Porphyran Attenuates Neuronal Loss in the Hippocampal CA1 Subregion Induced by Ischemia and Reperfusion in Gerbils by Inhibiting NLRP3 Inflammasome-Mediated Neuroinflammation.

Porphyran, a sulfated polysaccharide found in various species of marine red algae, has been demonstrated to exhibit diverse bioactivities, including anti-inflammatory effects. However, the protective effects of porphyran against cerebral ischemia and reperfusion (IR) injury have not been investigated. The aim of this study was to examine the neuroprotective effects of porphyran against brain IR injury and its underlying mechanisms using a gerbil model of transient forebrain ischemia (IR in the forebrain), which results in pyramidal cell (principal neuron) loss in the cornu ammonis 1 (CA1) subregion of the hippocampus on day 4 after IR. Porphyran (25 and 50 mg/kg) was orally administered daily for one week prior to IR. Pretreatment with 50 mg/kg of porphyran, but not 25 mg/kg, significantly attenuated locomotor hyperactivity and protected pyramidal cells located in the CA1 area from IR injury. The pretreatment with 50 mg/kg of porphyran significantly suppressed the IR-induced activation and proliferation of microglia in the CA1 subregion. Additionally, the pretreatment significantly inhibited the overexpressions of nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing protein-3 (NLRP3) inflammasome complex, and pro-inflammatory cytokines (interleukin 1 beta and interleukin 18) induced by IR in the CA1 subregion. Overall, our findings suggest that porphyran exerts neuroprotective effects against brain IR injury, potentially by reducing the reaction (activation) and proliferation of microglia and reducing NLRP3 inflammasome-mediated neuroinflammation.

Neuroprotective Effects of Aucubin against Cerebral Ischemia and Ischemia Injury through the Inhibition of the TLR4/NF-κB Inflammatory Signaling Pathway in Gerbils.

Aucubin, an iridoid glycoside, possesses beneficial bioactivities in many diseases, but little is known about its neuroprotective effects and mechanisms in brain ischemia and reperfusion (IR) injury. This study evaluated whether aucubin exhibited neuroprotective effects against IR injury in the hippocampal CA1 region through anti-inflammatory activity in gerbils. Aucubin (10 mg/kg) was administered intraperitoneally once a day for one week prior to IR. Neuroprotective effects of aucubin were assessed by neuronal nuclei (NeuN) immunofluorescence and Floro-Jade C (FJC) histofluorescence. Microgliosis and astrogliosis were evaluated using immunohistochemistry with anti-ionized calcium binding adapter protein 1 (Iba1) and glial fibrillary acidic protein (GFAP). Protein levels of proinflammatory cytokines interleukin1 beta (IL1ß) and tumor necrosis factor alpha (TNFα) were assayed using enzyme-linked immunosorbent assay and Western blot. Changes in toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) signaling pathway were assessed by measuring levels of TLR4, inhibitor of NF-κB alpha (IκBα), and NF-κB p65 using Western blot. Aucubin treatment protected pyramidal neurons from IR injury. IR-induced microgliosis and astrogliosis were suppressed by aucubin treatment. IR-induced increases in IL1ß and TNFα levels were significantly alleviated by the treatment. IR-induced upregulation of TLR4 and downregulation of IκBα were significantly prevented by aucubin treatment, and IR-induced nuclear translocation of NF-κB was reversed by aucubin treatment. Briefly, aucubin exhibited neuroprotective effects against brain IR injury, which might be related to the attenuation of neuroinflammation through inhibiting the TLR-4/NF-κB signaling pathway. These results suggest that aucubin pretreatment may be a potential approach for the protection of brain IR injury.

Increased risk of dementia after transient global amnesia: a nationwide population-based, longitudinal follow-up study in South Korea.

INTRODUCTION: The long-term cognitive outcomes after transient global amnesia (TGA) have been contradictory in the literature. Our study aimed to longitudinally investigate the association between TGA and incident dementia using long-term data from a nationwide population-based cohort in South Korea. METHODS: The study population was recruited between 2002 and 2020 using the International Classification of Diseases (tenth revision; ICD-10) codes from the Korean National Health Insurance Service database. The cumulative incidence curve was plotted to compare the incidence of dementia between the TGA (ICD-10 code G45.4; n = 10,276) and non-TGA (n = 27,389) groups, determined using 1:3 propensity score matching. Using Cox proportional hazard regression models, we obtained crude and adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for the incident dementia in patients with TGA compared to non-TGA controls. To examine independent variables determining dementia in the TGA group, logistic regression analysis was performed, and adjusted odds ratios (aORs) and 95% CIs were calculated. RESULTS: The TGA group had a significantly higher cumulative incidence of dementia than the non-TGA group (p <0.001, log-rank test). TGA was significantly associated with incident dementia in the univariate and multivariate Cox models (HR 1.34, 95% CI 1.28-1.39 and aHR 1.40, 95% CI 1.34-1.46, respectively). The adjusted logistic regression for incident dementia in the TGA group showed that age (per 1 year, aOR 1.09, 95% CI 1.09-1.10), female sex (aOR 1.31, 95% CI 1.18-1.45), diabetes (aOR 1.21, 95% CI 1.08-1.35), stroke (aOR 1.30, 95% CI 1.16-1.46), depression (aOR 1.53, 95% CI 1.33-1.76), anxiety (aOR 1.24, 95% CI 1.01-1.39), and rural residence (aOR 1.24, 95% CI 1.10-1.41) were independently associated with incident dementia. CONCLUSION: Our results suggest a longitudinal association of TGA with incident dementia.

