神經發炎(neuroinflammation)與興奮性神經毒性(excitotoxicity)被視為幾乎所
有中樞神經系統疾病的一個潛在致病因子。然而這類的疾病直至今日仍苦無有效
及較低副作用之治療方法，顯示藉助新藥研發來減緩或預防這些疾病的發生是一
重要與迫切的議題。雖然截至目前神經病變性疾病(neurological diseases)的分子
機轉仍不完全受世人所了解，但一般普遍認為中樞神經系統中的微膠質細胞
(microglia)在加劇神經發炎過程中扮演關鍵性的角色。近年來許多研究顯示臨床
用藥顆粒性白血球-群落刺激因子(Granulocyte colony-stimulating factor, G-CSF)
和海洋天然物刺冠軟珊瑚醇化合物GB9 極具開發潛力，可被應用於發展為抗神
經發炎藥物。因此本研究以微膠質細胞BV-2 為平台，利用第二型干擾素
(interferon-γ, IFN-γ)刺激微膠質細胞活化之離體發炎模式，探討G-CSF 及GB9 的
神經保護與抗發炎作用。結果顯示G-CSF 與GB9 可顯著抑制IFN-γ所引起誘發
型ㄧ氧化氮合成酶(inducible nitric oxide synthase, iNOS)、第二型環氧化酶
(cyclooxygenase-2, COX-2)等發炎性蛋白質表現量的增加。除此之外，西方點墨
法與免疫螢光染色的結果也發現，G-CSF 與GB9 能顯著減緩微膠質細胞所引起
的麩胺酸受器(glutamate receptor)活化與麩胺酸運輸(glutamate transporter)蛋白質
表現降低之現象。同時在椎管注射IFN-γ誘發微膠質細胞活化的活體動物實驗也
顯示，G-CSF 可顯著抑制IFN-γ引發活化細胞標的OX-42 免疫活性上升的作用。
綜合以上，我們認為G-CSF 和GB9 確實能抑制微膠質細胞活化的發炎反應，為
具抗神經發炎活性之藥物，未來可以運用於治療神經病變性疾病的藥物開發。

Neuroinflammation and excitotoxicity are frequently regarded as the classical hallmarks of all major central nervous system (CNS) diseases such as stroke and neurodegenerative disorders. However, the limited number of current clinical options for the treatment of these diseases and the side effects associated with these treatment options indicate that there is an urgent and important need to develop drugs that delay neurological diseases. Although the molecular mechanisms underlying these neurological diseases remain poorly understood, it is widely accepted that alterations in microglia function is the key causative factor. It was recently reported that granulocyte colony-stimulating factor (G-CSF) and a natural marine compound, GB9, show great potential as anti-inflammatory agents. In the present study, we used a model of neuroinflammation to investigate the neuroprotective effects of G-CSF and GB9, and whether they exert an anti-neuroinflammatory effect on IFN-γ-stimulated microglia (BV2). Our results revealed that both G-CSF and GB9 attenuate the upregulation of proinflammatory mediators such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in IFN-γ-stimulated microglia. Furthermore, Western blot and immunohistochemical analyses revealed that G-CSF or GB9 prevent downregulation of the glutamate transporter (Glu-Asp transporter, GLAST) and activation of the glutamate receptor in the IFN-γ-stimulated microglia. Additionally, our in vivo analyses revealed that centrally administered G-CSF could reverse the increase of OX-42 immunoactivity, which is the marker of IFN-γ-stimulated microglia. In summary, our findings support the hypotheses that G-CSF and the marine compound, GB9, possess anti-neuroinflammatory properties and could be pursued as potential therapeutic agents for CNS diseases.

目錄..............................................................................I
圖目錄.........................................................................II
表目錄........................................................................IV
Abstract………………………..................................V
摘要...........................................................................VI
縮寫表......................................................................VII
第壹章、前言.............................................................1
第貳章、實驗材料與方法.......................................10
第參章、實驗結果...................................................19
第肆章、實驗討論....................................................55
第伍章、未來展望....................................................65
第陸章、參考文獻....................................................66

Acarin L., Peluffo H., Gonzalez B., and Castellano B. (2002) Expression of inducible
nitric oxide synthase and cyclooxygenase-2 after excitotoxic damage to the
immature rat brain. J Neurosci Res 68:745-754.
Adachi K., Yimin Y., Satake K., Matsuyama Y., Ishiguro N., Sawada M., Hirata Y.,
and Kiuchi K. (2005) Localization of cyclooxygenase-2 induced following
traumatic spinal cord injury. Neurosci Res 51:73-80.
