本文選題：氟西汀 + 凋亡�。� 參考：《南京醫(yī)科大學》2016年碩士論文

【摘要】：神經(jīng)炎癥是多種神經(jīng)系統(tǒng)疾病的發(fā)病機制之一,參與缺血性腦卒中、神經(jīng)退行性病變、抑郁癥等神經(jīng)精神疾病的發(fā)生、發(fā)展。研究表明,白介素-1β(interleukin-1p, IL-1p)、腫瘤壞死因子-a(tumor necrosis factor-a, TNF-a)以及白介素-6(interleukelin-6, IL-6)等炎癥因子以不同方式誘導神經(jīng)損傷�？寡字委熂航�(jīng)探索性地應用于腦卒中、癲癇以及阿爾茲海默病(Alzheimer's disease,AD)中。因此在神經(jīng)系統(tǒng)疾病治療策略中,尋找有效的抗神經(jīng)炎癥靶點以及有力的神經(jīng)保護劑顯得尤為重要。氟西汀(Fluoxetine)是一種經(jīng)典的選擇性5-羥色胺(Serotonin,5-HT)再攝取抑制劑(Selective serotonin reuptake inhibitor, SSRI)。除了抗抑郁癥作用外,氟西汀尚有顯著的抗炎、抗腫瘤及神經(jīng)保護作用。越來越多的證據(jù)顯示,氟西汀對缺血性腦卒中患者以及腦卒中模型動物均具有神經(jīng)保護作用。研究表明氟西汀減少缺血性腦卒中模型大鼠腦梗死體積并降低其神經(jīng)功能評分。此外,氟西汀減少缺血性腦卒中模型大鼠腦內(nèi)TNF-a和IL-1p的釋放、抑制核轉錄因子-kB (Nuclear factor-kB, NF-kB)活性、抵抗生物胺的丟失。氟西汀對缺血性腦損傷的保護作用可能與其抗炎、抗凋亡作用相關,但其確切機制尚未闡明。p53是一種腫瘤抑制基因。野生型p53蛋白由373個氨基酸組成,包括四個功能域：①N端功能域,又分為轉錄活化區(qū)和脯氨酸富集區(qū)；②DNA結合域,負責與DNA序列的結合；③寡聚化結構域；④C端調(diào)控域,大部分的轉錄后修飾均發(fā)生于此。生理條件下,由于鼠雙微基因2(Mouse double minute 2 homolog, MDM2)的泛素化作用及蛋白酶體的降解,p53低水平表達。一旦發(fā)生DNA損傷,雙鍵斷裂促進FOXO3a、E2F1、YB1等轉錄因子的表達,促使ATM或ATR分別活化CHK2和CHK1,進而活化p53,調(diào)控下游靶基因的表達(尤其是凋亡蛋白Bax的表達)。p53功能廣泛,參與細胞周期阻滯、凋亡、老化、DNA損傷修復等,在腫瘤的發(fā)生、發(fā)展中發(fā)揮著重要作用。近年來,研究發(fā)現(xiàn)p53也參與神經(jīng)精神疾病的發(fā)生、發(fā)展,如缺血性腦卒中、神經(jīng)退行性病變、抑郁癥以及癲癇等。例如,在缺血性腦卒中模型中,p53通過死亡相關蛋白激酶1(Death-associated protein kinase 1, DAPK1)信號通路誘導神經(jīng)元凋亡。炎癥因子,尤其是IL-1β,通過誘導NF-κB核轉位,進而活化p53上調(diào)凋亡調(diào)控因子(p53-upregulated modulator of apoptosis, PUMA),后者促進p53與BcI-XL解離。游離的p53活化Bax,最終導致凋亡的發(fā)生。上述研究提示p53可能參與調(diào)控氟西汀的抗凋亡作用,然而其在氟西汀對缺血性腦損傷的神經(jīng)保護作用中的意義尚未見報道。本文通過在體與離體實驗研究氟西汀的神經(jīng)保護作用與p53的相關性及機制。研究發(fā)現(xiàn),氟西汀抑制短暫性大腦中動脈阻塞(Transient middle cerebral artery occlusion, tMCAO)模型小鼠腦內(nèi)神經(jīng)元凋亡、IL-113釋放及p53表達下降。離體培養(yǎng)原代皮層神經(jīng)元以及N2a細胞株,進一步離體研究發(fā)現(xiàn)氟西汀通過p38-p53信號通路發(fā)揮神經(jīng)保護作用。本文工作證實了氟西汀對缺血性腦卒中的神經(jīng)保護作用,并揭示了p53在其中的重要意義和調(diào)控機制,深化了對氟西汀藥理作用的認識,為氟西汀治療神經(jīng)系統(tǒng)疾病提供了實驗依據(jù)和學術基礎。目的：研究氟西汀對小鼠皮層神經(jīng)元的保護作用及其與p53的相關性。方法：1.氟西汀對小鼠腦缺血再灌注急性期損傷的治療作用。應用3月齡C57BL/6J雄性小鼠,建立tMCAO模型,缺血1 h,復灌1 h后腹腔注射(i.p.,bid.)氟西汀(40 mg/kg)。24 h后行神經(jīng)功能評分,TTC染色測定腦梗死體積,免疫組織化學計算NeuN陽性細胞數(shù),TUNEL法觀察凋亡細胞,Western Blot檢測Bax、Bcl-2、p53、IL-1p及proIL-1p蛋白表達。2.氟西汀對原代皮層神經(jīng)元的抗凋亡作用。(1)離體培養(yǎng)小鼠原代皮層神經(jīng)元,氟西汀(0.1、1、10μM)預處理1 h后,給予IL-1β(30 ng/ml)刺激24 h。應用Hoechst 33342熒光染色觀察細胞凋亡,顯微鏡明場觀察神經(jīng)元突起,LDH法檢測細胞活力,Western Blot檢測Bax、Bcl-2、NF-kB、p53蛋白表達,Real-time PCR檢測p53 mRNA表達,細胞免疫化學觀察p53分布。(2)離體培養(yǎng)小鼠原代皮層神經(jīng)元,cyanopindolol (10μM)或酮舍林(1 μM)預處理30 min后,給予上述相同藥物刺激。應用Hoechst33342熒光染色觀察細胞凋亡,Western Blot觀察Bax、Bcl-2蛋白表達變化。3.氟西汀通過p38-p53信號通路發(fā)揮抗凋亡作用。(1)培養(yǎng)N2a細胞株,轉染pcDNA3.1(-)-3HA-p53,氟西汀(1μM)預處理1 h后,給予IL-1β(30 ng/m1)刺激24 h。應用Hoechst 33342熒光染色觀察細胞凋亡,LDH法檢測細胞活力,流式細胞術觀察細胞凋亡,Western Blot觀察Bax、Bcl-2、NF-kB、p53蛋白表達。(2)培養(yǎng)N2a細胞株,氟西汀(1μM)預處理1 h后,給予茴香霉素(10 nM)或SB203580(10州)刺激11 h。WesternBlot觀察MAPK、p53蛋白表達,Real-time PCR檢測p53、FOXO3a mRNA表達。結果：1.氟西汀改善小鼠腦缺血再灌注急性期損傷。氟西汀(40mg/kg,i.p.,bid.)顯著改善tMCAO導致的神經(jīng)功能障礙,減小腦梗死體積,抑制神經(jīng)元丟失,緩解細胞凋亡,抑制IL-1p釋放。2. 氟西汀減少IL-1β導致的原代皮層神經(jīng)元凋亡和炎癥。離體培養(yǎng)小鼠原代皮層神經(jīng)元,氟西汀(1μM)預處理1 h,顯著抑制IL-1β(30 ng/ml)導致的神經(jīng)元突起縮短、LDH釋放、細胞核固縮、細胞凋亡、NF-κB信號通路活化。3.氟西汀通過抑制p38-p53信號通路的激活發(fā)揮抗凋亡及抗炎作用氟西汀下調(diào)原代皮層神經(jīng)元和N2a細胞株p53表達。p53過表達取消氟西汀的抗炎及抗凋亡作用。氟西汀下調(diào)p53的同時伴隨抑制p38磷酸化。p38激動劑茴香霉素可取消氟西汀對p53的下調(diào)作用。