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研究生:陳怡如
研究生(外文):Yi-Ju Chen
論文名稱:探討水溶性環氧化物水解酶抑制劑對於神經突觸可塑性的影響
論文名稱(外文):Effect of soluble epoxide hydrolase inhibition on synaptic plasticity
指導教授:林惠菁林惠菁引用關係
指導教授(外文):Hui-Ching Lin
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:生理學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2017
畢業學年度:105
語文別:中文
論文頁數:36
中文關鍵詞:環氧二十碳三烯酸海馬迴長期增益現象麩胺酸受體亞型N-甲基-D-天冬氨酸受體
外文關鍵詞:Epoxyeicosatrienoic acidshippocampuslong-term potentiationNMDA receptorforskolin
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環氧化酶為細胞色素P450(cytochrome P450, CYP 450)家族中的一個亞型,將花生四烯酸(arachidonic acid, AA)代謝成環氧二十碳三烯酸 (epoxyeicosatrienoic acid, EETs), EETs 可分為四個異構體分別為5,6-,8,9-,11,12-和14,15-EET。而 EETs 可藉由水溶性環氧化物水解酶(soluble epoxide hydrolase, sEH)代謝成二羥基二十碳三烯酸(dihydroxyeicosatrienoic acids, DHETs)。許多實驗證實,EETs 可作為血管擴張劑、促進血管生成並具有抗發炎作用。在大腦,EETs 在缺血-再灌流損傷這個模擬中風的模式下具神經保護的功能。先前研究表明,sEH 基因剔除的小鼠其血漿中 14,15-EET 的含量較高。而在腦中海馬迴是負責空間記憶和認知行為記憶的主要區域。然而到現在 EETs 對海馬迴相關突觸功能和認知功能的作用尚未明瞭。因此為了確定 EETs 對突觸功能的影響,在實驗過程我們利用 sEH 抑制劑 TPPU 和14,15–EET 測定是否會對高頻率刺激(high frequency stimulation, HFS)所誘導長期增益現象(long-term potentiation, LTP)及forskolin(FSK)所誘導LTP造成影響。結果顯示在給予 TPPU 和 14,15-EET 的處理下皆可顯著增加海馬迴 CA1 區域興奮性突觸後電位(field excitatory postsynaptic potential, fEPSP)的反應,同時增強 HFS 誘導的 LTP 和 FSK誘導的 LTP。而 TPPU 和 14,15-EET 增加 HFS-LTP,其可被麩胺酸受體亞型N-甲基-D-天冬氨酸受體(N-methyl-D-aspartate receptor, NMDA receptor)亞型NR2B 的拮抗劑阻斷。為了進一步探討 TPPU 和 14,15-EET 促進 FSK 所誘導的LTP 是否透過 cAMP/PKA 訊息傳遞路徑所調控,因此我們給予磷酸二酯酶 (phosphodiesterase, PDE) 抑制劑及 cAMP依賴性蛋白激酶 (cAMP-dependent protein kinase, PKA)抑制劑來進行實驗。在結果可看到PDE 抑制劑加強 TPPU 和 14,15-EET 促進 FSK 所誘導的 LTP, PKA 抑制劑會抑制 TPPU 和 14,15-EET 促進 FSK 所誘導的 LTP,顯示 TPPU 和14,15-EET 促進 FSK 所誘導的 LTP 是透過 cAMP/PKA 訊息傳遞路徑來調控的。此外,藉由新事物辨別測試(Novel object recognition test, NOR)發現給予 TPPU 和14,15-EET 的處理能增強學習和記憶。因此,本研究證實 EETs 能藉由cAMP-PKA 這條訊息傳遞路徑去增加 NMDAR 和 FSK 誘導的 LTP,並增強識別記憶。
The epoxygenases are a subgroup of enzymes in the cytochrome P450 (CYP 450) family that metabolize arachidonic acid (AA) into four regioisomers of epoxyeicosatrienoic acid (5,6-, 8,9-, 11,12-, and 14,15-EETs). EETs are metabolized into dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (sEH). Many experimental evidences show that EETs are potent vasodilators, pro-angiogenic and anti-inflammatory effects in rodent. In brain, EETs also protect neurons from ischemia-reperfusion injury. Previous study has demonstrated higher levels of 14,15-EET in sEH–/– mice. Hippocampus is a major region mediates memory such as spatial memory and cognitive behaviors. To date, the role of EETs on hippocampus-related synaptic function and cognitive function is still unclear. To determine the effect of EETs on synaptic function, we investigated