Akiyama H., Barger S., Barnum S., Bradt B., Bauer J., Cole G.M., Cooper N.R.,
Eikelenboom P., Emmerling M., Fiebich B.L.,Finch C.E., Frautschy S., Griffin
W.S., Hampel H., Hull M.,Landreth G., Lue L., Mrak R., Mackenzie I.R., McGeer
P.L.,O'Banion M.K., Pachter J., Pasinetti G., Plata-Salaman C.,Rogers J., Rydel R.,
Shen Y., Streit W., Strohmeyer R.,Tooyoma I., Van Muiswinkel F.L., Veerhuis R.,
Walker D.,Webster S., Wegrzyniak B., Wenk G., and Wyss-Coray T. (2000)
Inflammation and Alzheimer's disease. Neurobiol Aging 21:383-421.
Aloisi F. (2001) Immune function of microglia. Glia 36:165-179.
Aneiros A. and Garateix A. (2004) Bioactive peptides from marine sources:
pharmacological properties and isolation procedures. J Chromatogr B Analyt
Technol Biomed Life Sci 803:41-53.
Anthony J.C., Breitner J.C., Zandi P.P., Meyer M.R., Jurasova I., Norton M.C., and
Stone S.V. (2000) Reduced prevalence of AD in users of NSAIDs and H2 receptor
antagonists: the Cache County study. Neurology 54:2066-2071.
Arundine M. and Tymianski M. (2003) Molecular mechanisms of calcium-dependent
neurodegeneration in excitotoxicity. Cell Calcium 34:325-337.
Baba H., Kohno T., Moore K.A., and Woolf C.J. (2001) Direct activation of rat spinal
dorsal horn neurons by prostaglandin E2. J Neurosci 21:1750-1756.
Bal-Price A. and Brown G.C. (2001) Inflammatory neurodegeneration mediated by
nitric oxide from activated glia-inhibiting neuronal respiration, causing glutamate
release and excitotoxicity. J Neurosci 21:6480-6491.
Balasubramanian T. and Ajmal K.S. (2007) Multidisciplinary approach for studying
marine biology and biotechnology through decelopment and application of marine
bioinformatics. SDNP - ENVIS Newsletter Vol. 2.
Bao F. and Liu D. (2003) Peroxynitrite generated in the rat spinal cord induces
apoptotic cell death and activates caspase-3. Neuroscience 116:59-70.
Becher B., Prat A., and Antel J.P. (2000) Brain-immune connection:
immunoregulatory properties of CNS-resident cells. Glia 29:293-304.
Bezzi P., Domercq M., Brambilla L., Galli R., Schols D., De Clercq E., Vescovi A.,
Bagetta G., Kollias G., Meldolesi J., and Volterra A. (2001) CXCR4-activated
astrocyte glutamate release via TNF-alpha: amplification by microglia triggers
neurotoxicity. Nat Neurosci 4:702-710.
Bian Q., Kato T., Monji A., Hashioka S., Mizoguchi Y., Horikawa H., and Kanba S.
(2008) The effect of atypical antipsychotics, perospirone, ziprasidone and
quetiapine on microglial activation induced by interferon-gamma. Prog
Neuropsychopharmacol Biol Psychiatry 32:42-48.
Binns B.C., Huang Y., Goettl V.M., Hackshaw K.V., and Stephens Jr. R.L. (2005)
Glutamate uptake is attenuated in spinal deep dorsal and ventral horn in the rat
spinal nerve ligation model. Brain Res 1041:38-47.
Blasi E., Barluzzi R., Bocchini V., Mazzolla R., and Bistoni F. (1990)
Immortalization of murine microglial cells by a v-raf/v-myc carrying retrovirus. J
Neuroimmunol 27:229-237.
Block M.L. and Hong J.S. (2005) Microglia and inflammation-mediated
neurodegeneration: multiple triggers with a common mechanism. Prog Neurobiol
76:77-98.
Block M.L., Zecca L., and Hong J.S. (2007) Microglia-mediated
neurotoxicity:uncovering the molecular mechanisms. Nat Rev Neurosci 8:57-69.
Blunt J.W., Copp B.R., Hu W.P., Munro M.H., Northcote P.T., and Prinsep M.R.
(2009) Marine natural products. Nat Prod Rep 26:170-244.
Boneberg E.M., Hareng L., Gantner F., Wendel A., and Hartung T. (2000) Human
monocytes express functional receptors for granulocyte colony-stimulating factor
that mediate suppression of monokines and IFNγ. Blood 95:270-276.
Bridges D., Thompson S.W., and Rice A.S. (2001) Mechanisms of neuropathic pain.
Br J Anaesth 87:12-26.
