Withdrawal from 3-Fluoroethamphetamine induces hyperactivity and depression-like behaviors in male mice.

3-Fluoroethamphetamine (3-FEA) belongs to the amphetamine class of stimulant drugs and functions as a releasing agent for the monoamine neurotransmitters norepinephrine, dopamine, and serotonin. 3-FEA acts on the central nervous system and elicits physical and mental side effects, such as euphoria, increased heart rate, and excitement. However, little is known about the withdrawal symptoms and behavioral changes induced by 3-FEA administration. This study aimed to evaluate the short-term consequences of 3-FEA administration (twice a day, 7 days, i.p.; 1 and 10 mg/kg) in C57BL/6J mice (male, 7 weeks old) at three behavioral levels following 1-4 days of withdrawal. The evaluation included (1) withdrawal score, (2) hyperactivity (open field [OF], elevated plus maze [EPM], and cliff avoidance [CA] test), and (3) depression-like behavior (forced-swim test). In the withdrawal score test, withdrawal behavior increased in all 3-FEA groups at 16 and 40 h after withdrawal. In the OF, EPM, and CA tests, the 3-FEA administration group showed significant changes in terms of hyperactivity. In addition, in the forced-swim test, both the 1 mg/kg and 10 mg/kg 3-FEA groups showed increased immobility time. These findings indicate that 3-FEA administration may lead to physical dependence, demonstrated by the withdrawal score increase and significant changes in hyperactivity and depression-like behavior following repeated administration and drug cessation. In conclusion, this study reveals the adverse consequences of 3-FEA administration and highlights the need for awareness raising and regulatory action to control the use of this new psychoactive substance.

Lipocalin-2 Is a Key Regulator of Neuroinflammation in Secondary Traumatic and Ischemic Brain Injury.

Reactive glial cells are hallmarks of brain injury. However, whether these cells contribute to secondary inflammatory pathology and neurological deficits remains poorly understood. Lipocalin-2 (LCN2) has inflammatory and neurotoxic effects in various disease models; however, its pathogenic role in traumatic brain injury remains unknown. The aim of the present study was to investigate the expression of LCN2 and its role in neuroinflammation following brain injury. LCN2 expression was high in the mouse brain after controlled cortical impact (CCI) and photothrombotic stroke (PTS) injury. Brain levels of LCN2 mRNA and protein were also significantly higher in patients with chronic traumatic encephalopathy (CTE) than in normal subjects. RT-PCR and immunofluorescence analyses revealed that astrocytes were the major cellular source of LCN2 in the injured brain. Lcn2 deficiency or intracisternal injection of an LCN2 neutralizing antibody reduced CCI- and PTS-induced brain lesions, behavioral deficits, and neuroinflammation. Mechanistically, in cultured glial cells, recombinant LCN2 protein enhanced scratch injury-induced proinflammatory cytokine gene expression and inhibited Gdnf gene expression, whereas Lcn2 deficiency exerted opposite effects. Together, our results from CTE patients, rodent brain injury models, and cultured glial cells suggest that LCN2 mediates secondary damage response to traumatic and ischemic brain injury by promoting neuroinflammation and suppressing the expression of neurotropic factors.

Rewarding and Reinforcing Effects of 25H-NBOMe in Rodents.

The drug 25H-NBOMe is a new psychoactive substance (NPS). The use of these substances is likely to pose a threat to public health because they elicit effects similar to those of known psychoactive substances with similar chemical structures. However, data regarding the abuse potential of 25H-NBOMe are lacking. Here, we evaluated the abuse liability of 25H-NBOMe in rodents. The rewarding and reinforcing effects were evaluated through conditioned place preference (CPP) and self-administration (SA) tests after administration of 25H-NBOMe. To investigate the effects of 25H-NBOMe on the central nervous system, we determined the changes in dopamine levels by in vivo microdialysis. In the locomotor activity test, 25H-NBOme significantly increased locomotor activity in mice. In the place conditioning test, the 25H-NBOMe (0.1 and 0.5 mg/kg) groups showed a significantly increase in CPP in mice. In the SA test, the 25H-NBOMe (0.01 mg/kg) administered group showed a significant increased number of infusions and active lever presses. In microdialysis, the 25H-NBOMe (10 mg/kg) administered group was significantly increased in rats.

Depression before and during-COVID-19 by Gender in the Korean Population.

