Biological Studies on Alcohol-Induced Neuronal Damage

Masaru Tateno,Toshikazu Saito 대한신경정신의학회 2008 PSYCHIATRY INVESTIGATION Vol.5 No.1

Alcohol is a well-known cytotoxic agent which causes various kinds of neuronal damage. In spite of thousands of published studies, the true mechanism of alcohol-induced neuronal damage remains unclear. Neurogenesis is the generation of neurons from neural stem cells (NSCs) and occurs in predominantly two regions of the brain, the subventricular zone and the dentate gyrus of the hippocampus. NSCs are the self-renewing, multipotent precursor cells of neurons, strocytes, and oligodendrocytes in the central nervous system. Recent studies have begun to illuminate the role of neurogenesis in the biological and cellular basis of psychiatric disorders and several clinical symptoms seen in alcoholism such as depression, cognitive impairment, underlying stress and brain atrophy have been linked to impaired neurogenesis. Heavy alcohol consumption decreases neurogenesis in animals, while in vitro studies have shown decreased generation of new neurons after alcohol exposure. These findings suggest that decreased neurogenesis is important in the pathophysiology of alcoholism. Neurogenesis can be divided into four stages; proliferation, migration, differentiation and survival. Our in vitro studies on NSCs showed that alcohol decreased neuronal differentiation at doseslower than those that affected cell survival and suggested that neuron-restrictive silencer factor, or repressor element-1 silencing transcription factor (NRSF/REST) could be involved in alcohol-induced inhibition of neuronal differentiation. In an animal model of fetal alcohol effects behavioral symptoms improved after NSC transplantation. Neurogenesis could be the target for new strategies to treat alcohol related disorders. Alcohol is a well-known cytotoxic agent which causes various kinds of neuronal damage. In spite of thousands of published studies, the true mechanism of alcohol-induced neuronal damage remains unclear. Neurogenesis is the generation of neurons from neural stem cells (NSCs) and occurs in predominantly two regions of the brain, the subventricular zone and the dentate gyrus of the hippocampus. NSCs are the self-renewing, multipotent precursor cells of neurons, strocytes, and oligodendrocytes in the central nervous system. Recent studies have begun to illuminate the role of neurogenesis in the biological and cellular basis of psychiatric disorders and several clinical symptoms seen in alcoholism such as depression, cognitive impairment, underlying stress and brain atrophy have been linked to impaired neurogenesis. Heavy alcohol consumption decreases neurogenesis in animals, while in vitro studies have shown decreased generation of new neurons after alcohol exposure. These findings suggest that decreased neurogenesis is important in the pathophysiology of alcoholism. Neurogenesis can be divided into four stages; proliferation, migration, differentiation and survival. Our in vitro studies on NSCs showed that alcohol decreased neuronal differentiation at doseslower than those that affected cell survival and suggested that neuron-restrictive silencer factor, or repressor element-1 silencing transcription factor (NRSF/REST) could be involved in alcohol-induced inhibition of neuronal differentiation. In an animal model of fetal alcohol effects behavioral symptoms improved after NSC transplantation. Neurogenesis could be the target for new strategies to treat alcohol related disorders.

Isolation of Early Neurogenesis Genes with Xenopus cDNA Microarray

Saet-Byeol Yu,Ok-Joo Lee,Young-Ju Park,Sung-Young Lee,Seung-Hwan Lee,Jaeho Yoon,Yoo-Seok Hwang,Jong-Il Kim,Jae-Yong Lee,Jae-Bong Park,Sung Chan Kim,Jaebong Kim 한국실험동물학회 2010 Laboratory Animal Research Vol.26 No.1