the N-[1-(oxopropyl)-4-piperidinyl]-N’-[4-(trifluoromethoxy)phenyl)-urea (TPPU), which is a sEH inhibitor, and 14,15-EET on the high frequency stimulation (HFS)-long-term potentiation (LTP) and forskolin (FSK)-induced LTP in hippocampus. The results showed that TPPU- and 14,15-EET significantly increased the field excitatory postsynaptic potential (fEPSP) response in the CA1 area of the hippocampus, while additionally enhancing HFS-induced LTP and FSK-induced LTP. TPPU and 14,15-EET increased HFS-LTP, which could be blocked by an N-methyl-D-aspartate (NMDA) receptor subunit NR2B antagonist. TPPU- and 14,15-EET-facilitated FSK-mediated LTP can be potentiated by a phosphodiesterase inhibitor, but is prevented by a cAMP-dependent protein kinase (PKA) inhibitor. Furthermore, we found that TPPU and 14,15-EET treatment could enhanced learning and memory, which was assessed by novel object recognition test (NOR). Therefore, this study demonstrated that EETs increased NMDAR- and FSK-mediated LTP via the cAMP-PKA pathway and also enhances the recognition memory.
目錄
致謝--------I
摘要--------III
Abstract--------V
目錄--------VII
圖目錄--------VIII
序論--------1
研究動機--------5
研究目的--------5
實驗材料與方法--------6
實驗結果--------10
結論--------14
討論--------15
參考文獻--------19
實驗結果--------24

圖目錄
實驗結果
圖1. 給予14,15-EET的處理能增加海馬迴CA1區域興奮性突觸傳導--------25
圖2. 給予TPPU的處理能增加海馬迴CA1區域興奮性突觸傳導--------26
圖3. 給予14,15-EET或TPPU的處理能增加Forskolin誘導LTP的現象--------27
圖4. PKA調節位抑制劑Rp-cAMPs會抑制14,15-EET或TPPU增加Forskolin誘導的LTP--------28
圖5. PKA抑制劑KT 5720會抑制14,15-EET或TPPU增加Forskolin誘導的LTP--------29
圖6. PDE4抑制劑Ro20-1724能增加14,15-EET或sEH抑制劑TPPU增加Forskolin誘導的LTP--------30
圖7. 14,15-EET或TPPU增加Forskolin誘導LTP的現象透過cAMP/PKA訊息傳遞路徑調控--------31
圖8. 給予14,15-EET或TPPU的處理能增加高頻率刺激誘導LTP的現象………32
圖9. NMDA受體NR2B抑制劑Ro 25-6981會抑制14,15-EET或TPPU增加高頻率刺激誘導的LTP--------33
圖10. 14,15-EET或TPPU增加高頻率刺激誘導LTP的現象透過NMDA受體NR2B調控--------34
圖11. 給予14,15-EET或TPPU的處理能增加新事物辨別測試--------35

Abdu E, Bruun DA, Yang D, Yang J, Inceoglu B, Hammock BD, Alkayed NJ, Lein PJ (2011) Epoxyeicosatrienoic acids enhance axonal growth in primary sensory and cortical neuronal cell cultures. J Neurochem 117:632-642.
Ali DW, Salter MW (2001) NMDA receptor regulation by Src kinase signalling in excitatory synaptic transmission and plasticity. Curr Opin Neurobiol 11:336-342.
Alkayed NJ, Narayanan J, Gebremedhin D, Medhora M, Roman RJ, Harder DR (1996) Molecular characterization of an arachidonic acid epoxygenase in rat brain astrocytes. Stroke 27:971-979.
Antunes M, Biala G (2012) The novel object recognition memory: neurobiology, test procedure, and its modifications. Cogn Process 13:93-110.
Bliss TV, Collingridge GL (1993) A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361:31-39.