This study explored the association between Coronavirus disease (COVID-19) and depression by comparing Patient Health Questionnaire-9 (PHQ-9) results pre-pandemic (2019) and after the start of the pandemic (2020). Data of 444,051 participants (200,206 male (45.1%); 243,845 female (54.9%)) were obtained from the Korean Community Health Survey conducted from 2019 to 2020. The independent variable of interest in this study was the year, divided into binary categories, 2019 and 2020. The dependent variable was depression, measured by the PHQ-9 scale. This dependent variable was also binary, dividing those who are considered depressed or not by a cut-off score of 10. A logistic regression model was employed to examine the association. Our results reveal that compared to participants in 2019, patients from the study sample of 2020 were marginally more likely to be depressed, especially female patients (male OR: 1.092, 95% CI [0.998 to 1.195], female OR: 1.066, 95% CI [1.002 to 1.134]). Moreover, using the participants from the year 2019 as a reference group, those who appeared anxious in response to the COVID-19-related questions in the survey showed more tendency to have a PHQ-9 score of 10 or more. Compared to participants from the 2019 group, those from 2020 more likely to be depressed were those with no-one to contact in case of emergency due to COVID-19 (male OR: 1.45, 95% CI [1.26 to 1.66], female OR: 1.46, 95% CI [1.33 to 1.60]), and individuals with concerns regarding economic loss (male OR: 1.18, 95% CI [1.07 to 1.30], female OR: 1.11, 95% CI [1.04 to 1.18]) and infection of a vulnerable family member at home due to COVID-19 (male OR: 1.16, 95% CI [1.05 to 1.28], female OR: 1.09, 95% CI [ 1.02 to 1.16]).

Modified Protocol to Enable the Study of Hemorrhage and Hematoma in a Traumatic Brain Injury Mouse Model.

To date, many studies using the controlled cortical impact (CCI) mouse model of traumatic brain injury (TBI) have presented results without presenting the pathophysiology of the injury-core itself or the temporal features of hemorrhage (Hrr). This might be owing to the removal of the injury-core during the histological procedure. We therefore developed a modified protocol to preserve the injury-core. The heads of mice were obtained after perfusion and were post-fixed. The brains were then harvested, retaining the ipsilateral skull bone; these were post-fixed again and sliced using a cryocut. To validate the utility of the procedure, the temporal pattern of Hrr depending on the impacting depth was analyzed. CCI-TBI was induced at the following depths: 1.5 mm (mild Hrr), 2.5 mm (moderate Hrr), and 3.5 mm (severe Hrr). A pharmacological study was also conducted using hemodynamic agents such as warfarin (2 mg/kg) and coagulation factor VIIa (Coa-VIIa, 1 mg/kg). The current protocol enabled the visual observation of the Hrr until 7 days. Hrr peaked at 1-3 days and then decreased to the normal range on the seventh day. It expanded from the affected cortex (mild) to the periphery of the hippocampus (moderate) and the brain ventricle (severe). Pharmacological studies showed that warfarin pre-treatment produced a massively increased Hrr, concurrent with the highest mortality rate and brain injury. Coa-VIIa reduced the side effects of warfarin. Therefore, these results suggest that the current method might be suitable to conduct studies on hemorrhage, hematoma, and the injury-core in experiments using the CCI-TBI mouse model.

Anti-colitic effects of the modified Bojanggunbi-tang on dextran sulfate sodium-induced mouse colitis model.

Bojanggunbi-tang (BGT) is a well-known and widely used herbal prescription in Korea for colon diseases, with well-documented pharmacological effects on the digestive system. The current study aimed to develop a new simple and effective prescription using the original prescription. mBGT, a modified BGT, was developed by mixing the extracts of Lonicera japonica Thunb., Alisma orientalis and Atractylodes macrocephala based on a literature review and screening of 16 kinds of component herbs of BGT. A colitis mouse (Male, BALB/c) model was induced using dextran sulfate sodium (5%). The effects of BGT and mBGT on body weight, histological damage, clinical score, macroscopic score and colon length were compared. The mechanisms of action were analyzed based on cytokine production in colon tissue. mBGT at 300mg/kg showed similar effectiveness to that of BGT on colon shortening (P<0.01), clinical score (P<0.05), macroscopic score (P<0.01) and histological damage (P<0.01). In addition, mBGT decreased cytokines, including Interleukin 1 beta, tumor necrosis factor alpha and Interleukin 17, in a dose-dependent manner. In conclusion, mBGT could be a substitute prescription for BGT in clinics and a candidate for the development of a new BGT-based therapeutic agent against colitis.