Neurogenesis is the process that develops neuroectoderm from ectoderm. Bone morphogenetic protein (BMP) inhibition in ectodermal cells is necessary and sufficient for neurogenesis in Xenopus embryos. To isolate genes involved in early neurogenesis, Xenous Affymetrix gene chips representing 14,400 genes were analyzed in early stage of neuroectodermal cells that were produced by inhibition of BMP signaling with overexpression of a dominant-negative receptor. We identified 265 candidate genes including 107 ESTs which were newly expressed during the early neurogenesis by blocking BMP signaling. The candidates of 10 ESTs were selected and examined for upregulation in neuroectoderm. Five EST genes were confirmed to be upregulated in neuroectoderm and examined for time-dependent expression patterns in intact embryos. Two EST genes were cloned and identified as a homology of CYP26c (Xl.1946.1.A1_at) and Kielin containing VWC domain (Xl.15853.1.A1_at). One of them, CYP26c, was further characterized for its transcriptional regulation and role of anterior-posterior patterning during neurogenesis. Taken together, we analyzed and characterized genes expressed in early neurogenesis. The results suggest that neurogenesis by inhibition of BMP provides useful system to isolate genes involved in early events of neurogenesis during early vertebrate embryogenesis.

Zinc chelation reduces traumatic brain injury-induced neurogenesis in the subgranular zone of the hippocampal dentate gyrus

Choi, B.Y.,Kim, J.H.,Kim, H.J.,Lee, B.E.,Kim, I.Y.,Sohn, M.,Suh, S.W. Gustav Fischer 2014 Journal of trace elements in medicine and biology Vol.28 No.4

Numerous studies have demonstrated that traumatic brain injury (TBI) increases hippocampal neurogenesis in the rodent brain. However, the mechanisms underlying increased neurogenesis after TBI remain unknown. Continuous neurogenesis occurs in the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG) in the adult brain. The mechanism that maintains active neurogenesis in the hippocampal area is not known. A high level of vesicular zinc is localized in the presynaptic terminals of the SGZ (mossy fiber). The mossy fiber of dentate granular cells contains high levels of chelatable zinc in their terminal vesicles, which can be released into the extracellular space during neuronal activity. Previously, our lab presented findings indicating that a possible correlation may exist between synaptic zinc localization and high rates of neurogenesis in this area after hypoglycemia or epilepsy. Using a weight drop animal model to mimic human TBI, we tested our hypothesis that zinc plays a key role in modulating hippocampal neurogenesis after TBI. Thus, we injected a zinc chelator, clioquinol (CQ, 30mg/kg), into the intraperitoneal space to reduce brain zinc availability twice per day for 1 week. Neuronal death was evaluated with Fluoro Jade-B and NeuN staining to determine whether CQ has neuroprotective effects after TBI. The number of degenerating neurons (FJB (+)) and live neurons (NeuN (+)) was similar in vehicle and in CQ-treated rats at 1 week after TBI. Neurogenesis was evaluated using BrdU, Ki67 and doublecortin (DCX) immunostaining 1 week after TBI. The number of BrdU, Ki67 and DCX positive cell was increased after TBI. However, the number of BrdU, Ki67 and DCX positive cells was significantly decreased by CQ treatment. The present study shows that zinc chelation did not prevent neurodegeneration but did reduce TBI-induced progenitor cell proliferation and neurogenesis. Therefore, this study suggests that zinc has an essential role for modulating hippocampal neurogenesis after TBI.

Adult Neurogenesis in Insulted Brain

Kim, Byung-Woo,Son, Hyeon Korean Society of ToxicologyKorea Environmental Mu 2007 Toxicological Research Vol.23 No.2

Although there are some questions about the venues of adult neurogenesis, it is undoubtedly accepted that new neurons are born in adult brains. Adult neurogenesis is regulated by a wide array of factors. Insults harmful to brain, such as neurodegenerative diseases, seizure, ischemia and exposure to drugs of abuse, are intricately related to adult neurogenesis. Whereas neurodegenerative diseases are characterized by death or functional loss of specific neurons, recent studies report that they can be accompanied by neurogenesis. In addition, alcohol and drugs of abuse which have been reputed to cause irreversible damage to brain can also generate newly born cells in adult brain. As yet, however, we have little knowledge of the functional significance and roles of adult neurogenesis under pathological settings, not to mention under physiological settings. Accordingly, in this review we briefly summarize the results of studies which focus on adult neurogenesis in insulted brain, instead of trying to draw hurried conclusion regarding the relationship between adult neurogenesis and brain insults.

