Yeo Sung Yoon

Melatonin improves D-galactose-induced aging effects on behavior, neurogenesis, and lipid peroxidation in the mouse dentate gyrus via increasing pCREB expression.

Abstract:  Melatonin (N‐acetyl‐5‐methoxytryptamine) has multiple functions. In this study, we investigated the effects of melatonin on memory, cell proliferation, and neuroblast differentiation in the dentate gyrus of a mouse model of d‐galactose‐induced aging. d‐galactose was subcutaneously administered to 7‐wk‐old mice for 10 wk, and age‐matched mice were used as controls. Seven weeks after d‐galactose administration, vehicle (water) or melatonin (6 mg/L in water) was administered ad libitum to the mice for 3 wk. The administration of d‐galactose significantly increased the escape latency compared with that in the control mice on days 1–3. In addition, cells in the subgranular zone and in the granule cell layer of the dentate gyrus showed severe damage (cytoplasmic condensation) in the d‐galactose‐treated mice. However, melatonin supplementation to these mice for 3 wk significantly ameliorated the d‐galactose‐induced increase in escape latency and neuronal damage compared with the vehicle‐treated group. The administration of melatonin also significantly restored the d‐galactose‐induced reduction of proliferating cells (Ki67‐positive cells) and differentiating neuroblasts (doublecortin‐positive neuroblasts) in the dentate gyrus. Furthermore, the administration of melatonin significantly increased Ser133‐phosphorylated cyclic AMP response element binding protein in the dentate gyrus. The administration of melatonin significantly reduced d‐galactose‐induced lipid peroxidation in the dentate gyrus. These results suggest that melatonin may be helpful in reducing age‐related phenomena in the brain.

Strain-specific differences in cell proliferation and differentiation in the dentate gyrus of C57BL/6N and C3H/HeN mice fed a high fat diet

The authors investigated strain-specific cell proliferation and differentiation differences in the dentate gyri of C57BL/6N (susceptible strain to obesity) and C3H/HeN (resistant strain to obesity) mice. In addition, the influences of a high fat diet (HD) on neuronal differentiation in C57BL/6N and C3H/HeN mice fed a low-fat diet (LD) or HD for 4 or 12 weeks were investigated. Body weight and body weight gains were significantly higher in HD-fed C57BL/6N and C3H/HeN mice than in LD-fed C57BL/6N and C3H/HeN mice. In particular, body weight gains were significantly higher in C57BL/6N mice than in C3H/HeN mice. In both of HD- and LD-fed C57BL/6N and C3H/HeN mice for 4 weeks, some Ki67 and many DCX immunoreactive cells were detected in the subgranular zone of the dentate gyrus. In HD-fed C57BL/6N and C3H/HeN mice, the number of Ki67 immunoreactive cells and DCX immunoreactivities in the dentate gyri were significantly lower than in LD-fed C57BL/6N and C3H/HeN mice. However, the number of Ki67 immunoreactive cells and DCX immunoreactivities in HD-fed C57BL/6N mice were significantly lower than in HD-fed C3H/HeN mice. These results suggest that C57BL/6N mice are more vulnerable to HD induced obesity than C3H/HeN mice. In addition, the feeding of HD was found to exacerbate reduced cell proliferation and differentiation in the dentate gyri of C57BL/6N mice as compared with that in C3H/HeN mice.

Effects of Curcumin (Curcuma longa) on Learning and Spatial Memory as Well as Cell Proliferation and Neuroblast Differentiation in Adult and Aged Mice by Upregulating Brain-Derived Neurotrophic Factor and CREB Signaling

