The ameliorating effect of exercise on long-term memory impairment and dendritic retraction via the mild activation of AMP-activated protein kinase in chronically stressed hippocampal CA1 neurons

( Yea-hyun Leem ),( Hyukki Chang ) 한국운동영양학회 2018 Physical Activity and Nutrition (Phys Act Nutr) Vol.22 No.3

[Purpose] Chronic stress affects the neuronal architecture of hippocampal subfields including the Cornu Ammonis 1 (CA1) region, which governs long-term memory. Exercise exerts a beneficial effect on memory improvement via hippocampal AMP-activated protein kinase (AMPK) activation. However, the relationship between the two phenomena is poorly understood. This study used animal and cell culture experimental systems to investigate whether chronic stress-induced impairment of memory consolidation and maladaptation of the neuronal architecture in the hippocampal CA1 area is prevented by regular exercise through AMPK activation. [Methods] Mice underwent four weeks of treadmill running with or without a 6h/21d-restraint stress regimen, along with treatment with Compound C. Memory consolidation was assessed using the Morris Water Maze (MWM). Dendritic rearrangement of hippocampal CA1 neurons was evaluated using the Golgi-Cox stain and Sholl analysis. Additionally, the primary hippocampal culture system was adopted for in vitro experiments. [Results] Chronic stress-induced failure of memory retention and reduction in AMPK activation were ameliorated by the exercise regimen. Chronic stress- or repeated corticosterone (CORT)- provoked malformation of the neuronal architecture was also suppressed by both exercise and treatment with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR). [Conclusion] Chronic stress causes dendritic retraction among dorsal hippocampal CA1 neurons via the downregulation of AMPK activation, thereby leading to failure of memory retention. In contrast, regular exercise protects against chronic stress-evoked defects in memory consolidation and changes in neuronal morphology in the dorsal hippocampal CA1 area via mild activation of AMPK.

Changes in immunoreactivity of HSP60 and its neuroprotective effects in the gerbil hippocampal CA1 region induced by transient ischemia

Hwang, I.K.,Ahn, H.C.,Yoo, K.Y.,Lee, J.Y.,Suh, H.W.,Kwon, Y.G.,Cho, J.H.,Won, M.H. Academic Press 2007 Experimental neurology Vol.208 No.2

Heat shock proteins act as molecular chaperones and are involved in protein folding, refolding, transport, and translocation. In the present study, we observed changes in heat shock protein 60 (HSP60) immunoreactivity and protein level in the gerbil hippocampal CA1 region after 5 min of transient forebrain ischemia and its neuroprotective effect against ischemic damage. HSP60 immunoreactivity in the CA1 region began to increase in the stratum pyramidale at 30 min after ischemia/reperfusion, and peaked 24 h after ischemia/reperfusion. Thereafter, HSP60 immunoreactivity was decreased in the CA1 region with time. Seven days after ischemia/reperfusion, HSP60 immunoreactivity was increased again in the CA1 region: at this time point after ischemia/reperfusion, HSP60 immunoreactivity was expressed in glial cells in the ischemic CA1 region. HSP60 immunoreactive glial cells were astrocytes containing glial fibrillar acidic protein. In contrast, change in HSP60 immunoreactivity in the ischemic CA2/3 region was not significant compared with that in the ischemic CA1 region. In Western blot study, HSP60 protein level in the CA1 region was increased after ischemia/reperfusion and highest 24 h after ischemia/reperfusion. Animals treated with recombinant adenoviruses expressing Hsp60 (Ad-Hsp60) showed the neuroprotection of CA1 pyramidal neurons from ischemic damage. These results suggest that HSP60 may be associated with delayed neuronal death of CA1 pyramidal neurons after transient ischemia, and the induction of HSP60 protects the neurons from ischemic damage.