反之,p38抑制劑SB203580可模擬氟西汀對p53的下調(diào)作用。結論：1.氟西汀抗炎和對缺血性腦損傷的神經(jīng)保護作用與調(diào)節(jié)p53表達相關。2.氟西汀通過抑制p38磷酸化調(diào)節(jié)p53。綜上所述,本文工作的主要創(chuàng)新之處在于：1.證實氟西汀改善缺血再灌注急性期損傷本文研究發(fā)現(xiàn)氟西汀急性期用藥顯著減輕小鼠神經(jīng)功能障礙、腦梗死體積、神經(jīng)元丟失及細胞凋亡,提示氟西汀顯著改善缺血再灌注急性期損傷,為氟西汀用于腦卒中急性期治療提供實驗基礎和學術依據(jù)。2.闡明氟西汀通過p38-p53信號通路發(fā)揮神經(jīng)保護作用 氟西汀抑制IL-1β介導的原代皮層神經(jīng)元和N2a細胞株細胞損傷,該保護作用在p53過表達后被取消,且氟西汀通過抑制p38信號通路發(fā)揮了對p53的下調(diào)作用。本研究首次提出氟西汀通過抑制p38-p53信號通路發(fā)揮神經(jīng)保護作用,揭示了氟西汀神經(jīng)保護的新機制,為氟西汀治療腦卒中以及其他神經(jīng)系統(tǒng)疾病提供新思路。
[Abstract]:Neuroinflammation is one of the mechanisms of a variety of nervous system diseases. It participates in the occurrence and development of neuropsychiatric disorders such as ischemic stroke, neurodegenerative disease, depression and other neuropsychosis. Studies have shown that interleukin -1 beta (interleukin-1p, IL-1p), tumor necrosis factor -a (tumor necrosis factor-A, TNF-a), and interleukin -6 (interleukelin-6, IL-6) Inflammatory factors induce nerve damage in different ways. Anti-inflammatory therapy has been applied to stroke, epilepsy and Alzheimer's disease (AD). Therefore, it is particularly important to find effective anti neuroinflammatory targets and powerful neuroprotectant in the treatment strategy of nervous system disease. Fluoxetine (Fluox Etine) is a classic selective 5- serotonin (Serotonin, 5-HT) reuptake inhibitor (Selective serotonin reuptake inhibitor, SSRI). Besides antidepressant effect, fluoxetine has significant anti-inflammatory, anti-tumor and neuroprotective effects. More and more evidence shows that fluoxetine has an ischemic stroke patient and a stroke model. The study shows that fluoxetine reduces the volume of cerebral infarction in ischemic stroke model rats and reduces the neurological function score. In addition, fluoxetine reduces the release of TNF-a and IL-1p in the brain of ischemic stroke model rats, inhibits the activity of nuclear transcription factor -kB (Nuclear factor-kB, NF-kB), and resists biogenic amines. The protective effect of fluoxetine on ischemic brain injury may be related to its anti-inflammatory and anti apoptotic effects, but its exact mechanism has not yet elucidated that.P53 is a tumor suppressor. The wild type p53 protein consists of 373 amino acids, including four functional domains: (1) the N terminal functional domain, and also a transcriptional activation area and a proline enrichment region; (2) DNA binding Domain, which is responsible for the combination of DNA sequences; (3) oligomeric domains; (4) C terminal regulation domain, most of the posttranscriptional modification occurs. Under physiological conditions, the ubiquitination of mouse double microgene 2 (Mouse double minute 2 homolog, MDM2) and the degradation of proteasome, p53 low level expression. Once DNA damage occurs, double bond fracture promotes FOXO. The expression of transcription factors, such as 3a, E2F1 and YB1, urges ATM or ATR to activate CHK2 and CHK1 respectively, and then activate p53 and regulate the expression of the downstream target gene (especially the expression of apoptotic protein Bax).P53 functions widely, and participate in cell cycle arrest, apoptosis, aging, DNA damage repair and so