Butler M.S. (2005) Natural products to drugs: natural product derived compounds in
clinical trials. Nat Prod Rep 22:162-195.
Carte B.K. (1996) Biomedical potential of marine natural products. Bioscience
46:271-286.
Chang C.H., Wen Z.H., Wang S.K., and Duh C.Y. (2008) Capnellenes from the Formosan Soft Coral Capnella imbricate. J Nat Prod 71:619-621.
Chao C.C., Hu S., and Peterson P.K. (1995a) Glia, cytokines, and neurotoxicity. Crit
Rev Neurobiol 9:189-205.
Chao C.C., Hu S., Ehrlich L., and Peterson P.K. (1995b) Interleukin-1 and tumor
necrosis factor-alpha synergistically mediate neurotoxicity: involvement of nitric
oxide and of N-methyl-D-aspartate receptors. Brain Behav Immun 9:355-365.
Chen W.F., Sung C.S., Jean Y.H., Su T.M., Wang H.C., Ho J.T., Huang S.Y., Lin C.S.,
and Wen Z.H. (2010) Suppressive effects of intrathecal granulocyte
colony-stimulating factor on excessive release of excitatory amino acids in the
spinal cerebrospinal fluid of rats with cord ischemia: role of glutamate transporters.
Neuroscience 165:1217-1232.
Choi D.W. (1988) Glutamate neurotoxicity and diseases of neurons system. Neuron 1:
623-634.
Coll J.C., La Barre S, Sammarco P.W., Williams W.T., and Bakus G.J. (1982)
Chemical defenses in soft corals(Coelenterata: Octocorallia) of the Great Barrier
Reef: A study of comparative toxicities. Mar Ecol Prog Ser 8:271-278.
Chretien F., Vallat-Decouvelaere A.V., Bossuet C., Rimaniol A.C., Le Grand R., Le
Pavec G., Creminon C., Dormont D., Gray F., and Gras G. (2002) Expression of
excitatory amino acid transporter-2(EAAT-2) and glutamine synthetase(GS) in
brain macrophages and microglia of SIVmac251-infected macaques. Neuropathol
Appl Neurobiol 28:410-417.
Danbolt N.C. (2001) Glutamate uptake. Prog Neurobiol 65:1-105.
Danton G.H. and Dietrich W.D. (2003) Inflammatory mechanisms after ischemia and
stroke. J. Neuropathol Exp Neurol 62:127-136.
Daulhac L., Mallet C., Courteix C., Etienne M., Duroux E., Privat A.M., Eschalier A.,
Fialip J. (2006) Diabetes-induced mechanical hyperalgesia involves spinal
mitogen-activated protein kinase activation in neurons and microglia via
N-methyl-D-aspartate-dependent mechanisms. Mol Pharmacol 4:1246-1254.
De Leo J.A., Tawfik V.L., and LaCroix-Fralish M.L. (2006) The tetrapartite synapse:
path to CNS sensitization and chronic pain. Pain 122:17-21.
DeLeo J.A. and Yezierski R.P. (2001) The role of neuroinflammation and
neuroimmune activation in persistent pain. Pain 90:1-6.
Dirnagl U., Iadecola C., and Moskowitz M.A. (1999) Pathobiology of ischaemic
stroke: an integrated view. Trends Neurosci. 22:391-397.
Dubois R.N., Abramson S.B., Crofford L., Gupta R.A., Simon L.S., Van De Putte L.B.,
and Lipsky P.E. (1998) Cyclooxygenase in biology and disease. FASEB J
12:1063-1073.
Figiel M., Maucher T., Rozyczka J., Bayatti N., and Engele J. (2003) Regulation of
glial glutamate transporter expression by growth factors. Exp Neurol 183:124-135.
Frampton J.E., Lee C.R., and Faulds D. (1994) Filgrastim. A review of its
pharmacological properties and therapeutic efficacy in neutropenia. Drugs
48:731-760.
Gaestel M., Kotlyarov A., and Kracht M. (2009) Targeting innate immunity protein
kinase signalling in inflammation. Nat Rev Neurosci 8:480-499.
Gebicke-Haerter P.J. (2001) Microglia in Neurodegeneration: molecular aspects.
Microsc Res Tech 54:47-58.
Gibbons H.M. and Dragunow M. (2006) Microglia induce neural cell death via a
proximity-dependent mechanism involving nitric oxide. Brain Res 1084:1-15.
Gonzalez R., Glaser J., Liu M.T., Lane T.E., and Kierstead H.S. (2003) Reducing
inflammation decreases secondary degeneration and functional deficit after spinal
cord injury. Exp Neurol 184:456-463.