Ischemia-related changes in naive and mutant forms of ubiquitin and neuroprotective effects of ubiquitin in the hippocampus following experimental transient ischemic damage

Ahn, H.C.,Yoo, K.Y.,Hwang, I.K.,Cho, J.H.,Lee, C.H.,Choi, J.H.,Li, H.,Cho, B.R.,Kim, Y.M.,Won, M.H. Academic Press 2009 Experimental neurology Vol.220 No.1

Ubiquitin binds to short-lived proteins and denatured proteins produced by various forms of injury. The loss of ubiquitin leads to an accumulation of abnormal proteins and may affect cellular structure and function. The aim of the present study is to observe the chronological changes in ubiquitin naive form and its mutant form (ubiquitin<SUP>+1</SUP>) in the hippocampal CA1 region (CA1) after transient cerebral ischemia in gerbils. Delayed neuronal death in the CA1 was confirmed 4 days after ischemic insult with NeuN immunohistochemistry. Ubiquitin immunoreactivity and protein level in the CA1 were lowest at 12 h after ischemia/reperfusion; thereafter, they were increased with time. Ubiquitin<SUP>+1</SUP> immunoreactivity and protein levels in the CA1 were slightly decreased at 3 h after ischemia/reperfusion, and they were significantly increased 1 day after ischemia/reperfusion. In addition, ubiquitin and ubiquitin<SUP>+1</SUP> immunoreaction was expressed in astrocytes after delayed neuronal death in the ischemic CA1. To elucidate the protective effect of ubiquitin on ischemic damage, the animals were treated with ubiquitin (1.5 mg/kg body weight) intravenously via the femoral vein. Ubiquitin treatment significantly reduced ischemia-induced locomotor hyperactivity, neuronal death and reactive gliosis such as astrocytes and microglia. In addition, 5 days after ubiquitin treatment in the ischemic group, ubiquitin immunoreactivity was similar to that in the ubiquitin-treated sham group, however, ubiquitin<SUP>+1</SUP> immunoreactivity was higher than that in the ubiquitin-treated sham group. These findings indicate that the depletion of ubiquitin and the accumulation of ubiquitin<SUP>+1</SUP> in CA1 pyramidal neurons after transient cerebral ischemia may inhibit ubiquitin proteolytic pathway and this leads to delayed neuronal death of CA1 pyramidal neurons directly or indirectly after transient cerebral ischemia.

Age-Related Changes in Ionized Calcium-Binding Adapter Molecule 1 Immunoreactivity and Protein Level in the Gerbil Hippocampal CA1 Region

CHOI, Jung Hoon,LEE, Choong Hyun,HWANG, In Koo,WON, Moo Ho,SEONG, Je Kyung,YOON, Yeo Sung,LEE, Heungshik S.,LEE, In Se Japanese Society of Veterinary Science 2007 The Journal of veterinary medical science Vol.69 No.11

<P>Microglia are evenly distributed throughout the brain parenchyma. They respond rapidly to a variety of alterations in the microenvironment of the brain and act as sensors for pathological events in the brain. In the present study, we investigated the age-dependent changes in the immunoreactivity and protein level of ionized calcium-binding adapter molecule 1 (Iba-1), a microglial marker, in the CA1 region of the gerbil hippocampus. Iba-1 immunoreactive microglia were detected in the hippocampal CA1 region of the postnatal month 1 (PM 1) group. Iba-1 positive microglia were morphologically inactive between the PM 1 and PM 12 stages. Some Iba-1 immunoreactive microglia were present in the active form in the hippocampal CA1 region of the PM 18 and PM 24 groups. The Iba-1 protein levels in hippocampal CA1 homogenates were decreased in the PM 1 through PM 6 groups and increased in an age-dependent manner thereafter. These results suggest that Iba-1 immunoreactive microglia in the active form were detected in the hippocampal CA1 region in the PM 18 and PM 24 groups. This result may be associated with an age-dependent susceptibility to neurodegenerative diseases associated with the hippocampus.</P>

