Decreased Insulin-Like Growth Factor-I and Its Receptor Expression in the Hippocampus and Somatosensory Cortex of the Aged Mouse

Lee, Choong Hyun,Ahn, Ji Hyeon,Park, Joon Ha,Yan, Bing Chun,Kim, In Hye,Lee, Dae Hwan,Cho, Jeong-Hwi,Chen, Bai Hui,Lee, Jae-Chul,Cho, Jun Hwi,Lee, Yun Lyul,Won, Moo-Ho,Kang, Il-Jun Springer-Verlag 2014 Neurochem Res Vol.39 No.4

Melatonin improves vascular cognitive impairment induced by ischemic stroke by remyelination via activation of ERK1/2 signaling and restoration of glutamatergic synapses in the gerbil hippocampus

Chen, Bai Hui,Park, Joon Ha,Lee, Yun Lyul,Kang, Il Jun,Kim, Dae Won,Hwang, In Koo,Lee, Choong-Hyun,Yan, Bing Chun,Kim, Young-Myeong,Lee, Tae-Kyeong,Lee, Jae Chul,Won, Moo-Ho,Ahn, Ji Hyeon Elsevier 2018 BIOMEDICINE AND PHARMACOTHERAPY Vol.108 No.-

<P><B>Abstract</B></P> <P>Vascular dementia affects cognition by damaging axons and myelin. Melatonin is pharmacologically associated with various neurological disorders. In this study, effects of melatonin on cognitive impairment and related mechanisms were investigated in an animal model of ischemic vascular dementia (IVD). Melatonin was intraperitoneally administered to adult gerbils after transient global cerebral ischemia (tGCI) for 25 days beginning 5 days after tGCI. Cognitive impairment was examined using a passive avoidance test and the Barnes maze test. To investigate mechanisms of restorative effects by melatonin, neuronal damage/death, myelin basic protein (MBP, a marker for myelin), Rip (a marker for oligodendrocyte), extracellular signal-regulated protein kinase1/2 (ERK1/2) and phospho-ERK1/2 (p-ERK1/2), and vesicular glutamate transporter (VGLUT)-1 (a glutamatergic synaptic marker) in the hippocampal Cornu Ammonis 1 area (CA1) were evaluated using immunohistochemistry. Melatonin treatment significantly improved tGCI-induced cognitive impairment. Death of CA1 pyramidal neurons after tGCI was not affected by melatonin treatment. However, melatonin treatment significantly increased MBP immunoreactivity and numbers of Rip-immunoreactive oligodendrocytes in the ischemic CA1. In addition, melatonin treatment significantly increased ERK1/2 and p-ERK1/2 immunoreactivities in oligodendrocytes in the ischemic CA1. Furthermore, melatonin treatment significantly increased VGLUT-1 immunoreactive structures in the ischemic CA1. These results indicate that long-term melatonin treatment after tGCI improves cognitive deficit <I>via</I> restoration of myelin, increase of oligodendrocytes which is closely related to the activation of ERK1/2 signaling, and increase of glutamatergic synapses in the ischemic brain area.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Melatonin (Mel) improved impaired memory function after ischemia. </LI> <LI> Mel did not protect ischemia-induced (i-i) neuronal loss in the hippocampus. </LI> <LI> Mel recovered i-i damaged myelinated nerve fibers and oligodendrocytes. </LI> <LI> Mel increased ERK1/2 and p-ERK1/2 in oligodendrocytes in i-i hippocampus. </LI> <LI> Mel increased i-i damaged VGLUT-1 in the hippocampus. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Rufinamide, an antiepileptic drug, improves cognition and increases neurogenesis in the aged gerbil hippocampal dentate gyrus via increasing expressions of IGF-1, IGF-1R and <i>p</i>-CREB

Chen, Bai Hui,Ahn, Ji Hyeon,Park, Joon Ha,Song, Minah,Kim, Hyunjung,Lee, Tae-Kyeong,Lee, Jae Chul,Kim, Young-Myeong,Hwang, In Koo,Kim, Dae Won,Lee, Choong-Hyun,Yan, Bing Chun,Kang, Il Jun,Won, Moo-Ho Elsevier 2018 Chemico-biological interactions Vol.286 No.-

