Kyu-Yong Lee

The effect of epigallocatechin gallate on suppressing disease progression of ALS model mice

Epigallocatechin gallate (EGCG) is a constituent of green tea, and increasing evidence suggests that EGCG has neuroprotective effects on oxidative stress-injured neuronal cells, especially motoneurons. Although the neuroprotective effects of EGCG have been demonstrated in Parkinsons and Alzheimers diseases and ischemic stroke models, there has been no report on the effect of EGCG on an in vivo model of amyotrophic lateral sclerosis (ALS). This study was undertaken to evaluate the effect of EGCG on ALS model mice with the human G93A mutated Cu/Zn-superoxide dismutase (SOD1) gene. We treated each group of 11 ALS model mice with EGCG (1.5, 2.9, and 5.8 microg/g body weight), dissolved in 0.5 ml of 0.9% sterile NaCl, and one group of 11 with 0.5 ml of 0.9% sterile NaCl (control group) intraorally every day after 60 days of age (presymptomatic treatment). The treatment of more than 2.9 microg EGCG/g body weight significantly prolonged the symptom onset and life span, preserved more survival signals, and attenuated death signals. These data suggest that EGCG could be a potential therapeutic candidate for ALS as a disease-modifying agent.

Clinical associations of anti-endothelial cell antibodies in patients with systemic lupus erythematosus

Abstract The aim of this study was to define the clinical associations of anti-endothelial cell antibody (AECA) in systemic lupus erythematosus (SLE) patients by measuring serum AECA titers to correlate with the disease activity and clinical manifestations. Forty-one SLE patients and 27 controls were studied. Serum samples were collected at the time of patient presentation with disease exacerbation and 4 weeks after the start of treatment. The disease activity was evaluated by the SLE Disease Activity Index (SLEDAI). AECA was detected by enzyme-linked immunosorbent assay (ELISA) methods with the surface antigen of the immortalized human microvascular endothelial cell line (HMEC-1). The mean immunoglobulin (Ig)G-AECA and IgM-AECA optical densities (ODs) were significantly higher in patients with SLE compared with controls [mean ± standard deviation (SD), 0.32 ± 0.15 vs 0.18 ± 0.16 and 0.29 ± 0.14 vs 0.21 ± 0.09, respectively]. There was a positive correlation between IgG-AECA and the SLEDAI scores. The positivity rate of AECA in the groups with digital vasculitis, neuropsychiatric lupus, and anti-cardiolipin antibody was significant. In conclusion, AECA may be involved in the pathogenesis of SLE and was correlated with the disease activity. It was also associated with clinical manifestations such as digital vasculitis, neuropsychiatric lupus, and anti-cardiolipin antibody positivity.

Deafferentation–disconnection neglect induced by posterior cerebral artery infarction

Objective: To investigate patients with posterior cerebral artery (PCA) infarctions to learn whether hemispatial neglect is more frequent and severe after right than left PCA infarction; whether visual field defects (VFDs) influence the presence or severity of hemispatial neglect; and the anatomic loci of lesions that are associated with hemispatial neglect. Methods: The authors recruited 45 patients with PCA infarction that involved only the occipital lobe or the occipital lobe plus other areas served by the PCA. All subjects received seven neglect tests within 2 months after onset. Results: Overall, the frequency of hemispatial neglect was 42.2%. The frequency did not significantly differ between the right (48.0%) and left (35.0%) PCA groups, but the severity of hemispatial neglect was significantly greater in the right group. VFD alone did not influence the frequency or severity of neglect after controlling other variables. Isolated occipital lesions were rarely associated with hemispatial neglect, and it was only the occipital plus splenial lesion that significantly influenced the frequency and severity of neglect. Conclusions: This study suggests that after excluding such confounding factors as aphasia or hemiplegia, neglect frequency does not differ between the right and left posterior cerebral artery (PCA) groups, but the severity of neglect is greater after right PCA infarctions; even in the acute stage of PCA infarction; visual field defect from an isolated occipital lesion does not cause hemispatial neglect; and the injury to both the occipital lobe and the splenium of the corpus callosum is important for producing hemispatial neglect with PCA infarction.