Erratum: Correction of Text, Table 1, and Table 3 in the Article "Diagnostic Performance of a Tablet Computer-Based Cognitive Screening Test for Identification of Amnestic Mild Cognitive Impairment".

This corrects the article on p. e131 in vol. 38, PMID: 37128875.

Vertebral artery foraminal segment doppler sonography to detect vertebral and basilar artery stenosis or occlusion.

BACKGROUND AND PURPOSE: The diagnostic value of vertebral artery foraminal segment (V2) ultrasonography remains unclear. This study aimed to estimate the predictive value of V2 Doppler imaging for the detection of vertebrobasilar stenosis or occlusion. METHODS: Three hundred sixty-four vertebral arteries from 182 patients were investigated. Abnormal Doppler spectra were categorized as high-resistance flow (resistive index ≥0.9), low-resistance flow (resistive index ≤0.5), increased flow velocity (peak systolic velocity ≥137.5 cm/second), or no flow signal. On MR angiography, stenosis and occlusion were defined as >50% narrowing and absent flow signals, respectively. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. RESULTS: Sixty of 364 vertebral arteries (16.5%) had V2 Doppler abnormalities, while 89 vertebrobasilar arteries (24.5%) had a stenosis or occlusion. The Doppler abnormalities predicted any stenosis or occlusion in the vertebrobasilar artery with a sensitivity of 56.2% and specificity of 96.4% (PPV, 83.3%; NPV, 87.2%). The hypoplastic vertebral artery (lumen diameter ≤2.7 mm) was more frequently associated with vertebrobasilar stenosis or occlusion, and with abnormal Doppler spectra (mostly high-resistance flow), even when it was nonstenotic, than the normal-diameter vertebral artery (p < .001, chi-square test). CONCLUSIONS: The low sensitivity seems to be due to the high prevalence of non-V2 lesions not detected on V2 Doppler imaging, suggesting the necessity for a more extensive sonographic examination beyond V2. However, PPV and NPV ≥80% may suggest its usefulness in clinical practice.

Association of Hearing Loss With Anatomical and Functional Connectivity in Patients With Mild Cognitive Impairment.

Importance: Hearing loss is the most important modifiable risk factor for cognitive impairment; however, the association of hearing loss with anatomical and functional connectivity is not fully understood. This association may be elucidated by evaluating the findings of newer imaging technologies. Objectives: To evaluate the association of hearing loss with anatomical and functional connectivity in patients with mild cognitive impairment (MCI) by using multimodal imaging technology. Design, Setting, and Participants: This was a prospective cross-sectional study of patients with MCI under the care of a neurology clinic at the Soonchunhyang University Bucheon Hospital (Republic of Korea) from April to September 2021. Data were analyzed from April 1 to June 30, 2022. Main Outcomes and Measures: Pure tone averages (PTA) and word recognition scores were used to measure hearing acuity. Magnetic resonance imaging (MRI) and positron emission tomography scans of the brain were used to assess functional and anatomical connectivity. Results of diffusion MRI, voxel- and surface-based morphometric imaging, and global brain amyloid standardized uptake ratio were analyzed. Neuroimaging parameters of patients with MCI plus hearing loss were compared with those of patients with MCI and no hearing loss. Correlation analyses among neuroimaging parameters, PTA, and word recognition scores were performed. Results: Of 48 patients with MCI, 30 (62.5%) had hearing loss (PTA >25 dB) and 18 (37.5%) did not (PTA ≤25 dB). Median (IQR) age was 73.5 (69.0-78.0) years in the group with hearing loss and 75.0 (65.0-78.0) years in the group with normal hearing; there were 20 (66.7%) and 14 (77.8%) women in each group, respectively. The group with MCI plus hearing loss demonstrated decreased functional connectivity between the bilateral insular and anterior divisions of the cingulate cortex, and decreased fractional anisotropy in the bilateral fornix, corpus callosum forceps major and tapetum, left parahippocampal cingulum, and left superior thalamic radiation. Fractional anisotropy in the corpus callosum forceps major and bilateral parahippocampal cingulum negatively correlated with the severity of hearing loss shown by PTA testing. The 2 groups were not significantly different in global ß-amyloid uptake, gray matter volume, and cortical thickness. Conclusion and Relevance: The findings of this prospective cross-sectional study suggest that alterations in the salience network may contribute to the neural basis of cognitive impairment associated with hearing loss in patients who are on the Alzheimer disease continuum.