Icariin Improves Functional Behavior in a Mouse Model of Traumatic Brain Injury and Promotes Synaptic Plasticity Markers.

Epimedii Herba (EH) has been used in traditional Asian medicine to treat hemiplegia following stroke. Icariin, its major active component, is used as a quality-control marker and for its various pharmacological effects. We hypothesized that icariin would show protective effects following traumatic brain injury (TBI). The TBI mouse model was induced using a controlled cortical impact method. Body weight, brain damage, motor function, and cognitive function were evaluated. Synaptogenesis markers were analyzed to investigate potential mechanisms of action. The animals were divided into six groups: sham, control, minocycline-treated group, and icariin-treated (3, 10, and 30 mg/kg, p. o.) groups. The icariin 30 mg/kg-treated group regained body weight at 7 and 8 d post TBI. Icariin 30 mg/kg- and 10 mg/kg-treated groups showed enhanced sensory-motor function at 8 d post TBI in rotarod and balance beam tests. Icariin-treated groups showed increased recognition index in the novel object recognition test at all doses and increased spontaneous alternation in the Y-maze test at 30 mg/kg. Icariin upregulated brain-derived neurotrophic factor, synaptophysin and postsynaptic density protein 95 expressions. However, no protective effects against brain damage or neuronal death were observed. The current results provide a basis for using icariin following TBI and suggest that it could be a candidate for the development of therapeutic agents for functional recovery after TBI.

Brain injury induces HIF-1α-dependent transcriptional activation of LRRK2 that exacerbates brain damage.

Leucine-rich repeat kinase 2 (LRRK2), originally identified as a causative genetic factor in Parkinson's disease, is now associated with a number of pathologies. Here, we show that brain injury induces a robust expression of endogenous LRRK2 and suggest a role of LRRK2 after injury. We found that various in vitro and in vivo models of traumatic brain injury (TBI) markedly enhanced LRRK2 expression in neurons and also increased the level of hypoxia-inducible factor (HIF)-1α. Luciferase reporter assay and chromatin immunoprecipitation revealed direct binding of HIF-1α in LRRK2 proximal promoter. We also found that HIF-1α-dependent transcriptional induction of LRRK2 exacerbated neuronal cell death following injury. Furthermore, application of G1023, a specific, brain-permeable inhibitor of LRRK2, substantially prevented brain tissue damage, cell death, and inflammatory response and alleviated motor and cognitive defects induced by controlled cortical impact injury. Together, these results suggest HIF-1α-LRRK2 axis as a potential therapeutic target for brain injury.

Effects of Dangguisusan, a prescription of Korean medicine on controlled cortical impact-induced traumatic brain injury mouse model.

ETHNOPHARMACOLOGICAL RELEVANCE: Dangguisusan (DGSS) is a widely used prescription for the treatment of traumatic injury in Korean medicine. AIM OF THE STUDY: To demonstrate the effects of DGSS on a mouse model of traumatic brain injury (TBI) for providing scientific evidence in clinical use. MATERIALS AND METHODS: TBI was induced in a mouse model using the controlled cortical impact method. Water extract of DGSS (50, 150, and 450 mg/kg) was administered twice a day for 8 d. Histological analyses were performed 8 d after TBI. Moreover, beam-walking, grip-strength, and novel object recognition (NOR) tests were conducted to evaluate the effects on motor function, muscle strength, and cognitive memory function, respectively. RESULT: DGSS inhibited body weight loss, hippocampal damage, and neuronal loss in the thalamic region. Furthermore, it reduced transverse time and foot faults in the beam-walking test at 3 d and increased the muscle strength in the grip-strength test at 3 and 8 d. It also improved the recognition index (%) in the NOR test. However, DGSS did not show protective effects against total damage. CONCLUSIONS: DGSS might improve sensory-motor and cognitive functions after TBI with partial protective effects against brain damage. The present findings provide a scientific basis for the clinical use of DGSS in TBI.

Diseases concomitant with asthma in middle-aged and elderly subjects in Korea: a population-based study.