육미지황탕(六味地黃湯)이 국소(局所) 뇌허혈(腦虛血)로 유발된 기억력(記憶力) 손상(損傷) 백서(白鼠)에 미치는 영향(影響)

김경화 ( Kyung Hwa Kim ),김경수 ( Kyung Su Kim ),김경옥 ( Kyeong Ok Kim ) 대한한방신경정신과학회 2006 동의신경정신과학회지 Vol.17 No.3

Objective : Yukmijihwang-Tang(UJT) has been used for Dementia derived by deficiency of Kidney-Yin in the oriental medicine. This study was planned to examine the effects of UJT on the memory loss induced by focal brain ischemic injury in the rats. Methods : Experimental groups were divided into 4 groups ; Normal group, Control group, UJT1 group and UJT2 group. Control group were no treated after focal brain ischemic injury. UJT1 group were administered UJT 0.3 ㎖/㎏ to focal brain ischemic injuried rats for 21 days, UJT2 group were administered UJT 1.2 ㎖/㎏ to focal brain ischemic injuried rats for 21 days. The present author observed the number of errors on the eight-arm radial maze task, the rate of correct choice on the eight-arm radial maze task, the values of density of Cresyl violet-stained sections in the hippocampal CA1 and the values of density of Acetlycholine Esterase (AchE)stained nuclei in the hippocampal CA1. Results : The number of errors in the Eigth-arm radial maze task was significantly decreased in UJT1 group on 1, 2, 3, 5, 6days, And it was significantly decreased in UJT2 group on 1-6days compared with control group. The rate of correct choice in the eight-arm radial maze task was significantly increased in UJT1, UJT2 group compared with control group. The values of density of Cresyl violet-stained sections in the hippocampal CA1 were significantly increased in UJT1, UJT2 group compared with control group. The values of density of AchE in the hippocampal CA1 were increased in UJT1, UJT2 group compared with control group, but the values were not significant. Conclusions : The present author thought that Yukmijihwang-Tang could be used for curing dementia induced by focal brain ischemic injury.

반하백출천마탕(半夏白朮天麻湯)이 국소(局所) 뇌허혈(腦虛血)로 인(因)한 치매(痴매) 병태 백서(白鼠)에 미치는 영향(影響)

김수연 ( Su Youn Kim ),원호영 ( Ho Young Won ),최창원 ( Chang Won Choi ),김경수 ( Kyung Su Kim ),김경옥 ( Kyeong Ok Kim ),이동원 ( Dong Won Lee ) 대한한방신경정신과학회 2006 동의신경정신과학회지 Vol.17 No.2

Objective :This study was to investigate the effects of Banhabaekchulchunma-Tang(BCT) on Dementia induced by focal ischemic injury in the rats. Method :Experimental groups were divided into 4 groups ; Normal group, Control group, BCT1 group and BCT2 group. Control group were no treated after focal brain ischemic injury. BCT1 group were administered BCT 0.3 ㎖/㎏ to focal brain ischemic injuried rats for 21 days, BCT2 group were administered BCT 1.2 ㎖/㎏ to focal brain ischemic injuried rats for 21 days.The present author observed the number of errors on the eight-arm radial maze task , the rate of correct choice on the eight-arm radial maze task, the values of density of Cresyl Violet-stained sections in the hippocampal CA1 and the values of density of Acetlycholin Esterase(AchE) stained nuclei in the hippocampal CA1. Result :1. The number of errors in the eight-arm radial maze task was significantly decreased in BCT1 group on 1-6th days. And it was significantly decreased in BCT2 group on 1st, 2nd, 3rd and 6th day compared with control group.2. The rate of correct choice on the eight-arm radial maze task was increased in BCT1 group and BCT2 group compared with control group, but the value was not significant. 3. The values of density of Cresyl Violet-stained sections in the hippocampal CA1 were significantly increased in BCT1 group and BCT2 group compared with control group. 4. The values of density of AchE stained nuclei in the hippocampal CA1 were significantly increased in BCT1 group compared with control group. Conclusion : The present author thought that Banhabaekchulchunma-Tang could be used to cure dementia derived by the phlegm retention of fluid.