Diagnostic Performance of a Tablet Computer-Based Cognitive Screening Test for Identification of Amnestic Mild Cognitive Impairment.

BACKGROUND: Early and appropriate diagnosis of amnestic mild cognitive impairment (aMCI) is clinically important because aMCI is considered the prodromal stage of dementia caused by Alzheimer's disease (AD). aMCI is assessed using the comprehensive neuropsychological (NP) battery, but it is rater-dependent and does not provide quick results. Thus, we investigated the performance of the computerized cognitive screening test (Inbrain Cognitive Screening Test; Inbrain CST) in the diagnosis of aMCI and compared its performance to that of the Korean version of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) test (CERAD-K), a comprehensive and pencil-and-paper NP test. METHODS: A total of 166 participants were included in this cross-sectional study. The participants were recruited as part of a prospective, community-based cohort study for MCI (PREcision medicine platform for mild cognitive impairment on multi-omics, imaging, evidence-based R&BD; PREMIER). All participants were assessed using the CERAD-K and the Inbrain CST. The Inbrain CST comprised seven subtests that assessed the following five cognitive domains: attention, language, visuospatial, memory, and executive functions. Seventy-six participants underwent brain magnetic resonance imaging and [18F]-flutemetamol positron emission tomography (PET). We evaluated the diagnostic performance of the Inbrain CST for the identification of aMCI by comparing the findings with those of CERAD-K. We also determined the characteristics of aMCI patients as defined by the CERAD-K and Inbrain CST. RESULTS: Of the 166 participants, 93 were diagnosed with aMCI, while 73 were cognitively unimpaired. The sensitivity of the Inbrain CST for aMCI diagnosis was 81.7%, and its specificity was 84.9%. Positive and negative predictive values were 87.4% and 78.5%, respectively. The diagnostic accuracy was 83.1%, and the error rate was 16.9%. Demographic and clinical characteristics between individuals with aMCI defined by the Inbrain CST and CERAD-K were not significantly different. The frequency of positive amyloid PET scan, the hippocampal/parahippocampal volumes, and AD signature cortical thickness did not differ between the patients with aMCI defined by CERAD-K and those with aMCI defined by the Inbrain CST. CONCLUSION: The Inbrain CST showed sufficient sensitivity, specificity, and positive and negative predictive values for diagnosing objective memory impairment in aMCI. In addition, aMCI patients identified by CERAD-K and the Inbrain CST showed comparable clinical and neuroimaging characteristics. Therefore, the Inbrain CST can be considered an alternative test to supplement the limitations of existing pencil-and-paper NP tests.

Aucubin Exerts Neuroprotection against Forebrain Ischemia and Reperfusion Injury in Gerbils through Antioxidative and Neurotrophic Effects.

Aucubin is an iridoid glycoside that displays various pharmacological actions including antioxidant activity. However, there are few reports available on the neuroprotective effects of aucubin against ischemic brain injury. Thus, the aim of this study was to investigate whether aucubin protected against damage to hippocampal function induced by forebrain ischemia-reperfusion injury (fIRI) in gerbils, and to examine whether aucubin produced neuroprotection in the hippocampus against fIRI and to explore its mechanisms by histopathology, immunohistochemistry, and Western analysis. Gerbils were given intraperitoneal injections of aucubin at doses of 1, 5, and 10 mg/kg, respectively, once a day for seven days before fIRI. As assessed by the passive avoidance test, short-term memory function following fIRI significantly declined, whereas the decline in short-term memory function due to fIRI was ameliorated by pretreatment with 10 mg/kg, but not 1 or 5 mg/kg, of aucubin. Most of the pyramidal cells (principal cells) of the hippocampus died in the Cornu Ammonis 1 (CA1) area four days after fIRI. Treatment with 10 mg/kg, but not 1 or 5 mg/kg, of aucubin protected the pyramidal cells from IRI. The treatment with 10 mg/kg of aucubin significantly reduced IRI-induced superoxide anion production, oxidative DNA damage, and lipid peroxidation in the CA1 pyramidal cells. In addition, the aucubin treatment significantly increased the expressions of superoxide dismutases (SOD1 and SOD2) in the pyramidal cells before and after fIRI. Furthermore, the aucubin treatment significantly enhanced the protein expression levels of neurotrophic factors, such as brain-derived neurotrophic factor and insulin-like growth factor-I, in the hippocampal CA1 area before and after IRI. Collectively, in this experiment, pretreatment with aucubin protected CA1 pyramidal cells from forebrain IRI by attenuating oxidative stress and increasing neurotrophic factors. Thus, pretreatment with aucubin can be a promising candidate for preventing brain IRI.