Bollen E, Puzzo D, Rutten K, Privitera L, De Vry J, Vanmierlo T, Kenis G, Palmeri A, D'Hooge R, Balschun D, Steinbusch HM, Blokland A, Prickaerts J (2014) Improved long-term memory via enhancing cGMP-PKG signaling requires cAMP-PKA signaling. Neuropsychopharmacology 39:2497-2505.
Chavez-Noriega LE, Stevens CF (1992) Modulation of synaptic efficacy in field CA1 of the rat hippocampus by forskolin. Brain Res 574:85-92.
Chiba T, Yamada M, Aiso S (2009) Targeting the JAK2/STAT3 axis in Alzheimer's disease. Expert Opin Ther Targets 13:1155-1167.
Choi DW, Rothman SM (1990) The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death. Annu Rev Neurosci 13:171-182.
Collingridge GL, Kehl SJ, McLennan H (1983) Excitatory amino acids in synaptic transmission in the Schaffer collateral-commissural pathway of the rat hippocampus. J Physiol 334:33-46.
Dorrance AM, Rupp N, Pollock DM, Newman JW, Hammock BD, Imig JD (2005) An epoxide hydrolase inhibitor, 12-(3-adamantan-1-yl-ureido)dodecanoic acid (AUDA), reduces ischemic cerebral infarct size in stroke-prone spontaneously hypertensive rats. J Cardiovasc Pharmacol 46:842-848.
Falck JR, Reddy LM, Reddy YK, Bondlela M, Krishna UM, Ji Y, Sun J, Liao JK (2003) 11,12-epoxyeicosatrienoic acid (11,12-EET): structural determinants for inhibition of TNF-alpha-induced VCAM-1 expression. Bioorg Med Chem Lett 13:4011-4014.
Forrest D, Yuzaki M, Soares HD, Ng L, Luk DC, Sheng M, Stewart CL, Morgan JI, Connor JA, Curran T (1994) Targeted disruption of NMDA receptor 1 gene abolishes NMDA response and results in neonatal death. Neuron 13:325-338.
Fujii S, Sasaki H, Mikoshiba K, Kuroda Y, Yamazaki Y, Mostafa Taufiq A, Kato H (2004) A chemical LTP induced by co-activation of metabotropic and N-methyl-D-aspartate glutamate receptors in hippocampal CA1 neurons. Brain Res 999:20-28.
Grey KB, Burrell BD (2008) Forskolin induces NMDA receptor-dependent potentiation at a central synapse in the leech. J Neurophysiol 99:2719-2724.
Gross GJ, Hsu A, Falck JR, Nithipatikom K (2007) Mechanisms by which epoxyeicosatrienoic acids (EETs) elicit cardioprotection in rat hearts. J Mol Cell Cardiol 42:687-691.
Gross GJ, Gauthier KM, Moore J, Falck JR, Hammock BD, Campbell WB, Nithipatikom K (2008) Effects of the selective EET antagonist, 14,15-EEZE, on cardioprotection produced by exogenous or endogenous EETs in the canine heart. Am J Physiol Heart Circ Physiol 294:H2838-2844.
Harder DR, Alkayed NJ, Lange AR, Gebremedhin D, Roman RJ (1998) Functional hyperemia in the brain: hypothesis for astrocyte-derived vasodilator metabolites. Stroke 29:229-234.
Heizer ML, McKinney JS, Ellis EF (1991) 14,15-Epoxyeicosatrienoic acid inhibits platelet aggregation in mouse cerebral arterioles. Stroke 22:1389-1393.
Iliff JJ, Wang R, Zeldin DC, Alkayed NJ (2009) Epoxyeicosanoids as mediators of neurogenic vasodilation in cerebral vessels. Am J Physiol Heart Circ Physiol 296:H1352-1363.
Imig JD, Hammock BD (2009) Soluble epoxide hydrolase as a therapeutic target for cardiovascular diseases. Nat Rev Drug Discov 8:794-805.
Imig JD, Inscho EW, Deichmann PC, Reddy KM, Falck JR (1999) Afferent arteriolar vasodilation to the sulfonimide analog of 11, 12-epoxyeicosatrienoic acid involves protein kinase A. Hypertension 33:408-413.