Correlation between Brain Ischemia-Reperfusion Injury and Tumor Necrosis Factor-αfollowing Cardiac Arrest in Rats

Choi, Seung-Pil,Park, Kyu-Nam,Park, Seung-Hyun,Park, Sang-Hyun,Jeong, Si-Kyoung,Kim, Se-Kyung 가톨릭대학교 2000 Bulletin of The Catholic Research Institutes of Me Vol.28 No.-

Background : Tumor necrosis factor-α (TNF-α) has been thought to play a major role in neurological injury during global brain ischemia and subsequent reperfusion following resuscitation in cardiac arrest. So, we hypothesized that the elevation in TNF-α was dependent upon the duration of the global brain ischemia, and related to delayed neuronal damage. Methods : Fourteen rats were divided two groups: 1 minute-cardiac group (n=7) and 3 minute-cardiac arrest group (n=7). We induced cardiac arrest by chest compression and clamping of tracheal tube for 1 minute and 3 minutes respectively. And then, resuscitation was initiated. To measure the plasma activity of TNF-α, blood samples were drawn before and at the end of cardiac arrest, and 30, 60, 90, and 120 minutes after initiation reperfusion. At 72 hours after resuscitation, the ND (neurologic deficit) score was determined and the histopathologic outcome of hippocampal CA1 neuron was observed by the percent of dead hippocampal CA1 neurons. Results : 1.TNF-α level during the early reperfusion period (<2h) was significantly increased in 3 min-cardiac arrest group compared with 1 min-cardiac arrest group (P=0.0001). 2.There was no significant difference of neurologic deficit score between 1 min and 3 min-cardiac arrest. 3.Percent of dead hippocampal neurons were significantly increased in 3 min-cardiac arrest group compared with 1 min-cardiac arrest group (9.1˚æ1.2% vs 1.2˚æ0.9%, P<0.05). Conclusions : The results suggest that longer duration of global brain ischemia caused a more profound in plasma TNF-α level during the early reperfusion period (<2h) and more delayed neuronal damage than lesser duration of global brain ischemia, and that incresase in TNF-α level during the early reperfusion period (<2h) was related to delayed neuronal damage. (Journal of the Korean Society of Emergency Medicine 10(4):531-540, 1999)

Cell-autonomous reduction of CYFIP2 is insufficient to induce Alzheimer’s disease-like pathologies in the hippocampal CA1 pyramidal neurons of aged mice

Ruiying Ma,Yinhua Zhang,Huiling Li,강혜림,김윤희,한기훈 한국통합생물학회 2023 Animal cells and systems Vol.27 No.1

Cytoplasmic FMR1-interacting protein 2 (CYFIP2) is an evolutionarily conserved multifunctionalprotein that regulates the neuronal actin cytoskeleton, mRNA translation and transport, andmitochondrial morphology and function. Supporting its critical roles in proper neuronaldevelopment and function, human genetic studies have repeatedly identified variants of theCYFIP2 gene in individuals diagnosed with neurodevelopmental disorders. Notably, a fewrecent studies have also suggested a mechanistic link between reduced CYFIP2 level andAlzheimer’s disease (AD). Specifically, in the hippocampus of 12-month-old Cyfip2heterozygous mice, several AD-like pathologies were identified, including increased levels ofTau phosphorylation and gliosis, and loss of dendritic spines in CA1 pyramidal neurons. However, detailed pathogenic mechanisms, such as cell types and their circuits where thepathologies originate, remain unknown for AD-like pathologies caused by CYFIP2 reduction. In this study, we aimed to address this issue by examining whether the cell-autonomousreduction of CYFIP2 in CA1 excitatory pyramidal neurons is sufficient to induce AD-likephenotypes in the hippocampus. We performed immunohistochemical, morphological, andbiochemical analyses in 12-month-old Cyfip2 conditional knock-out mice, which havepostnatally reduced CYFIP2 expression level in CA1, but not in CA3, excitatory pyramidalneurons of the hippocampus. Unexpectedly, we could not find any significant AD-likephenotype, suggesting that the CA1 excitatory neuron-specific reduction of CYFIP2 level isinsufficient to lead to AD-like pathologies in the hippocampus. Therefore, we propose thatCYFIP2 reduction in other neurons and/or their synaptic connections with CA1 pyramidalneurons may be critically involved in the hippocampal AD-like phenotypes of Cyfip2heterozygous mice.