Functional and anatomical alterations in bilateral vestibulopathy: A multimodal neuroimaging study and clinical correlation.

Object: To study multimodal neuroimaging study including resting state functional MRI (rs-fMRI), anatomical connectivity and brain morphology in patients with bilateral vestibulopathy (BVP) and relationship with clinical correlation. Methods: Thirteen patients with BVP (7 women; mean age ± SD = 63.5 ± 14.7 years, 22-80 years) and eighteen age and gender-matched controls were compared rs-fMRI and anatomical MRI. Also, we analyzed the relationship between multimodal neuroimaging and Dizziness Handicap Inventory score (DHI), Vestibular Disorders Activities of Daily Living Scale (VDRL), Geriatric Depression Scale (GDS) and Hospital Anxiety and Depression Scale (HADS). Results: Compared with controls, BVP patients showed decreased functional connectivity among the key nodes of the salience network, auditory (including vestibular) network, bilateral posterior parahippocampal gyri, bilateral paracingulate gyri, and right frontoparietal network, and the anatomical connectivity in the right cerebellum, corpus callosum tapetum, and left fornix. BVP patients showed decreased gray matter volume in the bilateral parahippocampal gyri, right precentral gyrus, anterior cingulate gyrus, and right middle temporal gyrus and increased gray matter volume in the right superior frontal gyrus compared with controls. Correlation analyses showed rs-fMRI and clinical variables showed no significant result. DHI correlated negatively with anatomical connectivity in the bilateral frontal parahippocampal cingulum, corpus callosum, right inferior fronto-occipital fasciculus, bilateral fornix, and gray matter volumes in the bilateral middle occipital gyri, right superior occipital gyrus, left angular gyrus, and right cuneus in BVP. VADL correlated negatively with Anatomical connectivity in the corpus callosum, bilateral fornix, bilateral cerebellum, bilateral superior and anterior thalamic radiation, right inferior fronto-occipital fasciculus, bilateral fronto-parietal cingulum, right dentatoruburothalamic tract and gray matter volumes in the right angular gyri, bilateral parahippocampal gyri, right middle temporal gyrus, right cuneus, bilateral inferior occipital gyri, left middle occipital gyrus, right superior frontal gyrus, left fusiform gyrus, bilateral caudate, left cerebellar crus, and bilateral calcarine gyri in BVP. Conclusions: This study identified reductions in the volume of the hippocampus and alterations in functional and anatomical connectivity that concurs with previously established characteristics of BVP. The degree of disability can be inferred from the change in the connectivity and volume between vestibular cortical areas and their network.

Standardized Sanguisorba officinalis L. Extract Inhibits Adipogenesis and Promotes Thermogenesis via Reducing Oxidative Stress.

Obesity produces many health problems, including systemic oxidative stress. This study comprehensively investigated the effects of Sanguisorba officinalis L. extract (SO) as an antioxidant on abnormal lipid accumulation and oxidative stress in 3T3-L1 adipocytes and high-fat diet (HFD)-induced obese mice (n = 48). We evaluated the anti-adipogenic and antioxidant effects of SO on 3T3-L1 by cell viability, Oil red O staining, and NBT assays. The ameliorative effects of SO in HFD-induced C57BL/6J mice were investigated by measuring body weight, serum lipids, adipocyte size, hepatic steatosis, AMPK pathway-related proteins, and thermogenic factors. In addition, the effect of SO on oxidative stress in obese mice was evaluated by the activity of antioxidant enzymes and the production of lipid peroxidation products and ROS production in adipose tissue. We found that SO dose-dependently decreased lipid accumulation and ROS production in 3T3-L1 adipocytes. In C57BL/6J obese mice, SO (above 200 mg/kg) attenuated the HFD-induced gain in body weight and white adipose tissue (WAT) weight without affecting appetite. SO also decreased serum glucose, lipid, and leptin levels and attenuated adipocyte hypertrophy and hepatic steatosis. Furthermore, SO increased the expression of SOD1 and SOD2 in WAT, decreased ROS and lipid peroxides, and activated the AMPK pathway and thermogenic factors. In summary, SO reduces oxidative stress in adipose tissue by increasing antioxidant enzyme activity and improves obesity symptoms through AMPK-pathway-regulated energy metabolism and mitochondrial respiratory thermogenesis.

Therapeutic Treatment with Pycnogenol® Attenuates Ischemic Brain Injury in Gerbils Focusing on Cognitive Impairment, Neuronal Death, BBB Leakage and Neuroinflammation in the Hippocampus.