<P><B>Abstract</B></P> <P>Rufinamide is a novel antiepileptic drug and commonly used in the treatment of Lennox-Gastaut syndrome. In the present study, we investigated effects of rufinamide on cognitive function using passive avoidance test and neurogenesis in the hippocampal dentate gyrus using Ki-67 (a marker for cell proliferation), doublecortin (DCX, a marker for neuroblast) and BrdU/NeuN (markers for newly generated mature neurons) immunohistochemistry in aged gerbils. Aged gerbils (24-month old) were treated with 1 mg/kg and 3 mg/kg rufinamide for 4 weeks. Treatment with 3 mg/kg rufinamide, not 1 mg/kg rufinamide, significantly improved cognitive function and increased neurogenesis, showing that proliferating cells (Ki-67-immunoreactive cells), differentiating neuroblasts (DCX-immunoreactive neuroblasts) and mature neurons (BrdU/NeuN-immunoreactive cells) in the aged dentate gyrus compared with those in the control group. When we examined its mechanisms, rufinamide significantly increased immunoreactivities of insulin-like growth factor-1 (IGF-1), its receptor (IGF-1R), and phosphorylated cAMP response element binding protein (<I>p</I>-CREB). However, rufinamide did not show any increase in immunoreactivities of brain-derived neurotrophic factor and its receptor. Therefore, our results indicate that rufinamide can improve cognitive function and increase neurogenesis in the hippocampus of the aged gerbil via increasing expressions of IGF-1, IGF-1R and <I>p</I>-CREB.</P> <P><B>Highlights</B></P> <P> <UL> <LI> 4-week treatment of rufinamide (Ruf) increases short-term memory in the aged gerbil. </LI> <LI> Ruf increases neurogenesis in the aged hippocampal dentate gyrus (DG). </LI> <LI> Ruf treatment increases IGF-1, IGF-1R, and <I>p</I>-CREB in the aged DG. </LI> <LI> Ruf treatment does not affect expressions of BDNF and TrkB in the aged DG. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Melatonin attenuates scopolamine-induced cognitive impairment via protecting against demyelination through BDNF-TrkB signaling in the mouse dentate gyrus

Chen, Bai Hui,Park, Joon Ha,Lee, Tae-Kyeong,Song, Minah,Kim, Hyunjung,Lee, Jae Chul,Kim, Young-Myeong,Lee, Choong-Hyun,Hwang, In Koo,Kang, Il Jun,Yan, Bing Chun,Won, Moo-Ho,Ahn, Ji Hyeon Elsevier 2018 Chemico-biological interactions Vol.285 No.-

<P><B>Abstract</B></P> <P>Animal models of scopolamine-induced amnesia are widely used to study underlying mechanisms and treatment of cognitive impairment in neurodegenerative diseases such as Alzheimer's disease (AD). Previous studies have identified that melatonin improves cognitive dysfunction in animal models. In this study, using a mouse model of scopolamine-induced amnesia, we assessed spatial and short-term memory functions for 4 weeks, investigated the expression of myelin-basic protein (MBP) in the dentate gyrus, and examined whether melatonin and scopolamine cotreatment could keep cognitive function and MBP expression. In addition, to study functions of melatonin for keeping cognitive function and MBP expression, we examined expressions of brain-derived neurotrophic factor (BDNF) and tropomycin receptor kinase B (TrkB) in the mouse dentate gyrus. Scopolamine (1 mg/kg) and melatonin (10 mg/kg) were intraperitoneally treated for 2 and 4 weeks. Two and 4 weeks after scopolamine treatment, mice showed significant cognitive impairment; however, melatonin and scopolamine cotreatment recovered cognitive impairment. Two and 4 weeks of scopolamine treatment, the density of MBP immunoreactive myelinated nerve fibers was significantly decreased in the dentate gyrus; however, scopolamine and melatonin cotreatment significantly increased the scopolamine-induced reduction of MBP expression in the dentate gyrus. Furthermore, the cotreatment of scopolamine and melatonin significantly increased the scopolamine-induced decrease of BDNF and TrKB immunoreactivity in the dentate gyrus. Taken together, our results indicate that melatonin treatment exerts anti-amnesic effect and restores the scopolamine-induced reduction of MBP expression through increasing BDNF and TrkB expressions in the mouse dentate gyrus.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Long-term treatment of scopolamine (Sco) induces cognitive deficits. </LI> <LI> Long-term treatment of melatonin improves Sco-induced cognitive deficits. </LI> <LI> Sco significantly decreases MBP, BDNF, and TrkB in the dentate gyrus. </LI> <LI> Melatonin restores scopolamine-induced decreases in MBP, BDNF, and TrkB. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Changes in ribosomal protein S3 immunoreactivity and its protein levels in the gerbil hippocampus following subacute and chronic restraint stress.