Temporal changes in mammalian target of rapamycin (mTOR) and phosphorylated-mTOR expressions in the hippocampal CA1 region of rat with vascular dementia

박진아,이충현 대한수의학회 2017 Journal of Veterinary Science Vol.18 No.1

Mammalian target of rapamycin (mTOR) has an important role in various biological processes in cells. In the present study, we investigated temporal changes in mTOR and phosphorylated-mTOR (p-mTOR) expressions in the rat hippocampal CA1 region following chronic cerebral hypoperfusion (CCH) induced by permanent bilateral common carotid arteries occlusion (2VO). The mTOR immunoreactivity in the pyramidal neurons and mTOR protein level in the hippocampal CA1 region were markedly decreased at 21 and 28 days after 2VO surgery. However, p-mTOR protein expression was significantly increased at 7 days following CCH but then decreased with time. The results indicate that mTOR and p-mTOR expressions change in the hippocampal CA1 region after 2VO surgery and that reduced expressions of mTOR and p-mTOR may be closely related to the CCH-induced neuronal damage in the hippocampal CA1 region.

Berberry Extract Reduces Neuronal Damage and <i>N</i>-Methyl-<small>D</small>-aspartate Receptor 1 Immunoreactivity in the Gerbil Hippocampus after Transient Forebrain Ischemia

Yoo, Ki-Yeon,Hwang, In Koo,Lim, Beong Ou,Kang, Tae-Cheon,Kim, Dong-Woo,Kim, Sang Moo,Lee, Hyeon Yong,Kim, Jong Dai,Won, Moo Ho Pharmaceutical Society of Japan 2006 BIOLOGICAL & PHARMACEUTICAL BULLETIN Vol.29 No.4

<P>In the present study, we studied the neuroprotective effects of berberry extract (BE) against ischemic damage and the temporal and spatial alterations of <I>N</I>-methyl-<SMALL>D</SMALL>-aspartate receptor type 1 (NR1) and NR2A/2B immunoreactivities in the gerbil hippocampal CA1 region after transient ischemia to examine anti-ischemic effects and its role in transient forebrain ischemia. In the vehicle-treated group, the percentage of cresyl violet positive pyramidal cells in the CA1 region was about 11.4% compared to the sham-operated group 4 d after ischemic insult. BE showed neuroprotective effects against ischemic damage after ischemia-reperfusion. In the BE-treated groups, about 60—75% of CA1 pyramidal cells were stained with cresyl violet 4 d after ischemic insult. We observed the percentage of berberine (7.45+0.85 mg/g in BE) by HPLC, which is active ingredient of BE. NR1 immunoreactivity in the stratum pyramidale of the CA1 region in the vehicle-treated group was significantly increased at 30 min after transient forebrain ischemia, while at this time the NR1 immunoreactivity in the BE-treated groups was significantly low compared to the vehicle-treated group. The pattern of NR2A/B immunoreactivity in the stratum pyramidale of the BE-treated group and its protein levels were similar to that in the vehicle-treated group after ischemic insult. These results suggest that BE has potent neuroprotective effects against ischemic damage <I>via</I> the reduction of NR1 activity.</P>