BACKGROUND: A gerbil model of ischemia and reperfusion (IR) injury in the forebrain has been developed for studies on mechanisms, prevention and therapeutic strategies of IR injury in the forebrain. Pycnogenol® (PYC), a standardized extract of French maritime pine tree (Pinus pinaster Aiton) has been exploited as an additive for dietary supplement. In the present study, we investigated the neuroprotective effects of post-treatment with PYC and its therapeutic mechanisms in gerbils. METHODS: The gerbils were given sham and IR operation and intraperitoneally injected with vehicle and Pycnogenol® (25, 50 and 100 mg/kg, respectively) immediately, at 24 hours and 48 hours after sham and IR operation. Through 8-arm radial maze test and passive avoidance test, each spatial memory and short-term memory function was assessed. To examine the neuroprotection of Pycnogenol®, we conducted cresyl violet staining, immunohistochemistry for neuronal nuclei, and Fluoro-Jade B histofluorescence. Moreover, we carried out immunohistochemistry for immunoglobulin G (IgG) to investigate blood-brain barrier (BBB) leakage and interleukin-1ß (IL-1ß) to examine change in pro-inflammatory cytokine. RESULTS: We found that IR-induced memory deficits were significantly ameliorated when 100 mg/kg Pycnogenol® was treated. In addition, treatment with 100 mg/kg Pycnogenol®, not 25 mg/kg nor 50 mg/kg, conferred neuroprotective effect against IR injury. For its mechanisms, we found that 100 mg/kg Pycnogenol® significantly reduced BBB leakage and inhibited the expression of IL-1ß. CONCLUSIONS: Therapeutic treatment (post-treatment) with Pycnogenol® after IR effectively attenuated ischemic brain injury in gerbils. Based on these results, we suggest that PYC can be employed as an important material for ischemic drugs.

Risperidone Administration Attenuates Renal Ischemia and Reperfusion Injury following Cardiac Arrest by Antiinflammatory Effects in Rats.

Multi-organ dysfunction following cardiac arrest is associated with poor outcome as well as high mortality. The kidney, one of major organs in the body, is susceptible to ischemia and reperfusion; however, there are few studies on renal ischemia and reperfusion injury (IRI) following the return of spontaneous circulation (ROSC) after cardiac arrest. Risperidone, an atypical antipsychotic drug, has been discovered to have some beneficial effects beyond its original effectiveness. Therefore, the aim of the present study was to investigate possible therapeutic effects of risperidone on renal IRI following cardiac arrest. Rats were subjected to cardiac arrest induced by asphyxia for five minutes followed by ROSC. When serum biochemical analyses were examined, the levels of serum blood urea nitrogen, creatinine, and lactate dehydrogenase were dramatically increased after cardiac arrest, but they were significantly reduced by risperidone administration. Histopathology was examined using hematoxylin and eosin staining. Histopathological injury induced by cardiac arrest was apparently attenuated by risperidone administration. Furthermore, alterations in pro-inflammatory cytokines (interleukin-6 and tumor necrosis factor-α) and anti-inflammatory cytokines (interleukin-4 and interleukin-13) were examined by immunohistochemistry. Pro-inflammatory and anti-inflammatory cytokine immunoreactivities were gradually and markedly increased and decreased, respectively, in the kidneys following cardiac arrest; however, risperidone administration after cardiac arrest significantly attenuated the increased pro-inflammatory cytokine immunoreactivities and the decreased anti-inflammatory cytokine immunoreactivities. Collectively, our current results revealed that, in rats, risperidone administration after cardiac arrest protected kidneys from IRI induced by cardiac arrest and ROSC through anti-inflammatory effects.

Therapeutic Hypothermia after Cardiac Arrest Attenuates Hindlimb Paralysis and Damage of Spinal Motor Neurons and Astrocytes through Modulating Nrf2/HO-1 Signaling Pathway in Rats.