Inceoglu B, Schmelzer KR, Morisseau C, Jinks SL, Hammock BD (2007) Soluble epoxide hydrolase inhibition reveals novel biological functions of epoxyeicosatrienoic acids (EETs). Prostaglandins Other Lipid Mediat 82:42-49.
Inceoglu B, Bettaieb A, Trindade da Silva CA, Lee KS, Haj FG, Hammock BD (2015) Endoplasmic reticulum stress in the peripheral nervous system is a significant driver of neuropathic pain. Proc Natl Acad Sci U S A 112:9082-9087.
Inceoglu B, Zolkowska D, Yoo HJ, Wagner KM, Yang J, Hackett E, Hwang SH, Lee KS, Rogawski MA, Morisseau C, Hammock BD (2013) Epoxy fatty acids and inhibition of the soluble epoxide hydrolase selectively modulate GABA mediated neurotransmission to delay onset of seizures. PLoS ONE 8:e80922.
Kang H, Jia LZ, Suh KY, Tang L, Schuman EM (1996) Determinants of BDNF-induced hippocampal synaptic plasticity: role of the Trk B receptor and the kinetics of neurotrophin delivery. Learn Mem 3:188-196.
Kauer JA, Malenka RC (2007) Synaptic plasticity and addiction. Nat Rev Neurosci 8:844-858.
Kutsuwada T, Sakimura K, Manabe T, Takayama C, Katakura N, Kushiya E, Natsume R, Watanabe M, Inoue Y, Yagi T, Aizawa S, Arakawa M, Takahashi T, Nakamura Y, Mori H, Mishina M (1996) Impairment of suckling response, trigeminal neuronal pattern formation, and hippocampal LTD in NMDA receptor epsilon 2 subunit mutant mice. Neuron 16:333-344.
Le Duigou C, Wittner L, Danglot L, Miles R (2005) Effects of focal injection of kainic acid into the mouse hippocampus in vitro and ex vivo. J Physiol 569:833-847.
Li PL, Zhang DX, Ge ZD, Campbell WB (2002) Role of ADP-ribose in 11,12-EET-induced activation of K(Ca) channels in coronary arterial smooth muscle cells. Am J Physiol Heart Circ Physiol 282:H1229-1236.
Lu KT, Wu SP, Gean PW (1999) Promotion of forskolin-induced long-term potentiation of synaptic transmission by caffeine in area CA1 of the rat hippocampus. Chin J Physiol 42:249-253.
Lynch MA (2004) Long-term potentiation and memory. Physiol Rev 84:87-136.
McBain CJ, Mayer ML (1994) N-methyl-D-aspartic acid receptor structure and function. Physiol Rev 74:723-760.
Mitra R, Guo Z, Milani M, Mesaros C, Rodriguez M, Nguyen J, Luo X, Clarke D, Lamba J, Schuetz E, Donner DB, Puli N, Falck JR, Capdevila J, Gupta K, Blair IA, Potter DA (2011) CYP3A4 mediates growth of estrogen receptor-positive breast cancer cells in part by inducing nuclear translocation of phospho-Stat3 through biosynthesis of (+/-)-14,15-epoxyeicosatrienoic acid (EET). J Biol Chem 286:17543-17559.
Musleh W, Bi X, Tocco G, Yaghoubi S, Baudry M (1997) Glycine-induced long-term potentiation is associated with structural and functional modifications of alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid receptors. Proc Natl Acad Sci U S A 94:9451-9456.
Nicolas CS, Amici M, Bortolotto ZA, Doherty A, Csaba Z, Fafouri A, Dournaud P, Gressens P, Collingridge GL, Peineau S (2013) The role of JAK-STAT signaling within the CNS. JAKSTAT 2:e22925.
Node K, Ruan XL, Dai J, Yang SX, Graham L, Zeldin DC, Liao JK (2001) Activation of Galpha s mediates induction of tissue-type plasminogen activator gene transcription by epoxyeicosatrienoic acids. J Biol Chem 276:15983-15989.
Oliveira AM, Hawk JD, Abel T, Havekes R (2010) Post-training reversible inactivation of the hippocampus enhances novel object recognition memory. Learn Mem 17:155-160.