Prevalence of multiple sclerosis in Korea

Objective: The aim of this study was to estimate the prevalence of multiple sclerosis (MS) in Korea through a nationwide survey. Methods: We estimated the prevalence of MS in Korea using several sources collected between 2000 and 2005: verified cases from 38 major referral hospitals across the nation, the National Health Insurance (NHI) payment request data from NHI Corporation of Korea, and the national mortality dataset from Statistics Korea. We established a network of neurologists from 38 major referral hospitals and performed a nationwide hospital survey for MS cases. The diagnoses of MS were validated according to the McDonald criteria. The diagnostic validity of each hospital was evaluated from hospital survey data to reduce the uncertainty of NHI data and was applied to estimate the prevalence using novel statistical methods. Results: The estimated numbers of MS cases in Korea through 2 different statistical methods which adjust NHI data by the diagnostic validity of each hospital were very similar: 1,681 (95% confidence interval [CI] 1,490–1,902) by the stratification method and 1,640 (95% CI 1,402–1,789) by the linear regression method. The crude MS prevalence was 3.5–3.6 cases per 100,000 individuals. The estimated female-to-male ratio was 1.26. Conclusion: This study is the first nationwide survey for the prevalence of MS in Korea utilizing a national database in complementary way. We found an increase in the prevalence of MS that is consistent with reports from neighboring Asian countries.

Coenzyme Q10 protects against amyloid beta-induced neuronal cell death by inhibiting oxidative stress and activating the P13K pathway

Oxidative stress plays critical roles in the pathogenic mechanisms of several neurodegenerative disorders including Alzheimers disease (AD), thus much research effort has focused on antioxidants as potential treatment agents for AD. Coenzyme Q10 (CoQ10) is known to have powerful antioxidant effects. We investigated the neuroprotective effects of CoQ10 against Amyloid beta(25-35) (Aβ(25-35))-induced neurotoxicity in rat cortical neurons. To evaluate the neuroprotective effects of CoQ10 on Aβ(25-35)-injured neurons, primary cultured cortical neurons were treated with several concentrations of CoQ10 and/or Aβ(25-35) for 48h. CoQ10 protected neuronal cells against Aβ(25-35)-induced neurotoxicity in a concentration-dependent manner. These neuroprotective effects of CoQ10 were blocked by LY294002 (10μM), a phosphatidylinositol 3-kinase (PI3K) inhibitor. Aβ(25-35) concentration-dependent increased free radical levels in rat cortical neurons, while combined treatment with CoQ10 reduced these free radical levels in a dose-dependent manner. Meanwhile, CoQ10 treatment of Aβ(25-35)-injured primary cultured cortical neurons increased the expression levels of p85aPI3K, phosphorylated Akt, phosphorylated glycogen synthase kinase-3β, and heat shock transcription factor, which are proteins related to neuronal cell survival, and decreased the levels of cytosolic cytochrome c and cleaved caspase-3, which are associated with neuronal cell death. Together, these results suggest that the neuroprotective effects of CoQ10 on Aβ(25-35) neurotoxicity are mediated by inhibition of oxidative stress together with activation of the PI3-K/Akt pathway.

Hyperventilation-induced limb shaking TIA in Moyamoya disease

The authors present a case of hyperventilation-induced left upper limb shaking from an underlying Moyamoya disease. Video EEG monitoring and SPECT study were performed. Leptomeningeal collateral circulation was investigated by conventional angiography and by SPECT study with acetazolamide. Limb shaking in Moyamoya disease may result from a transient hypoperfusion of the contralateral frontoparietal cortex rather than basal ganglia.

The Role of Matrix Metalloproteinase 9 in Early Neurological Worsening of Acute Lacunar Infarction

The involvement of matrix metalloproteinases (MMPs) in ischemic-stroke-induced inflammatory response has recently been suggested; however, the relationship between MMPs and stroke progression has not been evaluated. We investigated the role of MMPs in neurological worsening of acute lacunar infarction. Forty-nine consecutive patients with an acute lacunar infarction (as defined by clinical and MRI criteria within 48 h after stroke onset) were evaluated. Clinical, biochemical, rheological, inflammatory and other parameters were compared between progressive and nonprogressive groups. Among the variables, only inflammatory parameters, including MMP-9 and erythrocyte sedimentation rate, were associated with neurological worsening of acute lacunar infarction (p < 0.05). These results suggest that the inflammatory process could play an important role in early neurological worsening of acute lacunar infarction.

Cilnidipine mediates a neuroprotective effect by scavenging free radicals and activating the phosphatidylinositol 3-kinase pathway.

