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Neurotrophin-induced ROS production and neuronal death
Gwag, Byoung Joo 이화여자대학교 세포신호전달연구센터 2004 고사리 세포신호전달 심포지움 Vol. No.6
The neurotrophins, a class of nerve growth factor-related growth factors, promote the differentiation, growth, and survival of neurons by binding to Trk receptor tyrosine kinases and p75(NTR). Once synthesized in target cells, neurotrophins are released, bound to the cell surface receptors, and internalized to promote neuronal survival by interfering with programmed cell death or apoptosis. In addition to neuroprotective potential of neurotrophins, neurotrophins potentiate neuronal injury under various pathological conditions. Moreover, evidence has accumulated showing that neurotrophins can induce neuronal death. While cellular and molecular mechanisms underlying anti-apoptosis action of neurotrophins have been well documented, mechanisms for pro-necrosis effects of neurotrophins remain to be unveiled. Here, we delineated the patterns and underlying mechanisms of neuronal death induced by neurotrophins.
Gwag, Byoung Joo 이화여자대학교 세포신호전달연구센터 2000 고사리 세포신호전달 심포지움 Vol. No.2
Free radicals appear to act as key mediators of neuronal death produced under certain pathological conditions such as stroke and neurodegenerative diseases. We have studied how reactive oxygen species(ROS) such as hydroxyl radical and superoxide produce neuronal death. We found that cortical cell cultures exposed to Fe^(2+)(produces hydroxyl radical through Fenton chemistry), buthionine sulfoximine(BSO, depletes glutathione), or menadione(produces superoxide) underwent neuronal death exclusively through necrosis sensitive to trolox or N-acetyl-L-cysteine. Death was accompanied by marked swelling of cell body, fenestration of plasma membrane prior to nuclear membrane, and scattering condensation of nuclear chromatin. Entry of zinc that causes neuronal death in hypoxic-ischemic brain also produces ROS-mediated neuronal cell necrosis. The ROS-mediated neuronal death was insensitive to glutamate antagonists and potentiated by growth factors that attenuate neuronal apoptosis induced in cortical cell cultures. Generation and neurotoxicity of ROS was prevented by maneuvers preventing activity of PKA or cyclooxygenases, but not by PKC inhibitor. Interestingly, increasing mitochondrial membrane and redox potentials protected cortical neurons from Fe^(2+)- or BSO-induced ROS injuries without beneficial effects on neuronal apoptosis resulting from exposure to staurosporine or cyclosporine A. This implies that execution of ROS neurotoxicity likely requires activation of PKA or cyclooxygenases without sharing pro-apoptosis pathway. Finally, we examined if ROS would contribute to selective neuronal death that underlies common features of neurodegenerative diseases. In striatal cell cultures, NADPH-diaphorase neurons that are selectively spared in Huntington's disease(HD) were highly resistant to injuries induced by Fe^(2+) or BSO. Single cell PCR analysis of striatal neurons demonstrated that levels of mRNAs encoding anti-oxidant enzymes were substantially high in NADPH-diaphorase neurons. It is hypothesized that intracellular levels of antioxidant defence enzymes as well as prooxidants may determine differential vulnerability to certain populations of neurons in HD and possibly other neurodegenerative diseases.
In vivo tracking of human mesenchymal stem cells in experimental stroke.
Kim, Daehong,Chun, Byoung-Gi,Kim, Yeon-Kyung,Lee, Yong Hyun,Park, Cheong-Soo,Jeon, Iksoo,Cheong, Chaejoon,Hwang, Tae-Sun,Chung, Hyungmin,Gwag, Byoung Joo,Hong, Kwan Soo,Song, Jihwan Pergamon Press ; Elsevier Science Ltd ; Elsevier S 2007 CELL TRANSPLANTATION Vol.16 No.10
<P>To understand the fates of human mesenchymal stem cells (hMSCs) following transplantation into a rodent model of middle cerebral artery occlusion (MCAo), magnetic resonance imaging (MRI) techniques were employed, hMSCs were labeled with ferumoxides (Feridex)--protamine sulfate complexes, which were visualized and examined by MRI up to 10 weeks following transplantation. Migration of the transplanted cells to the infarcted area was further confirmed by histological methods. We found that the hMSCs transplanted in MCAo models possess the capacity to migrate to the infarcted area extensively in both ipsilateral and contralateral injections, exhibiting a pathotropism. We also analyzed the detailed migration patterns of transplanted hMSCs. We speculate that the extensive migratory ability of hMSCs may represent a therapeutic potential for developing efficient cell transplantation strategies in stroke.</P>
Cellular and Molecular Pathways of Ischemic Neuronal Death
Kim, Doo Yeon,Gwag, Byoung Joo,Won, Seok Joon 생화학분자생물학회 1998 BMB Reports Vol.35 No.1
Three routes have been identified triggering neuronal death under physiological and pathological conditions. Excess activation of ionotropic glutamate receptors cause influx and accumulation of Ca^(2+) and Na^+ that result in rapid swelling and subsequent neuronal death within a few hours. The second route is caused by oxidative stress due to accumulation of reactive oxygen and nitrogen species. Apoptosis or programmed cell death that often occurs during developmental process has been coined as additional route to pathological neuronal death in the mature nervous system. Evidence is being accumulated that excitotoxicity, oxidative stress, and apoptosis propagate through distinctive and mutually exclusive signal transduction pathway and contribute to neuronal loss following hypoxic-ischemic brain injury. Thus, the therapeutic intervention of hypoxic-ischemic neuronal injury should be aimed to prevent excitotoxicity, oxidative stress, and apoptosis in a concerted way.