Transient global ischemia increases apoptosis and neurogenesis in rat dentate gyrus

Ko, Bok Hyun 東國大學校醫學硏究所 2003 東國醫學 Vol.10 No.2

흰쥐 치아이랑(dentate gyrus)의 과립세포들은 발생 중 뿐 만 아니라 성체에서도 형성되며 과립세포들에서의 세포자연사는 일생을 통하여 계속 진행된다는 것이 알려져 있다. 본 실험은 허혈로 초래되는 성체 흰쥐 치아이랑 과립세포들의 신경발생(neurogenesis)과 세포자연사(apoptosis) 그리고 이와 연관된 Bcl-2의 발현변화의 연관성을 알아보기 위하여 수행되었다. 본 실험에서는 또한 NMDA 수용체의 양적변화가 허혈로 초래되는 세포자연사 혹은 신경발생에 관여할 수 있다는 가설을 설정하였다. TUNEL 실험에서 허혈로 초래된 세포자연사는 치아이랑의 과립세포층 (granular zone)에서 주로 발생됨이 관찰되었고 proliferating cell nuclear antigen (PCNA), glial fibrillary acidic protein (GFAP), synapsin-α를 이용한 면역세포화학 실험을 통하여 신경발생은 주로 치아이랑의 과립세포하층 (subgranular zone)에서 발생한다는 것이 관찰되었다. Bcl-2 면역반응성의 점차적 증가는 치아이랑 과립세포하층에서의 신경발생시기와 일치하였으나 과립세포층의 세포자연사의 시기와는 일치하지 않았다. NR2A, NR2B의 anti-sense probe를 이용한 in situ hybridization에서는 허혈로 인한 NMDA 수용체의 유의한 감소가 치아이랑 과립세포들에서 관찰되었다. 이러한 결과들은 치아이랑 과립세포층의 세포자연사를 유도하는 허혈이 치아이랑에서의 신경발생의 직접적 자극이 될 수 있음을 제시한다. 또한 치아이랑 내 과립세포들의 자연사 여부는 과립세포들의 성숙정도와 관련이 있을 것으로 생각되며 이는 Bcl-2의 발현증가 여부와 밀접한 관련이 있을 것으로 생각된다. 마지막으로 본 실험은 허혈이 NMDA 수용체의 숫적 감소를 야기함으로서 치아이랑 과립세포하층에서의 신경발생을 촉진시킬 수 있는 가능성을 제시하였다. Granule neurons of the rat dentate gyrus (DG) are born in adulthood as well as during development. Apoptotic cell death also occurs normally in the population throughout the life of the rat brain. The present work was designed to determine whether the transient global ischemia can accelerate proliferation and apoptosis of DG granule cells which might be correlated with expression of Bcl-2 protein within the ischemic DG. We also hypothesized that the amount of functional N-methyl-D-aspartate (NMDA) receptor could be involved in ischemia-induced apoptosis or neurogenesis. TUNEL study revealed that significant apoptosis was in the granular zone (GZ) of the ischemic DG. However, immunocytochemical studies with proliferating cell nuclear antigen (PCNA), glial fibrillary acidic protein (GFAP) and synapsin-α demonstrated that neurogenesis occurred in subgranular zone (SGZ) of the ischemic DG. The gradual increase of the Bcl-2 expression is paralleled with neurogenesis in the SGZ but not with apoptosis in the GZ of the DG. In situ hybridization using the antisense probe to the NR2A and NR2B subunits revealed significant decrease of the functional NMDA receptors in the ischemic DG. These results suggest that neurogenesis in the DG may be stimulated by the ischemia which leads to the apoptotic cell death in the GZ of the DG. In addition, granule cell apoptosis in the DG depends on the expression of the Bcl-2 which determine the maturity of granule cells. Finally, we suggest the possibility that reduction of the dentate NMDA receptors by ischemia may be assocated with stimulation of neurogenesis in the SGZ of the DG.