Park, Joon Ha,Lee, Choong Hyun,Yan, Bing Chun,Ahn, Ji Hyeon,Lee, Young Joo,Park, Chan Woo,Cho, Jun Hwi,Choi, Soo Young,Lee, Yun Lyul,Won, Moo-Ho,Lee, Hui Young Kluwer Academic/Plenum Publishers 2012 Neurochem Res Vol.37 No.7

<P>Ribosomal protein S3 (rpS3), a multi-functional protein, has been known to participate in DNA repair mechanism. In this study, we investigated changes in rpS3 immunoreactivity and its protein levels in the sub-regions of the gerbil hippocampus following subacute and chronic restraint stress. Serum corticosterone levels were increased in both the subacute and chronic-stress-groups compared to the control-group: the level in the subacute-stress-group was much higher than that in the chronic-stress-group. We could not find any neuronal damage in all the sub-regions of the hippocampus after both the subacute and chronic restraint stress. In the subacute-stress-group, rps3 immunoreactivity was not different compared to the control-group. However, rps3 immunoreactivity in the chronic-stress-group was decreased compared to the subacute-stress-group: especially, the immunoreactivity was markedly decreased in the pyramidal cells of the hippocampus proper (CA1-CA3 region) and granule cells of the dentate gyrus. In addition, western blot analysis also showed that rpS3 protein levels in the chronic-stress-group were significantly decreased compared to those in the subacute-stress-group. These findings indicate that chronic stress, not subacute stress, can decrease rpS3 immunoreactivity.</P>

Systemic administration of low dosage of tetanus toxin decreases cell proliferation and neuroblast differentiation in the mouse hippocampal dentate gyrus

Bing Chun Yan,In Hye Kim,Joon Ha Park,Ji Hyeon Ahn,Jeong-Hwi Cho,Bai Hui Chen,Jae-Chul Lee,Jung Hoon Choi,Ki-Yeon Yoo,Choong Hyun Lee,Jun Hwi Cho,Jong-Dai Kim,Moo-Ho Won 한국실험동물학회 2013 Laboratory Animal Research Vol.29 No.3

In the present study, we investigated the effect of Tetaus toxin (TeT) on cell proliferation and neuroblast differentiation using specific markers: 5-bromo-2-deoxyuridine (BrdU) as an exogenous marker for cell proliferation, Ki-67 as an endogenous marker for cell proliferation and doublecortin (DCX) as a marker for neuroblasts in the mouse hippocampal dentate gyrus (DG) after TeT treatment. Mice were intraperitoneally administered 2.5 and 10 ng/kg TeT and sacrificed 15 days after the treatment. In both the TeT-treated groups, no neuronal death occurred in any layers of the DG using neuronal nuclei (NeuN, a neuron nuclei maker) and Fluoro-Jade B (F-J B, a high-affinity fluorescent marker for the localization of neuronal degeneration). In addition, no significant change in glial activation in both the 2.5 and 10 ng/kg TeT-treated-groups was found by GFAP (a marker for astrocytes) and Iba-1 (a marker for microglia) immunohistochemistry. However, in the 2.5 ng/kg TeT-treated-group, the mean number of BrdU, Ki-67 and DCX immunoreactive cells, respectively, were apparently decreased compared to the control group, and the mean number of each in the 10 ng/kg TeT-treated-group was much more decreased. In addition, processes of DCX-immunoreactive cells, which projected into the molecular layer, were short compared to those in the control group. In brief, our present results show that low dosage (10 ng/kg) TeT treatment apparently decreased cell proliferation and neuroblast differentiation in the mouse hippocampal DG without distinct gliosis as well as any loss of adult neurons.