Gonzalez-Scarano F. and Baltuch G. (1999) Microglia as mediators of inflammatory
and degenerative diseases. Annu Rev Neurosci 22:219-240.
GoÈrgen I., Hartung T., Leist M., NiehoÈrster M., Tiegs G., Uhlig S., Weitzel F., and
Wendel A. (1992) Granulocyte colony-stimulating factor treatment protects rodents
against lipopolysaccharide-induced toxicity via suppression of systemic tumor
necrosis factor-alpha. J Immunol 149:918-924.
Handy R.L.C. and Moore P.K. (1998) Effects of selective inhibitors of neuronal nitric
oxide synthase on carrageenan-induced mechanical and thermal hyperalgesia.
Neuropharmacology 37:37-43.
Hanisch U.K. (2002) Microglia as a Source and target of cytokines. Glia 40:140-155.
Hanisch U.K. and Kettenmann H. (2007) Microglia: active sensor and versatile
effector cells in the normal and pathologic brain. Nat Neurosci 10:1387-1394.
Hartung T., Döcke W.D., Gantner F., Krieger G., Sauer A., Stevens P., Volk H.D.,
and Wendel A. (1995) Effect of granulocyte colony-stimulating factor treatment on ex vivo blood cytokine response in human volunteers. Blood 85:2482-2489.
Hayashi M., Ueyama T., Nemato K., Tamaki T., and Senba E (2000) Sequential
mRNA expression for immediate early genes, cytokines, and neurotrophins in spinal
cord injury. J Neurotrauma 17:203-218.
Hickey W.F. (2001) Basic principles of immunological surveillance of the normal
central nervous system. Glia 36:118-124.
Hollmann M. and Heinemann S. (1994) Cloned glutamate receptors. Annu Rev
Neurosci 17:31-108.
Hotamisligil G.S. (2006) Inflammation and metabolic disorders. Nature 444:860-867.
Huang H.Y., Lin S.Z., Kuo J.S., Chen W.F., and Wang M.J. (2007) G-CSF protects
dopaminergic neurons from 6-OHDA-induced toxicity via the ERK pathway.
Neurobiol Aging 28:1258-1269.
Hurtado O., Moro M.A., Cárdenas A., Sanchez V., Fernández-Tome P., Leza J.C.,
Lorenzo P., Secades J.J., Lozano R., Dávalos A., Castillo J., and Lizasoain I. (2005)
Neuroprotection afforded by prior citicoline administration in experimental brain
ischemia: effects on glutamate transport. Neurobiol Dis 18:336-345.
Hwang S.H., Choi Y.G., Jeong M.Y., Hong Y.M., Lee J.H., and Lim S. (2009)
Microarray analysis of gene expression profile by treatment of Cinnamomi Ramulus
in lipopolysaccharide-stimulated BV-2 cells. Gene 1-2:83-90.
Iravani M.M., Kashefi K., Mander P., Rose S., and Jenner P. (2002) Involvement of
inducible nitric oxide synthase in inflammation-induced dopaminergic
neurodegeneration. Neuroscience 110:49-58.
Jacobsson J., Persson M., Hansson E., and Rönnbäck L.(2006) Corticosterone inhibits
expression of the microglial glutamate transporter GLT-1 in vitro. Neuroscience
2:457-483.
Jean Y.H., Chen W.F., Duh C.Y., Huang S.Y., Hsu C.H., Lin C.S., Sung C.S., Chen
I.M., and Wen Z.H. (2008) Inducible nitric oxide synthase and cyclooxygenase-2
participate in anti-inflammatory and analgesic effects of the natural marine
compound lemnalol from Formosan soft coral Lemnalia cervicorni. Eur J Pharmacol
578:323-331.
Jean Y.H., Chen W.F., Sung C.S., Duh C.Y., Huang S.Y., Lin C.S., Tai M.H., Tzeng
S.F., and Wen Z.H. (2009) Capnellene, a natural marine compound derived from
soft coral, attenuates chronic constriction injury-induced neuropathic pain in rats. Br
J Pharmacol 58:713-725.
Jin D.Q., Lim C.S., Sung J.Y., Choi H.G., Ha I., and Han J.S. (2006) Ulva conglobata,
a marine algae, has neuroprotective and anti-inflammatory effects in murine
hippocampal and microglial cells. Neurosci Lett 1-2:154-158.
Jones T.C. and Hunt R.D. (1983) Veterinary pathology fifth edition. Philadelphia: Lea
& Febiger.
Kanner B.I. and Schuldiner S. (1987) Mechanism of transport and storage of
neurotransmitters. CRC Crit Rev Biochem 22:1-38.