Lee, Hwan-Goo,Won, Sun-Mi,Gwag, Byoung-Joo,Lee, Yong-Beom Korean Society for Biochemistry and Molecular Bion 2011 Experimental and molecular medicine Vol.43 No.1
The possibility that $P2X_7$ receptor ($P2X_7R$) expression in microglia would mediate neuronal damage $via$ reactive oxygen species (ROS) production was examined in the $APP_{swe}$/PS1dE9 mouse model of Alzheimer's disease (AD). $P2X_7R$ was predominantly expressed in CD11b-immunopositive microglia from 3 months of age before A${\beta}$ plaque formation. In addition, $gp91^{phox}$, a catalytic subunit of NADPH oxidase, and ethidium fluorescence were detected in $P2X_7R$-positive microglial cells of animals at 6 months of age, indicating that $P2X_7$R-positive microglia could produce ROS. Postsynaptic density 95-positive dendrites showed significant damage in regions positive for $P2X_7R$ in the cerebral cortex of 6 month-old mice. Taken together, up-regulation of $P2X_7R$ activation and ROS production in microglia are parallel with A${\beta}$ increase and correlate with synaptotoxicity in AD.
Cellular and Molecular Pathways of Ischemic Neuronal Death
Won, Seok-Joon,Kim, Doo-Yeon,Gwag, Byoung-Joo Korean Society for Biochemistry and Molecular Biol 2002 Journal of biochemistry and molecular biology Vol.35 No.1
Three routes have been identified triggering neuronal death under physiological and pathological conditions. Excess activation of ionotropic glutamate receptors cause influx and accumulation of $Ca^{2+}$ and $Na^+$ that result in rapid swelling and subsequent neuronal death within a few hours. The second route is caused by oxidative stress due to accumulation of reactive oxygen and nitrogen species. Apoptosis or programmed cell death that often occurs during developmental process has been coined as additional route to pathological neuronal death in the mature nervous system. Evidence is being accumulated that excitotoxicity, oxidative stress, and apoptosis propagate through distinctive and mutually exclusive signal transduction pathway and contribute to neuronal loss following hypoxic-ischemic brain injury. Thus, the therapeutic intervention of hypoxic-ischemic neuronal injury should be aimed to prevent excitotoxicity, oxidative stress, and apoptosis in a concerted way.
Suh, Jaehong,Lee, Young Ae,Gwag, Byoung Joo Blackwell Science Ltd 2005 Journal of Neurochemistry Vol.95 No.3
<P>Abstract</P><P>Evidence has accumulated showing that pharmacological inhibition of proteasome activity can both induce and prevent neuronal apoptosis. We tested the hypothesis that these paradoxical effects of proteasome inhibitors depend on the degree of reduced proteasome activity and investigated underlying mechanisms. Murine cortical cell cultures exposed to 0.1 µ<SMALL>M</SMALL> MG132 underwent widespread neuronal apoptosis and showed partial inhibition of proteasome activity down to 30–50%. Interestingly, administration of 1–10 µ<SMALL>M</SMALL> MG132 almost completely blocked proteasome activity but resulted in reduced neuronal apoptosis. Similar results were produced in cortical cultures exposed to other proteasome inhibitors, proteasome inhibitor I and lactacystin. Administration of 0.1 µ<SMALL>M</SMALL> MG132 led to activation of a mitochondria-dependent apoptotic signaling cascade involving cytochrome <I>c</I>, caspase-9, caspase-3 and degradation of tau protein; such activation was markedly reduced with 10 µ<SMALL>M</SMALL> MG132. High doses of MG132 prevented the degradation of inhibitor of apoptosis proteins (IAPs) cIAP and X chromosome-linked IAP, suggesting that complete blockade of proteasome activity interferes with progression of apoptosis. In support of this, addition of high doses of proteasome inhibitors attenuated apoptosis of cortical neurons deprived of serum. Taken together, the present results indicate that inhibition of proteasome activity can induce or prevent neuronal cell apoptosis through regulation of mitochondria-mediated apoptotic pathways and IAPs.</P>