Neuroprotection in Schizophrenia and Its Therapeutic Implications

YongKu Kim,KyoungSae Na 대한신경정신의학회 2017 PSYCHIATRY INVESTIGATION Vol.14 No.4

Schizophrenia is a chronic and debilitating mental disorder. The persisting negative and cognitive symptoms that are unresponsive to pharmacotherapy reveal the impairment of neuroprotective aspects of schizophrenia. In this review, of the several neuroprotective factors, we mainly focused on neuroinflammation, neurogenesis, and oxidative stress. We conducted a narrative and selective review. Neuroinflammation is mainly mediated by pro-inflammatory cytokines and microglia. Unlike peripheral inflammatory responses, neuroinflammation has a role in various neuronal activities such as neurotransmission neurogenesis. The cross-talk between neuroinflammation and neurogenesis usually has beneficial effects in the CNS under physiological conditions. However, uncontrolled and chronic neuroinflammation exert detrimental effects such as neuronal loss, inhibited neurogenesis, and excessive oxidative stress. Neurogenesis is also a major component of neuroprotection. Adult neurogenesis mainly occurs in the hippocampal region, which has an important role in memory formation and processing. Impaired neurogenesis and an ineffective response to antipsychotics may be thought to indicate a deteriorating course of schizophrenia. Oxidative stress and excessive dopaminergic neurotransmission may create a vicious cycle and consequently disturb NMDA receptor-mediated glutamatergic neurotransmission. Based on the current evidences, several neuroprotective therapeutic approaches have been reported to be efficacious for improving psychopathology, but further longitudinal and large-sample based studies are needed.

An Aminopropyl Carbazole Derivative Induces Neurogenesis by Increasing Final Cell Division in Neural Stem Cells

( Jae Yeon Shin ),( Sun Young Kong ),( Hye Jin Yoon ),( Jih Yae Ann ),( Jee Woo Lee ),( Hyun Jung Kim ) 한국응용약물학회 2015 Biomolecules & Therapeutics(구 응용약물학회지) Vol.23 No.4

P7C3 and its derivatives, 1-(3,6-dibromo-9H-carbazol-9-yl)-3-(p-tolylamino)propan-2-ol (1) and N-(3-(3,6-dibromo-9H-carbazol- 9-yl)-2-hydroxypropyl)-N-(3-methoxyphenyl)-4-methylbenzenesulfonamide (2), were previously reported to increase neurogenesis in rat neural stem cells (NSCs). Although P7C3 is known to increase neurogenesis by protecting newborn neurons, it is not known whether its derivatives also have protective effects to increase neurogenesis. In the current study, we examined how 1 induces neurogenesis. The treatment of 1 in NSCs increased numbers of cells in the absence of epidermal growth factor (EGF) and fibroblast growth factor 2 (FGF2), while not affecting those in the presence of growth factors. Compound 1 did not induce astrocytogenesis during NSC differentiation. 5-Bromo-2``-deoxyuridine (BrdU) pulsing experiments showed that 1 significantly enhanced BrdU-positive neurons. Taken together, our data suggest that 1 promotes neurogenesis by the induction of final cell division during NSC differentiation.

20(S)-protopanaxadiol and oleanolic acid ameliorate cognitive deficits in APP/PS1 transgenic mice by enhancing hippocampal neurogenesis

Kaili Lin,Stephen Cho-Wing Sze,Bin Liu,Zhang Zhang,Zhu Zhang,Peili Zhu,Ying Wang,Qiudi Deng,Ken Kin-Lam Yung,Shiqing Zhang 고려인삼학회 2021 Journal of Ginseng Research Vol.45 No.2