PURPOSE: Asthma is prevalent in many countries. Few studies have investigated the association between asthma and concomitant diseases. We retrospectively analyzed the fourth Korean National Health and Nutrition Survey database, performed in 2008 using nationwide stratified random sampling to obtain a representative cohort of the Korean population. METHODS: We evaluated the association between both self-reported ever-asthmatics and wheezers and concomitant diseases such as arthritis, hypertension, gastrointestinal (GI) ulcers, dyslipidemia, diabetes mellitus, rhinitis, depression, stroke, and obesity in subjects aged ≥40 years. A multivariate analysis was performed to identify concomitant diseases independently associated with asthma, after adjustment for age, gender, income, cigarette smoking, and other chronic diseases. RESULTS: Of the total of 4,445 subjects, 2,596 (58.4%) were female and the mean age was 58.3 years. Of the 4,445 subjects, 195 (4.4%) had been diagnosed with asthma at some point, and 444 (10%) were wheezers. Multivariate analysis showed that arthritis (odds ratio [OR] 1.74, 95% confidence interval [CI] 1.26-2.42), rhinitis (OR 1.78, 95% CI 1.14-2.78), depression (OR 1.45, 95% CI 1.05-2.07), and obesity (OR 1.61, 95% CI 1.08-2.40) were significantly associated with self-reported ever-asthma, and arthritis (OR 1.50, 95% CI 1.19-1.909), hypertension (OR 1.34, 95% CI 1.07-1.67), GI ulcers (OR 1.48, 95% CI 1.05-2.08), rhinitis (OR 1.60, 95% CI 1.16-2.19), depression (OR 1.94, 95% CI 1.51-2.48), and obesity (OR 1.56, 95% CI 1.17-2.09) were significantly associated with wheezers. CONCLUSIONS: These findings indicate that arthritis, rhinitis, depression, and obesity may be associated with both self-reported ever asthma and wheezers in the Korean population.

Comorbidities of chronic obstructive pulmonary disease in Koreans: a population-based study.

Chronic obstructive pulmonary disease (COPD) includes pulmonary components with increased comorbidity rates, as well as being a systemic disease. Comorbidities may frequently occur in COPD patients over 40 yr old. We report the comorbidities of patients with COPD, diagnosed by spirometry, in a population-based epidemiologic survey in Korea. Data were derived from the fourth Korean Health and Nutrition Examination Survey in 2008, a stratified multistage clustered probability design survey of a sample representing the entire population of Korea. Results of spirometry and various health-related questionnaires were analyzed in 2,177 subjects aged ≥ 40 yr. The prevalence of COPD (FEV(1)/FVC < 0.7) in subjects ≥ 40 yr of age was 14.1%. Multivariate analysis showed that underweight (odds ratio [OR] 3.07, 95% confidence interval [CI] 1.05-8.98), coronary heart disease (OR, 0.43; 95% CI, 0.20-0.93) and dyslipidemia (OR, 0.61; 95% CI, 0.45-0.82) were significantly associated with COPD, whereas allergic rhinitis, anemia, arthritis, chronic renal failure, depression, diabetes mellitus, hypertension, gastrointestinal ulcer, and osteoporosis were not. Underweight might be more prevalent but coronary heart disease and dyslipidemia are less prevalent in Koreans with than without COPD in population setting.

Preparation of alginate/chitosan microcapsules and enteric coated granules of mistletoe lectin.

The aqueous extract of European mistletoe (Viscum album, L.) has been used in cancer therapy. The purified mistletoe lectins, main components of mistletoe, have demonstrated cytotoxic and immune-system-stimulating activities. Korean mistletoe (Viscum album L. coloratum), a subspecies of European mistletoe, has also been reported to possess anticancer and immunological activities. A galactose- and N-acetyl-D-galactosamine-specific lectin (Viscum album L. coloratum agglutinin, VCA) with Mr 60 kDa was isolated from Korean mistletoe. Mistletoe preparations have been given subcutaneously due to the low stability of lectin in the gastrointestinal (GI) tract. In the present study, we investigated the possibility of alginate/chitosan microcapsules as a tool for oral delivery of mistletoe lectin. In addition, our strategy has been to develop a system composed of stabilizing cores (granules), which contain mistletoe lectin, extract or powder, coated by a biodegradable polymer wall. Our results indicated that successful incorporation of VCA into alginate/chitosan microcapsules has been achieved and that the alginate/chitosan microcapsule protected the VCA from degradation at acidic pH values. And coating the VCA with polyacrylic polymers, Eudragit, produced outstanding results with ideal release profiles and only minimal losses of cytotoxicity after manufacturing step. The granules prepared with extract or whole plant produced the best results due to the stability in the extract or whole plant during manufacturing process.