Changes in the expression of DNA-binding/differentiation protein inhibitors in neurons and glial cells of the gerbil hippocampus following transient global cerebral ischemia

LEE, JAE-CHUL,CHEN, BAI HUI,CHO, JEONG-HWI,KIM, IN HYE,AHN, JI HYEON,PARK, JOON HA,TAE, HYUN-JIN,CHO, GEUM-SIL,YAN, BING CHUN,KIM, DAE WON,HWANG, IN KOO,PARK, JINSEU,LEE, YUN LYUL,CHOI, SOO YOUNG,WON, SPANDIDOS PUBLICATIONS 2015 MOLECULAR MEDICINE REPORTS Vol.11 No.4

<P>Inhibitors of DNA-binding/differentiation (ID) proteins bind to basic helix-loop-helix (bHLH) transcription factors, including those that regulate differentiation and cell-cycle progression during development, and regulate gene transcription. However, little is known about the role of ID proteins in the brain under transient cerebral ischemic conditions. In the present study, we examined the effects of ischemia-reperfusion (I-R) injury on the immunoreactivity and protein levels of IDs 1–4 in the gerbil hippocampus proper <I>Cornu Ammonis</I> regions CA1–3 following 5 min of transient cerebral ischemia. Strong ID1 immunoreactivity was detected in the nuclei of pyramidal neurons in the hippocampal CA1–3 regions; immunoreactivity was significantly changed following I-R in the CA1 region, but not in the CA2/3 region. Five days following I-R, ID1 immunoreactivity was not detected in the CA1 pyramidal neurons. ID1 immunoreactivity was detected only in GABAergic interneurons in the ischemic CA1 region. Weak ID4 immunoreactivity was detected in non-pyramidal cells, and immunoreactivity was again only changed in the ischemic CA1 region. Five days following I-R, strong ID4 immunoreactivity was detected in non-pyramidal cells, which were identified as microglia, and not astrocytes, in the ischemic CA1 region. Furthermore, changes in the protein levels of ID1 and ID4 in the ischemic CA1 region studied by western blot were consistent with patterns of immunoreactivity. In summary, these results indicate that immunoreactivity and protein levels of ID1 and ID4 are distinctively altered following transient cerebral ischemia only in the CA1 region, and that the changes in ID1 and ID4 expression may relate to the ischemia-induced delayed neuronal death.</P>

Long-term administration of scopolamine interferes with nerve cell proliferation, differentiation and migration in adult mouse hippocampal dentate gyrus, but it does not induce cell death

Yan, Bing Chun,Park, Joon Ha,Chen, Bai Hui,Cho, Jeong-Hwi,Kim, In Hye,Ahn, Ji Hyeon,Lee, Jae-Chul,Hwang, In Koo,Cho, Jun Hwi,Lee, Yun Lyul,Kang, Il-Jun,Won, Moo-Ho Medknow PublicationsMedia Pvt Ltd 2014 Neural regeneration research Vol.9 No.19

<P>Long-term administration of scopolamine, a muscarinic receptor antagonist, can inhibit the survival of newly generated cells, but its effect on the proliferation, differentiation and migration of nerve cells in the adult mouse hippocampal dentate gyrus remain poorly understood. In this study, we used immunohistochemistry and western blot methods to weekly detect the biological behaviors of nerve cells in the hippocampal dentate gyrus of adult mice that received intraperitoneal administration of scopolamine for 4 weeks. Expression of neuronal nuclear antigen (NeuN; a neuronal marker) and Fluoro-Jade B (a marker for the localization of neuronal degeneration) was also detected. After scopolamine treatment, mouse hippocampal neurons did not die, and Ki-67 (a marker for proliferating cells)-immunoreactive cells were reduced in number and reached the lowest level at 4 weeks. Doublecortin (DCX; a marker for newly generated neurons)-immunoreactive cells were gradually shortened in length and reduced in number with time. After scopolamine treatment for 4 weeks, nearly all of the 5-bromo-2′-deoxyuridine (BrdU)-labeled newly generated cells were located in the subgranular zone of the dentate gyrus, but they did not migrate into the granule cell layer. Few mature BrdU/NeuN double-labeled cells were seen in the subgranular zone of the dentate gyrus. These findings suggest that long-term administration of scopolamine interferes with the proliferation, differentiation and migration of nerve cells in the adult mouse hippocampal dentate gyrus, but it does not induce cell death.</P>

Increased cyclooxygenase-2 and nuclear factor-κB/p65 expression in mouse hippocampi after systemic administration of tetanus toxin