Cardiac arrest (CA) and return of spontaneous circulation (ROSC), a global ischemia and reperfusion event, lead to neuronal damage and/or death in the spinal cord as well as the brain. Hypothermic therapy is reported to protect neurons from damage and improve hindlimb paralysis after resuscitation in a rat model of CA induced by asphyxia. In this study, we investigated roles of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) in the lumbar spinal cord protected by therapeutic hypothermia in a rat model of asphyxial CA. Male Sprague-Dawley rats were subjected to seven minutes of asphyxial CA (induced by injection of 2 mg/kg vecuronium bromide) and hypothermia (four hours of cooling, 33 ± 0.5 °C). Survival rate, hindlimb motor function, histopathology, western blotting, and immunohistochemistry were examined at 12, 24, and 48 h after CA/ROSC. The rats of the CA/ROSC and hypothermia-treated groups had an increased survival rate and showed an attenuated hindlimb paralysis and a mild damage/death of motor neurons located in the anterior horn of the lumbar spinal cord compared with those of the CA/ROSC and normothermia-treated groups. In the CA/ROSC and hypothermia-treated groups, expressions of cytoplasmic and nuclear Nrf2 and HO-1 were significantly higher in the anterior horn compared with those of the CA/ROSC and normothermia-treated groups, showing that cytoplasmic and nuclear Nrf2 was expressed in both motor neurons and astrocytes. Moreover, in the CA/ROSC and hypothermia-treated group, interleukin-1ß (IL-1ß, a pro-inflammatory cytokine) expressed in the motor neurons was significantly reduced, and astrocyte damage was apparently attenuated compared with those found in the CA/ROSC and normothermia group. Taken together, our results indicate that hypothermic therapy after CA/ROSC attenuates CA-induced hindlimb paralysis by protecting motor neurons in the lumbar spinal cord via activating the Nrf2/HO-1 signaling pathway and attenuating pro-inflammation and astrocyte damage (reactive astrogliosis).

Therapeutic Administration of Oxcarbazepine Saves Cerebellar Purkinje Cells from Ischemia and Reperfusion Injury Induced by Cardiac Arrest through Attenuation of Oxidative Stress.

Research reports using animal models of ischemic insults have demonstrated that oxcarbazepine (a carbamazepine analog: one of the anticonvulsant compounds) extends neuroprotective effects against cerebral or forebrain injury induced by ischemia and reperfusion. However, research on protective effects against ischemia and reperfusion cerebellar injury induced by cardiac arrest (CA) and the return of spontaneous circulation has been poor. Rats were assigned to four groups as follows: (Groups 1 and 2) sham asphyxial CA and vehicle- or oxcarbazepine-treated, and (Groups 3 and 4) CA and vehicle- or oxcarbazepine-treated. Vehicle (0.3% dimethyl sulfoxide/saline) or oxcarbazepine (200 mg/kg) was administered intravenously ten minutes after the return of spontaneous circulation. In this study, CA was induced by asphyxia using vecuronium bromide (2 mg/kg). We conducted immunohistochemistry for calbindin D-28kDa and Fluoro-Jade B histofluorescence to examine Purkinje cell death induced by CA. In addition, immunohistochemistry for 4-hydroxy-2-nonenal (4HNE) was carried out to investigate CA-induced oxidative stress, and immunohistochemistry for Cu, Zn-superoxide dismutase (SOD1) and Mn-superoxide dismutase (SOD2) was performed to examine changes in endogenous antioxidant enzymes. Oxcarbazepine treatment after CA significantly increased the survival rate and improved neurological deficit when compared with vehicle-treated rats with CA (survival rates ≥ 63.6 versus 6.5%), showing that oxcarbazepine treatment dramatically protected cerebellar Purkinje cells from ischemia and reperfusion injury induced by CA. The salvation of the Purkinje cells from ischemic injury by oxcarbazepine treatment paralleled a dramatic reduction in 4HNE (an end-product of lipid peroxidation) and increased or maintained the endogenous antioxidant enzymes (SOD1 and SOD2). In brief, this study shows that therapeutic treatment with oxcarbazepine after CA apparently saved cerebellar neurons (Purkinje cells) from CA-induced neuronal death by attenuating oxidative stress and suggests that oxcarbazepine can be utilized as a therapeutic medicine for ischemia and reperfusion brain (cerebellar) injury induced by CA.

Anti-stress effects of Fameyes in in vitro and in vivo models of stresses.

BACKGROUND: Fameyes (a mixture of Clematis mandshurica Rupr. extract (CMRE) and Erigeron annuus (L.) Pers. extract (EAPE)) containing scutellarin and chlorogenic acid as major components has been reported to relieve mental stress in human subjects, which is reflected in improved scores in psychometric tests measuring levels of depression, anxiety, well-being, and mental fitness. The aim of this study was to examine the anti-stress activity of Fameyes and to investigate the mechanisms of the anti-stress activity using in vitro and in vivo models of stresses. RESULTS: First, we tested the effect of Fameyes on corticosterone-induced cytotoxicity in SH-SY5Y cells (human neurofibroma cell lines). Corticosterone induced apoptosis and decreased cell viability and mitochondrial membrane potential, but treatment with Fameyes inhibited these cytotoxic effects in a dose-dependent manner. However, CMRE and EAPE (components of Fameyes) did not inhibit the cytotoxic effect of corticosterone individually. Next, we tested the effects of Fameyes on rats that were exposed to different kinds of stresses for four weeks. When the stressed rats were treated with Fameyes, their immobility time in forced swim and tail suspension tests decreased. A reduction was also observed in the serum levels of adrenocorticotropic hormone (ACTH) and corticosterone. Furthermore, upon oral administration of Fameyes, serum serotonin levels increased. These in vitro and in vivo results support the anti-stress effects of Fameyes. CONCLUSIONS: In vitro experiments showed anti-stress effects of Fameyes in cell viability, apoptosis, and mitochondrial membrane potential. In addition, in vivo experiments using rats showed anti-stress effects of Fameyes in blood and tissue levels of ACTH, corticosterone, and serotonin, as well as the immobility time in the forced swim and tail suspension tests. However, we did not specifically investigate which ingredient or ingredients showed anti-stress effects, although we reported that Fameyes contained chlorogenic acid and scutellarin major ingredients.