Otmakhov N, Khibnik L, Otmakhova N, Carpenter S, Riahi S, Asrican B, Lisman J (2004) Forskolin-induced LTP in the CA1 hippocampal region is NMDA receptor dependent. J Neurophysiol 91:1955-1962.
Paoletti P, Bellone C, Zhou Q (2013) NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease. Nat Rev Neurosci 14:383-400.
Pratt PF, Rosolowsky M, Campbell WB (2002) Effects of epoxyeicosatrienoic acids on polymorphonuclear leukocyte function. Life Sci 70:2521-2533.
Preston AR, Eichenbaum H (2013) Interplay of hippocampus and prefrontal cortex in memory. Curr Biol 23:R764-773.
Ren Q, Ma M, Ishima T, Morisseau C, Yang J, Wagner KM, Zhang JC, Yang C, Yao W, Dong C, Han M, Hammock BD, Hashimoto K (2016) Gene deficiency and pharmacological inhibition of soluble epoxide hydrolase confers resilience to repeated social defeat stress. Proc Natl Acad Sci U S A 113:E1944-1952.
Roman RJ (2002) P-450 metabolites of arachidonic acid in the control of cardiovascular function. Physiol Rev 82:131-185.
Rosenkranz JA, Frick A, Johnston D (2009) Kinase-dependent modification of dendritic excitability after long-term potentiation. J Physiol 587:115-125.
Sakamoto K, Karelina K, Obrietan K (2011) CREB: a multifaceted regulator of neuronal plasticity and protection. J Neurochem 116:1-9.
Shipton OA, Paulsen O (2014) GluN2A and GluN2B subunit-containing NMDA receptors in hippocampal plasticity. Philos Trans R Soc Lond B Biol Sci 369:20130163.
Simpkins AN, Rudic RD, Schreihofer DA, Roy S, Manhiani M, Tsai HJ, Hammock BD, Imig JD (2009) Soluble epoxide inhibition is protective against cerebral ischemia via vascular and neural protection. Am J Pathol 174:2086-2095.
Sobczyk A, Scheuss V, Svoboda K (2005) NMDA receptor subunit-dependent [Ca2+] signaling in individual hippocampal dendritic spines. J Neurosci 25:6037-6046.
Strack S, Colbran RJ (1998) Autophosphorylation-dependent targeting of calcium/ calmodulin-dependent protein kinase II by the NR2B subunit of the N-methyl- D-aspartate receptor. J Biol Chem 273:20689-20692.
Tanimizu T, Kono K, Kida S (2017) Brain networks activated to form object recognition memory. Brain Res Bull.
Ulu A, Appt S, Morisseau C, Hwang SH, Jones PD, Rose TE, Dong H, Lango J, Yang J, Tsai HJ, Miyabe C, Fortenbach C, Adams MR, Hammock BD (2012) Pharmacokinetics and in vivo potency of soluble epoxide hydrolase inhibitors in cynomolgus monkeys. Br J Pharmacol 165:1401-1412.
Volianskis A, France G, Jensen MS, Bortolotto ZA, Jane DE, Collingridge GL (2015) Long-term potentiation and the role of N-methyl-D-aspartate receptors. Brain Res 1621:5-16.
Wang SJ, Cheng LL, Gean PW (1999) Cross-modulation of synaptic plasticity by beta-adrenergic and 5-HT1A receptors in the rat basolateral amygdala. J Neurosci 19:570-577.
Wu HF, Yen HJ, Huang CC, Lee YC, Wu SZ, Lee TS, Lin HC (2015) Soluble epoxide hydrolase inhibitor enhances synaptic neurotransmission and plasticity in mouse prefrontal cortex. J Biomed Sci 22:94.
Yuan L, Liu J, Dong R, Zhu J, Tao C, Zheng R, Zhu S (2016) 14,15-epoxyeicosatrienoic acid promotes production of brain derived neurotrophic factor from astrocytes and exerts neuroprotective effects during ischaemic injury. Neuropathol Appl Neurobiol 42:607-620.
Zaphiropoulos PG, Wood T (1993) Identification of the major cytochrome P450s of subfamily 2C that are expressed in brain of female rats and in olfactory lobes of ethanol treated male rats. Biochem Biophys Res Commun 193:1006-1013.
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