Aging is a progressive process, and it may lead to the initiation of neurological diseases. In this study, we investigated the effects of wild Indian Curcuma longa using a Morris water maze paradigm on learning and spatial memory in adult and D-galactose-induced aged mice. In addition, the effects on cell proliferation and neuroblast differentiation were assessed by immunohistochemistry for Ki67 and doublecortin (DCX) respectively. The aging model in mice was induced through the subcutaneous administration of D-galactose (100 mg/kg) for 10 weeks. C. longa (300 mg/kg) or its vehicle (physiological saline) was administered orally to adult and D-galactose-treated mice for the last three weeks before sacrifice. The administration of C. longa significantly shortened the escape latency in both adult and D-galactose-induced aged mice and significantly ameliorated D-galactose-induced reduction of cell proliferation and neuroblast differentiation in the subgranular zone of hippocampal dentate gyrus. In addition, the administration of C. longa significantly increased the levels of phosphorylated CREB and brain-derived neurotrophic factor in the subgranular zone of dentate gyrus. These results indicate that C. longa mitigates D-galactose-induced cognitive impairment, associated with decreased cell proliferation and neuroblast differentiation, by activating CREB signaling in the hippocampal dentate gyrus.

Effects of luteolin on spatial memory, cell proliferation, and neuroblast differentiation in the hippocampal dentate gyrus in a scopolamine-induced amnesia model

Abstract Objectives: Luteolin, a common flavonoid from many plants, has various pharmacological activities, including a memory-improving effect. In this study, we investigated the effects of luteolin on spatial memory, cell proliferation, and neuroblast differentiation in the hippocampal dentate gyrus in a rat model of scopolamine (SCO)-induced amnesia. Methods: Scopolamine was subcutaneously administered for 28 days via an Alzet minipump (44 mg/ml delivered at 2·5 μl/h) along with a daily intraperitoneal administration of vehicle (saline) 10 mg/kg luteolin or 5 mg/kg galantamine (GAL) (a control drug for acetylcholinesterase (AChE) inhibitor) for 28 days. Results: The administration of SCO significantly decreased the spatial alteration percentage in the Y-maze test compared to that in the vehicle (saline)-treated group. The administration of luteolin or GAL significantly improved the spatial alteration percentage compared to that in the SCO-treated group. Similarly, the administration of SCO significantly decreased the cell proliferation (Ki67-positive cells) and neuroblast differentiation (doubleocortin-positive cells) in the dentate gyrus. The administration of luteolin or GAL significantly mitigated the SCO-induced reduction of Ki67- and doublecortin-immunoreactive cells in the dentate gyrus. In addition, the administration of luteolin significantly decreased the lipid peroxidation (malondialdehyde (MDA) levels) and increased the brain-derived neurotrophic factor (BDNF) and AChE levels in the hippocampal homogenates compared to the SCO-treated group. Conclusion: These results suggest that the luteolin treatment improves the SCO-induced reduction of cell proliferation and neuroblast differentiation in the dentate gyrus. The mechanism underlying the amelioration of SCO-induced amnesia by luteolin may be associated with the increase in BDNF, acetylcholine, and the decrease in lipid peroxidation.

Age-related Differentiation in Newly Generated DCX Immunoreactive Neurons in the Subgranular Zone of the Gerbil Dentate Gyrus

In the present study, we investigated age-related changes of newborn neurons in the gerbil dentate gyrus using doublecortin (DCX), a marker of neuronal progenitors which differentiate into neurons in the brain. In the postnatal month 1 (PM 1) group, DCX immunoreactivity was detected in the subgranular zone of the dentate gyrus, but DCX immunoreactive neurons did not have fully developed processes. Thereafter, DCX immunoreactivity and its protein levels in the dentate gyrus were found to decrease with age. Between PM 3 and PM 18, DCX immunoreactive neuronal progenitors showed well-developed processes which projected to the granular layer of the dentate gyrus, but at PM 24, a few DCX immunoreactive neuronal progenitors were detected in the subgranular zone of the dentate gyrus. DCX protein level in the dentate gyrus at PM 1 was high, thereafter levels of DCX were decreased with time. The authors suggest that a decrease of DCX immunoreactivity and its protein level with age may be associated with aging processes in the hippocampal dentate gyrus.