Katchman A.N. and Hershkowitz N. (1997) Nitric oxide modulates synaptic
glutamate release during anoxia. Neurosci Lett 228:50-54.
Kijjoa A. and Sawangwong P. (2004) Drugs and Cosmetics from the Sea. Mar Drugs
2:73-82.
Kim H.S., Whang S.Y., Woo M.S., Park J.S., Kim W.K., and Han I.O. (2004) Sodium
butyrate suppresses interferon-gamma-, but not lipopolysaccharide-mediated
induction of nitric oxide and tumor necrosis factor-alpha in microglia. J
Neuroimmunol 151:85-93.
Kjaer K., Strobaek D., Christophersen P., and Ronn L.C. (2009) Chloride channel
blockers inhibit iNOS expression and NO production in IFN-gamma-stimulated
microglial BV-2 cells. Brain Res 1281:15-24.
Korn T., Magnus T., and Jung S. (2005) Autoantigen specific T cells inhibit glutamate
uptake in astrocytes by decreasing expression of astrocytic glutamate transporter
GLAST: a mechanism mediated by tumor necrosis factor-alpha. FASEB J
19:1878–1880.
Koshinaga M., Katayama Y., Fukushima M., Oshima H., Suma T., and Takahata T.
(2000) Rapid and widespread microglial activation induced by traumatic brain
injury in rat brain slices. J Neurotrauma 17:185-192.
Krizman-Genda E., Gonzalez M.I., Zelenaia O., and Robinson M.B. (2005) Evidence
that Akt mediates platelet-derived growth factor-dependent increases in activity and
surface expression of the neuronal glutamate transporter, EAAC1. europharmacology
49:872-882.
Kuno R., Wang J., Kawanokuchi J., Takeuchi H., Mizuno T., and Suzumura A. (2005)
Autocrine activation of microglia by tumor necrosis factor-alpha. J. Neuroimmunol 162:89-96.
Ladeby R., Wirenfeldt M., Garcia-Ovejero D., Fenger C., Dissing-Olesen L., Dalmau
I., and Finsen B. (2005) Microglial cell population dynamics in the injured adult
central nervous system. Brain Res Brain Res Rev 48:196-206.
Lee P., Son D., Lee J., Kim Y.S., Kim H., and Kim, S.Y. (2003) Excessive production
of nitric oxide induces the neuronal cell death in lipopolysaccharide-treated rat
hippocampal slice culture. Neurosci Lett 349:33-36.
Lee S.M., Yune T.Y., Kim S.J., Park D.W., Lee Y.K., Kim Y.C., Oh Y.J., Markelonis
G.J., and Oh T.H. (2003) Minocycline reduces cell death and improves functional
recovery after traumatic spinal cord injury in the rat. J Neurotrauma 20:1017-1027.
Ledeboer A., Sloane E.M., Milligan E.D., Frank M.G., Mahony J.H., and Maier S.F.
(2005) Minocycline attenuates mechanical allodynia and proinflammatory cytokine
expression in rat models of pain facilitation. Pain 115:71-83.
Ling E.A. and Wong W.C. (1993) The origin and nature of ramified and amoeboid
microglia: a historical review and current concepts. Glia7:9-18.
Liang J., Hideyuki Takeuchi H., Jin S., Noda M., Li H., Doi Y., Kawanokuchi J.,
Sonobe Y., Mizuno T., and Suzumura A. (2010) Glutamate induces neurotrophic
factor production from microglia via protein kinase C pathway. Brain Research
1322:8-23
Lipton S.A. and Rosenberg P.A. (1994) Excitatory amino acids as a final common
pathway for neurologic disorders. N Engl J Med 330:613-622.
Lowenstein C.J., Alley E.W., Raval P., Snowman A.M., Synder S.H., Russell S.W.
and Murphy W.J. (1993) Macrophage nitric oxide synthase gene: Two upstream
regions mediate induction by interferon-gand lipopolysaccharide. Proc Natl Acad
Sci USA 90:9730-9734.
Luchetti S., Beck K.D., Galvan M.D., Silva R., Cummings B.J., and Anderson A
(2009) Comparison of immunopathology and locomotor recovery in C57BL/6,
BUB/BnJ and NOD-scid mice after contusion spinal cord injury. J Neurotrauma
27:411-412.
Maggon K. (2009) Global Pharmaceutical Market Review & World Top Ten/Twenty
Drugs 2008. Retrieved December 17, 2009, from Google, Knol Web site:
http://knol.google.com/k
Ma X.C., Gottschall P.E., Chen Li.T., Wiranowska M., and Phelps C.P. (2002/2003)
Role and mechanisms of interleukin-1 in the modulation of neurotoxicity.