on. It plays an important role in the development of tumor. In recent years, research has been studied. It is found that p53 also participates in the occurrence and development of neuropsychiatric disorders, such as ischemic stroke, neurodegenerative disease, depression, and epilepsy. For example, in ischemic stroke model, p53 induces neuronal apoptosis through the signal pathway of death related protein kinase 1 (Death-associated protein kinase 1, DAPK1). Inflammatory factors, especially IL-1 beta, are induced. By inducing the transposition of NF- kappa B, then activating p53 to regulate the apoptosis regulating factor (p53-upregulated modulator of apoptosis, PUMA), and the latter promotes the dissociation of p53 and BcI-XL. The free p53 activation Bax, which eventually leads to the apoptosis, may be involved in the regulation of the anti apoptosis effect of fluoxetine, however, it is in fluoxetine for ischemic brain. The significance of the neuroprotective effect of injury has not yet been reported. In this paper, the correlation and mechanism of the neuroprotective effect of fluoxetine to p53 was studied in vivo and in vitro. It was found that fluoxetine inhibited neuronal apoptosis in the brain of Transient middle cerebral artery occlusion (tMCAO) model mice, IL-1 13 release and p53 expression decline. In vitro culture of primary cortical neurons and N2a cells. Further in vitro studies have found that fluoxetine plays a neuroprotective role through the p38-p53 signaling pathway. This work confirms the neuroprotective effect of fluoxetine on ischemic stroke, and reveals the significance and regulatory mechanism of p53 in it. The pharmacological effects of fluoxetine were known to provide experimental basis and academic basis for the treatment of fluoxetine in the treatment of nervous system diseases. Objective: To study the protective effect of fluoxetine on mouse cortical neurons and the correlation with p53. Methods: the therapeutic effect of 1. fluoxetine on acute cerebral ischemia reperfusion injury in mice. 3 month old C57BL/6J was used. In male mice, tMCAO model was established, ischemia was 1 h, and after reperfusion for 1 h, after intraperitoneal injection of (i.p., bid.) fluoxetine (40 mg/kg).24 h, the nerve function was scored, the volume of cerebral infarction was measured by TTC staining, the number of NeuN positive cells was calculated by immunohistochemistry, and apoptotic cells were observed by TUNEL method. The antiapoptotic effect on primary cortical neurons. (1) the primary cortical neurons of mice were cultured in vitro. After 1 h preconditioning with fluoxetine (0.1,1,10 mu M), IL-1 beta (30 ng/ml) was given to 24 h. To observe cell apoptosis by Hoechst 33342 fluorescence staining, microscopic field observation of neuron protuberance, LDH method to detect cell viability, Western Blot detection Bax, Bcl-2, Bcl-2. -kB, p53 protein expression, Real-time PCR detection of p53 mRNA expression, cell immuno chemical observation of p53 distribution. (2) in vitro culture of primary cortical neurons in mice, cyanopindolol (10 mu) or ketone shlin (1 mu M) pretreated 30 min, give the same drug stimulation. Protein expression change.3. fluoxetine exerts anti