We investigated the neuroprotective effect and mechanisms of action of cilnidipine, a long‐acting, second‐generation 1,4‐dihydropyridine inhibitor of L‐ and N‐type calcium channels, in PC12 cells that were neuronally differentiated by treatment with nerve growth factor (nPC12 cells). To evaluate the effect of cilnidipine on viability, nPC12 cells were treated with several concentrations of this drug before performing viability assays. Free radical levels and intracellular signaling proteins were measured with the fluorescent probe, 2′,7′‐dichlorodihydrofluorescein diacetate and western blotting, respectively. Cell viability was not affected by low concentrations of cilnidipine up to 150 μM, but it was slightly decreased at 200 μM cilnidipine. Following H2O2 exposure, the viability of nPC12 cells decreased significantly; however, treatment with cilnidipine increased the viability of H2O2‐injured nPC12 cells in a concentration‐dependent manner. Treatment with H2O2 resulted in a concentration‐dependent increase in free radical levels in nPC12 cells, and cilnidipine treatment reduced free radical levels in H2O2‐injured nPC12 cells in a dose‐dependent manner. Cilnidipine treatment increased the expression of p85aPI3K (phosphatidylinositol 3‐kinase) phosphorylated Akt, phosphorylated glycogen synthase kinase‐3 (pGSK‐3β), and heat shock transcription factor (HSTF‐1) which are proteins related to neuronal cell survival, and decreased levels of cytosolic cytochrome c, activated caspase 3, and cleaved poly (ADP‐ribose) polymerase (PARP), which are associated with neuronal cell death, in H2O2‐injured nPC12 cells. These results indicate that cilnidipine mediates its neuroprotective effects by reducing oxidative stress, enhancing survival signals (e.g., PI3K, phosphorylated Akt, pGSK‐3β, and HSTF‐1), and inhibiting death signals from cytochrome c release, caspase 3 activation, and PARP cleavage.

Coenzyme Q10 restores amyloid beta-inhibited proliferation of neural stem cells by activating the PI3K pathway.

Neurogenesis in the adult brain is important for memory and learning, and the alterations in neural stem cells (NSCs) may be an important part of Alzheimers disease pathogenesis. The phosphatidylinositol 3-kinase (PI3K) pathway has been suggested to play an important role in neuronal cell survival and is highly involved in adult neurogenesis. Recently, coenzyme Q10 (CoQ10) was found to affect the PI3K pathway. We investigated whether CoQ10 could restore amyloid β (Aβ)25-35 oligomer-inhibited proliferation of NSCs by focusing on the PI3K pathway. To evaluate the effects of CoQ10 on Aβ25-35 oligomer-inhibited proliferation of NSCs, NSCs were treated with several concentrations of CoQ10 and/or Aβ25-35 oligomers. BrdU labeling, Colony Formation Assays, and immunoreactivity of Ki-67, a marker of proliferative activity, showed that NSC proliferation decreased with Aβ25-35 oligomer treatment, but combined treatment with CoQ10 restored it. Western blotting showed that CoQ10 treatment increased the expression levels of p85α PI3K, phosphorylated Akt (Ser473), phosphorylated glycogen synthase kinase-3β (Ser9), and heat shock transcription factor, which are proteins related to the PI3K pathway in Aβ25-35 oligomers-treated NSCs. To confirm a direct role for the PI3K pathway in CoQ10-induced restoration of proliferation of NSCs inhibited by Aβ25-35 oligomers, NSCs were pretreated with a PI3K inhibitor, LY294002; the effects of CoQ10 on the proliferation of NSCs inhibited by Aβ25-35 oligomers were almost completely blocked. Together, these results suggest that CoQ10 restores Aβ25-35 oligomer-inhibited proliferation of NSCs by activating the PI3K pathway.

Branch occlusive disease Clinical and magnetic resonance angiography findings

Background: We evaluated the clinicoradiologic characteristics of patients with branch occlusive disease (BOD)–type intracranial atherosclerotic stroke (ICAS) compared with those of patients with non-BOD–type ICAS or with small artery disease (SAD). Methods: We analyzed 201 consecutive patients with acute infarcts within the middle cerebral artery (MCA) distribution but no demonstrable carotid or cardiac embolism sources. According to the diffusion-weighted imaging (DWI) distribution and the presence of ipsilateral MCA stenosis, of any degree, on magnetic resonance angiography (3-T MRI), we divided patients into 3 groups: 1) BOD: subcortical infarcts with MCA stenosis (n = 46); 2) non-BOD: infarcts beyond the subcortical area with MCA stenosis (n = 52); and 3) SAD (n = 103). We compared risk factors, degree of stenoses and distribution, and radiologic features of microangiopathy (leukoaraiosis and cerebral microbleeds) among the groups. Results: Risk factor profiles were similar among the groups, except that hypertension and current smoking were more prevalent in the non-BOD than in the BOD group (p = 0.032 and 0.045). The relevant MCA had more severe and focal stenosis in the non-BOD than in the BOD group (stenosis of ≥70%; 76.9% vs 28.3%; p < 0.001), but the degree of nonrelevant stenosis was similar across the groups. Although clinical features, DWI lesion patterns, and microangiopathy findings were similar between the BOD and SAD groups, nonrelevant stenosis was more prevalent in the BOD than in the SAD group (p < 0.01). Conclusions: BOD is prevalent (47% of ICAS) and shares common characteristics with non-BOD–type ICAS, although its clinicoradiologic features may resemble those of SAD. The morphologic characteristics of stenosis and risk factors may associate with a stroke phenotype in patients with ICAS.