Effects of age and treadmill exercise in chronic diabetic stages on neuroblast differentiation in a rat model of type 2 diabetes

In the present study, we investigated the effects of type 2 diabetes and treadmill exercise in chronic diabetic stages on neuroblast differentiation using doublecortin (DCX) in the subgranular zone of the dentate gyrus (SZDG) in Zucker diabetic fatty (ZDF) rats. Four-, 12-, 20- and 30-week-old Zucker lean control (ZLC) and ZDF rats were used to elucidate age-dependent changes of DCX-immunoreactive neuroblasts. DCX-immunoreactive neuroblasts were significantly decreased with age in the SZDG. This reduction was prominent in the age-matched ZDF rats compared to that in the ZLC rats. To investigate the effects of treadmill exercise, ZLC and ZDF rats at 23 weeks of age were put on the treadmill with or without running for 1 h/day/5 consecutive days at 12-16 m/min for 7 weeks. Treadmill exercise significantly increased the tertiary dendrites of DCX-immunoreactive neuroblasts in both ZLC and ZDF rats. In addition, exercise significantly increased the number of DCX-immunoreactive neuroblasts in the ZLC rats, but not in the ZDF rats. These results suggest that diabetes significantly decreases neuroblast differentiation and treadmill exercise in chronic diabetic animals has limitation to increase neuroblast differentiation although it increases neural plasticity.

Very virulent infectious bursal disease virus isolated from wild birds in Korea: Epidemiological implications

To explore the epidemiological link between infectious bursal disease virus (IBDV) in wild birds and domestic chickens in Korea, we examined 107 free-living wild birds, representing 7 species, that were found dead of apparent natural causes in Korea over the past two years for the presence of IBDV. Five birds were tested positive for IBDV by RT-PCR assay: black-billed magpie (n=1), mallard duck (n=2), bean goose (n=1) and white-fronted goose (n=1). IBDV was isolated from RT-PCR-positive tissues following chicken embryo inoculation. Sequence analysis of the VP2 gene indicated that all of the isolates from the wild birds encode amino acids A222, I242, I256, I294 and S299 of VP2, which are conserved among strains of very virulent IBDV (vvIBDV). Phylogenetic analysis revealed that the wild bird IBDV isolates are closely related to strains of vvIBDV. An IBDV isolate from a magpie showed 60% mortality in SPF chickens and severe bursal atrophy. The epidemiological implications of IBDV in free-living wild birds are discussed. To our knowledge, this is the first report of vvIBDV in free-living wild birds.

Sodium butyrate, a histone deacetylase Inhibitor, ameliorates SIRT2-induced memory impairment, reduction of cell proliferation, and neuroblast differentiation in the dentate gyrus

Abstract Objectives: Histone deacetylases (HDACs) play a key role in synaptic plasticity and learning and memory. Sirtuin 2 (SIRT2), a class III HDAC, is abundantly expressed in neurons and functions as a mitotic exit regulator in dividing cells. In this study, we investigated the role of SIRT2 in cell proliferation and neuroblast differentiation in the mouse dentate gyrus. Methods: To facilitate the delivery of SIRT2 into neurons, we constructed a PEP-1-SIRT2 fusion protein. Mice were divided into three groups: vehicle (PEP-1), SIRT2, and SIRT2 with sodium butyrate (an HDAC inhibitor). PEP-1 or PEP-1-SIRT2 fusion protein was administered intraperitoneally to 7-week-old mice once a day for 3 weeks, and the mice were killed 2 h after the last administration. Sodium butyrate, an HDAC inhibitor, was subcutaneously administered in parallel with PEP-1-SIRT2 once a day for 3 weeks. Results: The administration of PEP-1-SIRT2 alone significantly reduced the time spent exploring a new object in the novel object recognition test, whereas treatment with sodium butyrate increased the time spent exploring a new object. Results of Ki67 and doublecortin immunohistochemistry revealed that the administration of PEP-1-SIRT2 significantly reduced cell proliferation and neuroblast differentiation, respectively, in the dentate gyrus. However, the administration of sodium butyrate significantly ameliorated the SIRT2-induced reduction in cell proliferation and neuroblast differentiation. Conclusion: This result suggests that histone acetylation and deacetylation are key factors modulating hippocampal functions such as memory formation, cell proliferation, and neuroblast differentiation in the dentate gyrus.

