, or 4 days after ischemia, resulted in a better functional recovery and a greater reduction in hemispheric atrophy than injection starting at day 7. The vascular surface area, the vascular branch points, the vascular length, the number of BrdU(+) endothelial cells, and eNOS/angiopoietin-2 expression were significantly increased in the G-CSF group compared with the ischemia-only group. G-CSF injection starting at 1 day induced larger endothelial proliferation compared with injection starting at 7 days. In this study, we provide evidences that G-CSF enhances the angiogenesis and reduces the ischemic damage, which promotes the long-term functional recovery.

Angiopoietin-1↗

PubMed2005

Granulocyte colony-stimulating factor induces sensorimotor recovery in intracerebral hemorrhage.

Granulocyte colony-stimulating factor (G-CSF) has been used in the treatment of neutropenia in hematologic disorders. The neuroprotective and anti-inflammatory effects of G-CSF were reported in various neurological disease models. In this study, we examined whether G-CSF induces functional recovery after intracerebral hemorrhage (ICH). ICH was induced using collagenase injection in adult rats. Either G-CSF (50 microg/kg, i.p.) or saline was given from 2 h after ICH and every 24 h for 3 days. 72 h after ICH induction, the rats were sacrificed for histological analysis and measurement of brain edema. Behavioral tests were performed before and 1, 7, 14, 21, 28, and 35 days after ICH. We also measured the blood-brain barrier (BBB) permeability using Evans blue dye injection method. G-CSF-treated rats recovered better on rotarod and limb placing tests, starting from 14 days throughout 5 weeks after ICH. The brain water content and BBB permeability of G-CSF-treated group decreased in the lesioned hemispheres compared with those of ICH-only group. In G-CSF-treated group, the number of TUNEL+, myeloperoxidase+, and OX42+ cells was smaller than that of ICH-only group in the periphery of hematoma. These findings suggest that G-CSF induces long-term sensorimotor recovery after ICH with reduction of brain edema, inflammation, and perihematomal cell death.

Animals↗

PubMed2005

Wilson disease with an initial manifestation of polyneuropathy.

BACKGROUND: Recognition of Wilson disease (WD) is sometimes difficult because of its diverse manifestations. Peripheral neuropathy is rarely reported in the context of WD. OBJECTIVE: To report an unusual patient with WD whose initial manifestation was peripheral neuropathy. DESIGN: Case report. SETTING: Neurology department in a tertiary referral center. METHOD: Personal observation. RESULT: A 17-year-old man, who was eventually diagnosed with WD, was initially seen with polyneuropathy at least 6 months prior to developing more typical symptoms of WD. Electrophysiological and pathological studies suggested a neuropathy of mixed type. Treatment for WD resulted in clinical and electrophysiological improvement. CONCLUSION: Wilson disease may initially appear as a treatable polyneuropathy.

Adolescent↗

PubMed2004

Human neural stem cell transplantation reduces spontaneous recurrent seizures following pilocarpine-induced status epilepticus in adult rats.

Transplantation of neural stem cells (NSCs) can replace lost neurons and improve the functional deficits. Cell transplantation strategies have been tried in the epileptic disorder, but the effect of exogenous NSCs is unknown. In this study, we attempted to test the anti-epileptogenic effect of NSCs in adult rats with status epilepticus. Experimental status epilepticus was induced by lithium-pilocarpine injection, and beta galactosidase-encoded human NSCs were transplanted intravenously on the next day of status epilepticus. Spontaneous recurrent seizures were monitored with Racine's seizure severity scale. Immunohistochemistry with anti-beta gal, Tuj-1, NeuN, GFAP, CNPase, GluR2, parvalbumin, and GABA were performed and extracellular field excitatory postsynaptic potentials (fEPSP) were recorded. Human NSCs suppressed spontaneous recurrent seizure formation and transplanted NSCs were differentiated into GABA-immunoreactive interneurons in the damaged hippocampus. Amplitude of fEPSP in the hippocampal CA1 was reduced, which was reversed by picrotoxin. These findings suggest that NSCs could be differentiated into inhibitory interneurons and decrease neuronal excitability, which could prevent spontaneous recurrent seizure formation in adult rats with pilocarpine-induced status epilepticus.

Aggression↗