Neuroimmunomodulation 10:199-207.
Markenson J. (1999) Clinical Implications of Cyclooxygenase Enzymes:
COX-1/COX-2 Role of the New NSAIDs. Cancer Control 6:22-25.
Marletta M.A. (1994) Nitric oxide synthase: aspects concerning structure and
catalysis. Cell 78:927-930.
Medzhitov R. (2008) Origin and physiological roles of inflammation. Nat Rev
Neurosci 454:428-435.
Medzhitov R. and Horng T. (2009) Transcriptional control of the inflammatory
response. Nat Rev Neurosci 9:692-703.
Merrill J.E. and Benveniste E.N. (1996) Cytokines in inflammatory brain lesions:
helpful and harmful. Trends Neurosci 19:331-338.
McGeer P.L. and McGeer E.G. (2004) Inflammation and neurodegeneration in
Parkinson's disease. Parkinsonism Relat Disord 10:S3-S7.
McGeer P.L., Schulzer M., and McGeer E.G. (1996) Arthritis and anti-inflammatory
agents as possible protective factors for Alzheimer's disease: a review of 17
epidemiologic studies Neurology 47:425-432.
McTigue D.M., Tani M., Krivacic K., Chernosky A., Kelner G.S., Maciejewski D.,
Maki R., Ransohoff R.M., and Stokes B.T. (1998) Selective chemokine mRNA
accumulation in the rat spinal cord after contusion injury. J Neurosci Res
53:368-376.
Milligan E.D., Twining C., Chacur M., Biedenkapp J., O’Connor K., and Poole S.
(2003) Spinal glia and proinflammatory cytokines mediate mirror-image
neuropathic pain in rats. J Neurosci 23:1026-1040.
Milligan E.D. and Watkins L.R. (2009) Pathological and protective roles of glia in
chronic pain. Nat Rev Neurosci 10:23-36.
Minghetti L. and Levi G. (1995) Induction of prostanoid biosynthesis by bacterial
lipopolysaccharide and isoproterenol in rat microglial cultures. J Neurochem.
6:2690-2698.
Minghetti L. and Levi G. (1998) Microglia as effector cells in brain damage and
repair: focus on prostanoids and nitric oxide. Prog Neurobiol 54:99-125.
Mir M., Tolosa L., Asensio V.J., Lladó J., and Olmos G. (2008) Complementary roles
of tumor necrosis factor alpha and interferon gamma in inducible microglial nitric
oxide generation. J Neuroimmunol. 1-2:101-109.
Molinski T.F., Dalisay D.S., Lievens S.L., and Saludes J.P. (2009) Drug development
from marine natural products. Nat Rev Drug Discov 8:69-85.
Munch G., Gasic-Milenkovic J., Dukic-Stefanovic S., Kuhla B., Heinrich K., Riederer
P., Huttunen H.J., Founds H., and Sajithlal G. (2003) Microglial activation induces
cell death, inhibits neurite outgrowth and causes neurite retraction of differentiated
neuroblastoma cells. Exp Brain Res 150:1-8.
Munoz-Fernandez M.A. and Fresno M. (1998) The role of tumor necrosis factor,
interleukin-6, interferon-gamma and inducible nitric oxide synthase in the
development and pathology of the nervous system. Prog Neurobiol 56:307-340.
Myers R.R., Campana W.M., and Shubayev V.I. (2006) The role of
neuroinflammation in neuropathic pain: mechanisms and therapeutic targets. Drug
Discov Today 11:8-20.
Nakamura Y. (2002) Regulating factors for microglial activation. Biol Pharm Bull
25:945–953.
Nathan C. and Xie Q.W. (1994) Nitric oxide synthases: roles, tolls, and controls. Cell
78:915-918.
Newman D.J. and Cragg G.M. (2007) Natural products as sources of new drugs over
the last 25 years. J Nat Prod 70:461-477.
Nishizawa Y. (2001) Glutamate release and neuronal damage in ischemia. Life Sci
69:369-381.
Noda M., Nakanishi H., and Akaike N. (1999) Glutamate release from microglia via
glutamate transporter is enhanced by amyloid-β peptide. Neuroscience
92:1465-1474.
O'Neill G.P. and Ford-Hutchinson A.W. (1993) Expression of mRNA for
cyclooxygenase-1 and cyclooxygenase-2 in human tissues. FEBS Lett 330:156-160.
Orr C.F., Rowe D.B., and Halliday G.M. (2002) An inflammatory reviewof
Parkinson's disease. Prog Neurobiol 68:325-340.