Protective Effects of Topical Administration of Laminarin in Oxazolone-Induced Atopic Dermatitis-like Skin Lesions.

Laminarin is a polysaccharide isolated from brown marine algae and has a wide range of bioactivities, including immunoregulatory and anti-inflammatory properties. However, the effects of laminarin on atopic dermatitis have not been demonstrated. This study investigated the potential effects of topical administration of laminarin using a Balb/c mouse model of oxazolone-induced atopic dermatitis-like skin lesions. Our results showed that topical administration of laminarin to the ear of the mice improved the severity of the dermatitis, including swelling. Histological analysis revealed that topical laminarin significantly decreased the thickening of the epidermis and dermis and the infiltration of mast cells in the skin lesion. Serum immunoglobulin E levels were also significantly decreased by topical laminarin. Additionally, topical laminarin significantly suppressed protein levels of oxazolone-induced proinflammatory cytokines, such as interleukin-1ß, tumor necrosis factor-α, monocyte chemoattractant protein-1, and macrophage inflammatory protein-1α in the skin lesion. These results indicate that topical administration of laminarin can alleviate oxazolone-induced atopic dermatitis by inhibiting hyperproduction of IgE, mast cell infiltration, and expressions of proinflammatory cytokines. Based on these findings, we propose that laminarin can be a useful candidate for the treatment of atopic dermatitis.

Effects of Brain Factor­7® against motor deficit and oxidative stress in a mouse model of MPTP­induced Parkinson's disease.

Oxidative stress is strongly implicated in the pathogenesis of Parkinson's disease (PD) through degeneration of dopaminergic neurons. The present study was designed to investigate the underlying mechanisms and therapeutic potential of Brain Factor-7® (BF-7®), a natural compound in silkworm, in a mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP (20 mg/kg) was intraperitoneally injected into mice to cause symptoms of PD. Mice were orally administered BF-7® (a mixture of silk peptides) before and after MPTP treatment. Rotarod performance test was used to assess motor performance. Fluoro-Jade B staining for neurons undergoing degeneration and immunohistochemistry of tyrosine hydroxylase for dopaminergic neurons, 4-hydroxy-2-nonenal (4HNE) for lipid peroxidation, 8-hydroxy-2'-deoxyguanosine (8OHdG) for DNA damage and superoxide dismutase (SOD) 1 and SOD2 for antioxidative enzymes in the pars compacta of the substantia nigra were performed. Results showed that BF-7® treatment significantly improved MPTP-induced motor deficit and protected MPTP-induced dopaminergic neurodegeneration. Furthermore, BF-7® treatment significantly ameliorated MPTP-induced oxidative stress. Increased 4HNE and 8OHdG immunoreactivities induced by MPTP were significantly reduced by BF-7®, whereas SOD1 and SOD2 immunoreactivities decreased by MPTP were significantly enhanced by BF-7®. In conclusion, BF-7® exerted protective and/or therapeutic effects in a mouse model of PD by decreasing effects of oxidative stress on dopaminergic neurons in the substantia nigra pars compacta.

Creutzfeldt-Jakob disease presenting with bilateral hearing loss: A case report.

BACKGROUND: Sporadic Creutzfeldt-Jakob disease (sCJD) is a prion disease characterized as a fatal transmissible neurodegenerative disorder. Dizziness is often the first presenting symptom of sCJD, but hearing loss as an early manifestation is very rare. CASE SUMMARY: A 76-year-old man presented with bilateral sudden hearing impairment and dizziness for 10 d. He was taking medications for hypertension and diabetes. He denied any difficulty with activities of daily living or hearing impairment before the onset of symptoms. Pure tone audiometry showed bilateral severe hearing impairment. Brain magnetic resonance imaging (MRI) and laboratory tests were within normal limits. Given his diagnosis of sudden sensory hearing loss, the patient received corticosteroid treatment but it was ineffective. Two weeks later, he complained of aggravated gait impairment, disorientation, and cognitive impairment. Repeat brain MRI showed diffuse cortical high signal intensities on diffusion-weighted imaging. In cerebrospinal fluid analysis, the real-time quaking-induced conversion assay was positive, and 14-3-3 protein was detected in the by western blotting. Considering all the data, we diagnosed probable sCJD, and the patient's symptoms rapidly progressed into akinetic mutism. CONCLUSION: For patients with abrupt bilateral hearing impairment, especially in the elderly, various differential diagnoses, including sCJD, should be considered.