Background: Alzheimer"s disease (AD) is one of the most prevalent neurodegenerative disorders. Enhancing hippocampal neurogenesis by promoting proliferation and differentiation of neural stem cells (NSCs) is a promising therapeutic strategy for AD. 20(S)-protopanaxadiol (PPD) and oleanolic acid (OA) are small, bioactive compounds found in ginseng that can promote NSC proliferation and neural differentiation in vitro. However, it is currently unknown whether PPD or OA can attenuate cognitive deficits by enhancing hippocampal neurogenesis in vivo in a transgenic APP/PS1 AD mouse model. Here, we administered PPD or OA to APP/PS1 mice and monitored the effects on cognition and hippocampal neurogenesis. Methods: We used the Morris water maze, Y maze, and open field tests to compare the cognitive capacities of treated and untreated APP/PS1 mice. We investigated hippocampal neurogenesis using Nissl staining and BrdU/NeuN double labeling. NSC proliferation was quantified by Sox2 labeling of the hippocampal dentate gyrus. We used western blotting to determine the effects of PPD and OA on Wnt/GSK3β/β-catenin pathway activation in the hippocampus. Results: Both PPD and OA significantly ameliorated the cognitive impairments observed in untreated APP/PS1 mice. Furthermore, PPD and OA significantly promoted hippocampal neurogenesis and NSC proliferation. At the mechanistic level, PPD and OA treatments resulted in Wnt/GSK-3β/β-catenin pathway activation in the hippocampus. Conclusion: PPD and OA ameliorate cognitive deficits in APP/PS1 mice by enhancing hippocampal neurogenesis, achieved by stimulating the Wnt/GSK-3β/β-catenin pathway. As such, PPD and OA are promising novel therapeutic agents for the treatment of AD and other neurodegenerative diseases.

성체 뇌 조직의 신경발생

김식현,김상수,Kim, Sik-Hyun,Kim, Sang-Su 대한고유수용성신경근촉진법학회 2008 PNF and Movement Vol.6 No.3

Purpose : This paper focuses on the emerging concept that adult central nervous system neurogenesis can be regulated by various physical activity, enriched environment, and pathological conditions. Neurogenesis-the production of new neuron-is an ongoing process that persists in the adult brain of mammalian, including humans. Result : The adult brain was thought be limited in its regenerative function. However, this concepts changed, recent evidence of neurogenesis in certain adult brain areas such as SVZ(subventricular zone) and SGZ(subgranular zone) in hippocampus, raised possibility for improved treatment for patient with stroke. Neural plasticity has an adaptive purpose, because an ability of the brain to change in response to peripheral stimulation, physical activity, experience, and injury. Conclusions : The major function of the neurogenesis in adult brain seems to be replacing the neuron that die regularly in discrete adult brain regions. These cells are capable of functionally integrating into neighboring neural cells, and reconnecting to the correct neural networks. This review suggest that various intervention, including physical activity, voluntary movement training, skilled forelimb reaching training, and enriched environment, induced neural cell production in certain adult brain, and associated with functional recovery after stroke.

Signal Transducer and Activator of Transcription-3 Maintains the Stemness of Radial Glia at Mid-Neurogenesis

Hong, Seulgi,Song, Mi-Ryoung Society for Neuroscience 2015 The Journal of neuroscience Vol.35 No.3

<P>Radial glial cells are stem cell-like populations of glial nature that supply neurons either directly or indirectly via basal progenitors that give rise to neurons. Here we show that signal transducer and activator of transcription-3 (STAT3) signaling, a cytokine signaling mediated by Janus tyrosine kinase (Jak), is active during neurogenesis in radial glia (RG) but not in basal progenitors. Enhanced STAT3 signaling in cortical progenitors caused more RG to persist rather than become neurons. Targeted deletion or RNAi-mediated knockdown of <I>Stat3</I> resulted in fewer radial glial cells and more basal progenitors and led to premature neurogenesis. The neuronal populations affected in <I>Stat3</I> mutant mice were the late-born neurons that constitute the upper cortical layers rather than early-born neurons, thus supporting the view that the role of STAT3 at mid-neurogenesis is layer specific. Analysis of dividing RG revealed that STAT3 selectively increased the proportion of dividing RG, whereas downregulation of STAT3 reduced the proportion. Consistent with this, STAT3 activity in dividing RG was associated frequently with vertical cleavage. Pair-cell analysis showed that elevated STAT3 activity correlated with symmetric division of RG, producing more RG, whereas elimination of STAT3 generated more neurogenic cells. Together, our results suggest that STAT3 maintains the stemness of RG and inhibits their transition to basal progenitors at mid-neurogenesis, so probably preserving a pool of RG for later neurogenesis or gliogenesis.</P>