Valeriana officinalis extract and its main component, valerenic acid, ameliorate D-galactose-induced reductions in memory, cell proliferation, and neuroblast differentiation by reducing corticosterone levels and lipid peroxidation.

Valeriana officinalis is used in herbal medicine of many cultures as mild sedatives and tranquilizers. In this study, we investigated the effects of extract from valerian root extracts and its major component, valerenic acid on memory function, cell proliferation, neuroblast differentiation, serum corticosterone, and lipid peroxidation in adult and aged mice. For the aging model, D-galactose (100 mg/kg) was administered subcutaneously to 6-week-old male mice for 10 weeks. At 13 weeks of age, valerian root extracts (100 mg/kg) or valerenic acid (340 μg/kg) was administered orally to control and D-galactose-treated mice for 3 weeks. The dosage of valerenic acid (340 μg/kg), which is the active ingredient of valerian root extract, was determined by the content of valerenic acid in valerian root extract (3.401±0.066 mg/g) measured by HPLC. The administration of valerian root extract and valerenic acid significantly improved the preferential exploration of new objects in novel object recognition test and the escape latency, swimming speeds, platform crossings, and spatial preference for the target quadrant in Morris water maze test compared to the D-galactose-treated mice. Cell proliferation and neuroblast differentiation were significantly decreased, while serum corticosterone level and lipid peroxidation in hippocampus were significantly increased in the D-galactose-treated group compared to that in the control group. The administration of valerian root extract significantly ameliorated these changes in the dentate gyrus of both control and D-galactose-treated groups. In addition, valerenic acid also mitigated the D-galactose-induced reduction of these changes. These results indicate that valerian root extract and valerenic acid enhance cognitive function, promote cell proliferation and neuroblast differentiation, and reduce serum corticosterone and lipid peroxidation in aged mice.

Activation of microglia and induction of pro-inflammatory cytokines in the hippocampus of type 2 diabetic rats

Abstract Objectives: The majority of immune cells in the brain are comprised of microglia, which undergo morphological changes when activated to remove damaged neurons and infectious agents from the brain tissue. In this study, we investigated the effects of type 2 diabetes on microglial activation and the subsequent secretion of pro-inflammatory cytokines, such as interferon-gamma (IFN-gamma) and interleukin-1beta (IL-1beta), in the hippocampus using Zucker diabetic fatty (ZDF) rats and Zucker lean control (ZLC) rats at various diabetic stages. Methods: Zucker lean control and Zucker diabetic fatty rats were sacrificed at 12 (early diabetic stage), 20, or 30 weeks of age (chronic diabetic stage), and the hippocampus was obtained via transcardiac perfusion or dissection for immunohistochemistry and western blot analysis, respectively. Results: Zucker diabetic fatty rats demonstrated significantly higher glucose levels at 12 and 30 weeks of age compared to ZLC rats. Microglia immunoreactive to ionized calcium-binding adapter molecule 1 (Iba-1) had hypertrophied cytoplasm with retracted processes at 30 weeks of age. In contrast, Iba-1-immunoreactive microglia displayed similar morphology in ZDF and ZLC rats at 12 and 20 weeks of age. Similarly, IFN-gamma and IL-1beta protein levels were significantly increased in ZDF rats compared to ZLC rats at 30 weeks of age, but not at 12 and 20 weeks of age. Interleukin-1beta immunoreactivity in the ZDF rats predominantly increased in the dentate gyrus and CA1 region of the hippocampus compared to that of ZLC rats at 30 weeks of age. In addition, IL-1beta immunoreactive structures in ZDF rats at 30 weeks of age were detected near the astrocytes and microglia. Conclusion: These results suggest that chronic diabetes activates microglia and significantly increases pro-inflammatory cytokine levels in the hippocampus.