Persson M., Brantefjord M., Hansson E., and Rönnbäck L. (2005) Lipopolysaccharide
increases microglial GLT-1 expression and glutamate uptake capacity in vitro by a
mechanism dependent on TNF-alpha. Glia 51:111-120.
Petrova T.V., Akama K.T., and Van Eldik L.J. (1999) Selective modulation of BV-2
microglial activation by prostaglandin E2: differential effects on
endotoxin-stimulated cytokine induction. J Biol Chem 274:28823-28827.
Pocock J.M. and Kettenmann H. (2007) Neurotransmitter receptors on microglia.
Trends Neurosci 10:527-535.
Popovich P.G., Guan Z., Wei P., Huitinga I., van Rooijen N., and Stokes B.T. (1999)
Depletion of hematogenous macrophages promotes partial hindlimb recovery and
neuroanatomical repair after experimental spinal cord injury. Exp Neurol
158:351-365.
Randall R.D. and Thayer S.A. (1992) Glutamate-induced calcium transient triggers
delayed calcium overload and neurotoxicity in rat hoppocampal neurons. J Neurosci
12:1882-1895.
Resnick D.K., Graham S.H., Dixon C.E., and Marion D.W. (1998) Role of
cyclooxygenase 2 in acute spinal cord injury. J Neurotrauma 15:1005-1013.
Rock R.B., Gekker G., Hu S., Sheng W.S., Cheeran M., Lokensgard J.R., and Peterson
P.K. (2004) Role of microglia in central nervous system infections. Clin Microbiol
Rev 17:942-64.
Robbins S.L., Cotran R.S., and Kumar V. (1984) Pathologic basis of disease.
Philadelphia: Saunders.
Rothstein J.D., Dykes-Hoberg M., Pardo C.A., Bristol L.A., Jin L., Kuncl R.W.,
Kanai Y., Hediger M.A., Wang Y., Schielke J.P., and Welty D.F. (1996) Knockout of
glutamate transporters reveals a major role for astroglial transport in excitotoxicity
and clearance of glutamate. Neuron 16:675-686.
Roy A., Fung Y.K, Liu X., and Pahan K. (2006) Up-regulation of microglial CD11b
expression by nitric oxide. J Biol Chem 281:14971-14980.
Ruggieri G.D. (1976) Drugs from the sea. Science 194:491-497.
Schabitz W.R., Kollmar R., Schwaninger M., Juettler E., Bardutzky J.,Scholzke M.N.,
Sommer C., and Schwab S. (2003) Neuroprotective effect of granulocyte
colony-stimulating factor after focal cerebral ischemia. Stroke 34:745-751.
Schneider A., Kuhn H.G., and Schabitz W.R. (2005) A role of G-CSF
(granulocyte-colony stimulating factor) in the central nervous system. Cell Cycle
4:1753-1757.
Scholz J. and Woolf C.J. (2007) The neuropathic pain triad: neurons, immune cells
and glia. Nat Neurosci 10:1361-1368.
Schroder K., Hertzog P.J., Ravasi T., and Hume D.A. (2004) Interferon-gamma: an
overview of signals, mechanisms and functions. J Leukoc Biol 75:163-189.
Schwartz M., Shaked I., Fisher J., Mizrahi T., and Schori H. (2003) Protective autoimmunity against the enemy within: fighting glutamate toxicity. Trends
Neurosci 26:297-302.
Sims K.D. and Robinson M.B. (1999) Expression patterns and regulation of glutamate
transporters in the developing and adult nervous system. Crit Rev Neurobiol
13:169-197.
South S.M., Kohno T., Kaspar B.K., Hegarty D., Vissel B., Drake C.T., Ohata M.,
Jenab S., Sailer A.W., Malkmus S., Masuyama T., Horner P., Bogulavsky J., Gage
F.H., Yaksh T.L., Woolf C.J., Heinemann S.F., and Inturrisi C.E. (2003) A
conditional deletion of the NR1 subunit of the NMDA receptor in adult spinal cord
dorsal horn reduces NMDA currents and injury-induced pain. J Neurosci
23:5031-5040.
Streit W.J., Mrak R.E., and Griffin WS.T. (2004) Microglia and neuroinflammation: a
pathological perspective. J Neuroinflammation 1:14-17.
Suter M.R., Wen Y.R., Decosterd I., and Ji R.R. (2007) Do glial cells control pain?
Neuron Glia Biol 3:255-268.
Tai Y.H., Wang Y.H., Wang J.J., Tao P.L., Tung C.S., and Wong C.S. (2006)
Amitriptyline suppresses neuroinflammation and upregulates glutamate transporters
in morphine-tolerant rats. Pain 124:77-86.