In Vitro and In Vivo Anti-Inflammatory Effects of TEES-10®, a Mixture of Ethanol Extracts of Ligularia stenocephala Matsum. & Koidz. and Secale cereale L. Sprout, on Gingivitis and Periodontitis.

Gingivitis and periodontitis are inflammatory disorders caused by dental plaque and calculus. These disorders often lead to tooth loss if not treated properly. Although antibiotics can be used, it is hard to treat them due to the difficulty in supplying effective doses of antibiotics to lesion areas and side effects associated with long-term use of antibiotics. In the present study, attempts were made to provide in vitro and in vivo evidence to support anti-inflammatory activities of TEES-10®, a mixture of ethanol extracts of Ligularia stenocephala (LSE) and Secale cereale L. sprout (SCSE) toward gingivitis and periodontitis by performing the following experiments. TEES-10® with a ratio of 6:4 (LSE:SCSE) showed the best effects in both stimulating the viability and inhibiting the cytotoxicity. In in vitro experiments, TEES-10® showed an ability to scavenge 2,2-diphenyl-1-picrylhydrazyl and superoxide radicals and remove ROS generated in periodontal ligament cells treated with lipopolysaccharide. TEES-10® also enhanced the viability of stem cells from human exfoliated deciduous teeth and stimulated the osteogenic differentiation of deciduous teeth cells. In in vivo experiments using rats with induced periodontitis, TEES-10® significantly decreased inflammatory cell infiltration and the numbers of osteoclasts, increased alveolar process volume and the numbers of osteoblasts, decreased serum levels of IL-1ß and TNF-α (pro-inflammatory cytokines), and increased serum levels of IL-10 and IL-13 (anti-inflammatory cytokines). These results strongly support the theory that TEES-10® has the potential to be developed as a health functional food that can treat and prevent gingival and periodontal diseases and improve dental health.

A Randomized, Double-Blind, Sham-Controlled Trial of Transcranial Direct Current Stimulation for the Treatment of Persistent Postural-Perceptual Dizziness (PPPD).

Background: Persistent postural-perceptual dizziness (PPPD) is a functional vestibular disorder that causes chronic dizziness interfering with daily activities. Transcranial direct current stimulation (tDCS) has reportedly improved dizziness in patients with phobic postural vertigo in an open-label trial. However, no randomized, double-blind, sham-controlled study has been conducted on its therapeutic efficacy in PPPD. Objective: This study was conducted to investigate the efficacy and safety of tDCS as an add-on treatment to pharmacotherapy in patients with PPPD. In addition, functional neuroimaging was used to identify the neural mechanisms underlying the effects of tDCS. Materials and Methods: In a randomized, double-blind, sham-controlled trial, 24 patients diagnosed with PPPD were randomized to receive active (2 mA, 20 min) or sham tDCS to the left dorsolateral prefrontal cortex (DLPFC), administered in 15 sessions over 3 weeks. The clinical measures that assess the severity of dizziness, depression, and anxiety were collected at baseline, immediate follow-up, 1-month follow-up, and 3-month follow-up. Adverse events were also observed. The effect of tDCS on regional cerebral blood flow (rCBF) was evaluated with single photon emission tomography before and after tDCS sessions. Results: For the primary outcome measure of the Dizziness Handicap Inventory (DHI) score, a significant main effect of time was found, but neither the treatment-by-time interaction effect nor the main effect of treatment was significant. For the Hamilton Depression Rating Scale (HDRS) score, there was a statistical significance for the treatment-by-time interaction effect and the main effect of time, but not for the main effect of treatment. However, the treatment-by-time interaction effect and the main effect of time on HDRS score appear to be due to one data point, an increase in depressive symptoms reported by the sham group at the 3-month follow-up. For the Activities-specific Balance Confidence (ABC) Scale and the Hamilton Anxiety Rating Scale scores, there were no significant main effects of time, treatment, and treatment-by-time interaction. In a comparison with the changes in rCBF between the groups, a significant treatment-by-time interaction effect was found in the right superior temporal and left hippocampus, controlling for age and sex. Conclusion: Active tDCS was not found to be significantly more efficacious than sham tDCS on dizziness symptoms in patients with PPPD. It is conceivable that tDCS targeting the DLPFC may not be an optimal treatment option for reducing dizziness symptoms in PPPD. Our findings encourage further investigation on the effects of tDCS in PPPD, which considers different stimulation protocols in terms of stimulation site or the number of sessions. Clinical Trial Registration: cris.nih.go.kr, identifier: KCT0005068.