YAN, BING CHUN,JEON, YONG HWAN,PARK, JOON HA,KIM, IN HYE,CHO, JEONG-HWI,AHN, JI HYEON,CHEN, BAI HUI,TAE, HYUN-JIN,LEE, JAE-CHUL,AHN, JI YUN,KIM, DONG WON,CHO, JUN HWI,WON, MOO-HO,HONG, SEONGKWEON SPANDIDOS PUBLICATIONS 2015 MOLECULAR MEDICINE REPORTS Vol.12 No.6

<P>Brain inflammation has a crucial role in various diseases of the central nervous system. The hippocampus in the mammalian brain exerts an important memory function, which is sensitive to various insults, including inflammation induced by exo/endotoxin stimuli. Tetanus toxin (TeT) is an exotoxin with the capacity for neuronal binding and internalization. The present study investigated changes in inflammatory mediators in the mouse hippocampus proper (CA1-3 regions) and dentate gyrus (DG) after TeT treatment. The experimental mice were intraperitoneally injected with TeT at a low dosage (100 ng/kg), while the control mice were injected with the same volume of saline. At 6, 12 and 24 h after TeT treatment, changes in the hippocampal levels of inflammatory mediators cyclooxygenase-2 (COX-2) and nuclear factor kappa-B (NF-κB/p65) were assessed using immunohistochemical and western blot analysis. In the control group, moderate COX-2 immunoreactivity was observed in the stratum pyramidal (SP) of the CA2-3 region, while almost no expression was identified in the CA1 region and the DG. COX-2 immunoreactivity was increased by TeT in the SP and granule cell layer (GCL) of the DG in a time-dependent manner. At 24 h post-treatment, COX-2 immunoreactivity in the SP of the CA1 region and in the GCL of the DG was high, and COX-2 immunoreactivity in the SP of the CA2/3 region was highest. Furthermore, the present study observed that NF-κB/p65 immunoreactivity was obviously increased in the SP and GCL at 6, 12 and 24 h after TeT treatment. In conclusion, the present study demonstrated that systemic treatment with TeT significantly increased the expression of COX-2 and NF-κB/p65 in the mouse hippo-campus, suggesting that increased COX-2 and NF-κB/65 expression may be associated with inflammation in the brain induced by exotoxins.</P>

Ethanol extract of <i>Oenanthe javanica</i> increases cell proliferation and neuroblast differentiation in the adolescent rat dentate gyrus

Chen, Bai Hui,Park, Joon Ha,Cho, Jeong Hwi,Kim, In Hye,Shin, Bich Na,Ahn, Ji Hyeon,Hwang, Seok Joon,Yan, Bing Chun,Tae, Hyun Jin,Lee, Jae Chul,Bae, Eun Joo,Lee, Yun Lyul,Kim, Jong Dai,Won, Moo-Ho,Kang Medknow PublicationsMedia Pvt Ltd 2015 Neural regeneration research Vol.10 No.2

<P><I>Oenanthe javanica</I> is an aquatic perennial herb that belongs to the <I>Oenanthe genus</I> in Apiaceae family, and it displays well-known medicinal properties such as protective effects against glutamate-induced neurotoxicity. However, few studies regarding effects of <I>Oenanthe javanica</I> on neurogenesis in the brain have been reported. In this study, we examined the effects of a normal diet and a diet containing ethanol extract of <I>Oenanthe javanica</I> on cell proliferation and neuroblast differentiation in the subgranular zone of the hippocampal dentate gyrus of adolescent rats using Ki-67 (an endogenous marker for cell proliferation) and doublecortin (a marker for neuroblast). Our results showed that <I>Oenanthe javanica</I> extract significantly increased the number of Ki-67-immunoreactive cells and doublecortin-immunoreactive neuroblasts in the subgranular zone of the dentate gyrus in the adolescent rats. In addition, the immunoreactivity of brain-derived neurotrophic factor was significantly increased in the dentate gyrus of the <I>Oenanthe javanica</I> extract-treated group compared with the control group. However, we did not find that vascular endothelial growth factor expression was increased in the <I>Oenanthe javanica</I> extract-treated group compared with the control group. These results indicate that <I>Oenanthe javanica</I> extract improves cell proliferation and neuroblast differentiation by increasing brain-derived neurotrophic factor immunoreactivity in the rat dentate gyrus.</P>