Takeuchi H., Mizuno T., Zhang G.,Wang J., Kawanokuchi J., Kuno R., and Suzumura
A. (2005) Neuritic beading induced by activated microglia is an early feature of
neuronal dysfunction toward neuronal death by inhibition of mitochondrial
respiration and axonal transport. J Biol Chem 280:10444-10454.
Takeuchi H., Jin S., Wang J., Zhang G., Kawanokuchi J., Kuno R., Sonobe Y., Mizuno
T., and Suzumura A. (2006) Tumor necrosis factor-alpha induces neurotoxicity via
glutamate release from hemichannels of activated microglia in an autocrine manner.
J Biol Chem 281:21362-21368.
Tilleux S. and Hermans E. (2007) Neuroinflammation and regulation of glial
glutamate uptake in neurological disorders. J Neurosci Res 85:2059-2070.
Tsai K.J., Tsai Y.C., and Shen C.K. (2007) G-CSF rescues the memory impairment of
animal models of Alzheimer’s disease. J Exp Med 204:1273-1280.
Tomimoto H., Akiguchi I., Wakita H., Lin J.X., and Budka H. (2000)
Cyclooxygenase-2 is induced in microglia during chronic cerebral ischemia in humans. Acta Neuropathol 99:26-30.
Vanegas H. and Schaible H.G. (2001) Prostaglandins and cyclooxygenases in the
spinal cord. Prog Neurobiol 64:327-363.
Vikman K.S., Duggan A.W., and Siddall P.J. (2007) Interferon-γ induced disruption
of GABAergic inhibition in the spinal dorsal horn in vivo. Pain 133 18-28.
Vincent V.A., Van Dam A.M., Persoons J.H., Schotanus K., Steinbusch H.W.,
Schoffelmeer A.N., and Berkenbosch F. (1996) Gradual inhibition of inducible nitric
oxide synthase but not of interleukin-1 beta production in rat microglial cells of
endotoxin-treated mixed glial cell cultures. Glia 2:94-102.
Watkins L.R. and Maier S.F. (2002). Beyond neurons: evidence that immune and glial
cells contribute to pathological pain states. Physiol Rev 82:981-1011
Watkins L.R. and Maier S.F. (2003) Glia: a novel drug discovery target for clinical
pain. Nat Rev Drug Discov 2:973-985.
Wang C.X., Nuttin B., Heremans H., Dom R., and Gybels J. (1996) Production of
tumor necrosis factor in spinal cord following traumatic injury in rats. J
Neuroimmunol 69:151-156.
Wang Z., Pekarskava O., Bencheikh M., Chao W., Gelbard H.A., Ghorpade A.,
Rothstein J.D., and Volsky D.J. (2003) Reduced expression of glutamate transporter
EAAT2 and impaired glutamate transport in human primary astrocytes exposed to
HIV-1 or gp120. Virology 20:60-73.
Warfield C.A. and Fausett H.J. (2002) Manual of Pain Management. Lippincott
Williams and Wilkins, Philadelphia.
Wu D.C., Jackson-Lewis V., Vila M., Tieu K., Teismann P., Vadseth C., Choi D.K.,
Ischiropoulos H., and Przedborski S. (2002) Blockade of microglial activation is
neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model
of Parkinson disease. J Neurosci 22:1763-1771.
Wu K.K. (1995) Inducible cyclooxygenase and nitric oxide synthase. Adv Pharmacol
33:179-207.
Yaksh T.L. and Rudy T.A. (1976) Analgesia mediated by a direct spinal action of
narcotics. Science 192:1357-1358.
Yune T.Y., Lee J.Y., Cui C.M., Kim H.C., and Oh T.H. (2009) Neuroprotective effect
of Scutellaria baicalensis on spinal cord injury in rats. J Neurochem 110:1276-1287.
Zhao Z., Chen S.R., Eisenach J.C., Busija D.W., and Pan H.L. (2000) Spinal cyclooxygenase-2 is involved in development of allodynia after nerve injury in rats.
Neuroscience 97:743-748.
Zhao W., Xie W., Le W., Beers D.R., He Y., Henkel J.S., Simpson E.P., Yen A.A.,
Xiao Q., and Appel S.H. (2004) Activated microglia initiate motor neuron injury by
a nitric oxide and glutamate-mediated mechanism. J Neuropathol Exp Neurol 63:964-977.
Zivadinov R., Rudick R.A., De Masi R., Nasuelli D., Ukmar M., Pozzi-Mucelli R.S.,
Grop A., Cazzato G., and Zorzon M. (2001) Effects of IV methylprednisolone on brain atrophy in relapsing-remitting MS. Neurology 7:1239-1247.