apoptosis effect through p38-p53 signaling pathway. (1) culture N2a cell line, transfection pcDNA3.1 (-) -3HA-p53, fluoxetine (1 M) pretreatment 1 h, IL-1 beta (30 ng/m1) stimulation 24 h. application Hoechst 33342 fluorescence staining to observe cell apoptosis, LDH method to detect cell viability, flow cytometry observation cell apoptosis, Estern Blot observed Bax, Bcl-2, NF-kB, and p53 protein expression. (2) culture N2a cell lines, and fluoxetine (1 micron M) pretreated 1 h, and gave anisomycin (10 nM) or SB203580 (10 state) to stimulate 11 h.WesternBlot to observe and express. Results: 1. fluoxetine improved the acute phase of cerebral ischemia reperfusion injury in mice. 40mg/kg (i.p., bid.) significantly improved the neurological dysfunction caused by tMCAO, reduced the volume of cerebral infarction, inhibited neuron loss, alleviated apoptosis, and inhibited the release of.2. fluoxetine to reduce the apoptosis and inflammation of primary cortical neurons induced by IL-1 beta, in vitro culture of the primary cortical neurons in mice, and the preconditioning of fluoxetine (1 mu M) was 1 h in vitro. Inhibition of IL-1 beta (30 ng/ml) induced neurite protuberance, LDH release, nuclear condensation, cell apoptosis, NF- kappa B signaling pathway activating.3. fluoxetine to inhibit apoptosis and anti-inflammatory effects of fluoxetine down regulation of fluoxetine down regulation of primary cortical neurons and N2a cells p53 expression by.P53 overexpression and canceling the anti inflammation of fluoxetine And antiapoptotic effect. Fluoxetine downregulates p53 while inhibiting p38 phosphorylation.P38 agonist anisomycin cancels fluoxetine's down regulation of p53. Conversely, p38 inhibitor SB203580 can mimic the down-regulation of fluoxetine to p53. Conclusion: 1. fluoxetine and the neuroprotective effect on ischemic brain injury are associated with the regulation of p53 expression. The main innovations of this work are: 1. the main innovations of this work are: 1. the findings of fluoxetine to improve the acute phase of ischemia-reperfusion injury in fluoxetine showed that the acute phase of fluoxetine significantly alleviated the dysfunction of the nerve in mice, the volume of cerebral infarction, the loss of neurons and the apoptosis of the cells, suggesting that fluoxetine was significant. Improving the acute phase of ischemia-reperfusion injury, providing experimental basis and academic basis for the treatment of acute phase of cerebral apoplexy by fluoxetine,.2. clarifies that fluoxetine exerts neuroprotective effect on the p38-p53 signaling pathway to inhibit IL-1 beta mediated primary cortical neurons and N2a cell cell damage, and the protective effect is taken after p53 overexpression. In addition, fluoxetine plays a downregulation effect on p53 by inhibiting the p38 signaling pathway. This study first proposed that fluoxetine played a neuroprotective role by inhibiting the p38-p53 signaling pathway and revealed a new mechanism for the protection of fluoxetine, providing new ideas for fluoxetine in the treatment of stroke and other nervous system diseases.

【學位授予單位】：南京醫(yī)科大學
【學位級別】：碩士
【學位授予年份】：2016
【分類號】：R743

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