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研究生：	王亮超 Wang, Liang-Chao
論文名稱：	免疫調控在缺血性腦中風多元治療之角色探討 The role of immunomodulation in multimodal therapy for ischemic stroke
指導教授：	蔡坤哲 Tsai, Kuen-Jer
學位類別：	博士 Doctor
系所名稱：	醫學院 - 臨床醫學研究所 Institute of Clinical Medicine
論文出版年：	2016
畢業學年度：	104
語文別：	英文
論文頁數：	85
中文關鍵詞：	缺血性腦中風、發炎、鎂離子、乙型還氧化酶抑制劑、胸腺前素
外文關鍵詞：	ischemia, inflammation, magnesium, cyclooxygenase-2 inhibitor, prothymosin
相關次數：	點閱：109 下載：8
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中樞神經細胞在缺血失去能量供應後，數分鐘內即會引發一連串的反應而導致細胞壞死，細胞壞死釋放大量化學物質引發後續的的細胞凋亡及發炎反應。發炎及免疫反應在缺血性腦損傷的病理進程中扮演重要角色。對免疫發炎過程的調控，可能有助於減緩急性期的神經損傷。由於缺血性腦中風的病理機轉複雜，針對多個病理機轉的多元治療是目前治療發展的重要趨勢。抗壞死，抗凋亡及抗發炎皆是治療的重要目標。本實驗使用兩種策略來發展缺血性腦中風之治療藥物。 (1)合併使用可能具有療效的製劑以降低個別藥劑之治療劑量及副作用。(2)藉著改變蛋白質的結構調整蛋白質的功能，去除有害的部分，使之能針對多個病理機轉作用而加強其療效。
鎂離子(Mg2+)在具有拮抗N-甲基-D-天門冬胺酸 (NMDA)之作用，硫酸鎂 (MgSO4)於活體及離體實驗皆被認為可以用來治療缺血性腦中風。然而硫酸鎂有抑制心血管功能之副作用。乙型還氧化酶(COX-2)抑制劑，如nimesulide，因其抗發炎的作用，也被認為可以用於治療血性腦中風，但有效治療劑量高，臨床應用有限。本實驗之第一部分合併使用MgSO4 及 nimesulide 來降低個別藥物的有效劑量，減低副作用，並加強其療效。暫時性缺血性腦中風之大鼠接受不同的治療，包括安慰劑，單獨MgSO4，單獨nimesulide，及複方MgSO4加nimesulide治療。治療的結果予以壞死區域染色評估及行為評估。並評估各治療藥物對發炎反應相關因子(COX-2, MPO, PGE2,)及細胞凋亡因子(caspase 3) 的影響。我們的實驗結果發現，單獨低劑量的MgSO4，或nimesulide 無法治療缺血性腦中風，而合併兩者使用可以減少壞死面積及降低神經功能損傷。複方使用也可以降低發炎因子及細胞凋亡因子的表現，顯示其抗發炎及抗凋亡的效果。
有研究指出，胸腺前素(ProT)對腦缺血性損傷有抗壞死的保護作用。然而胸腺前素同時也具有促進發炎反應的功用。缺血後的發炎反應將加重組織損傷。胸腺前素促進發炎反應的訊息和入核訊息都在該蛋白質的碳端 (a.a.109~113)。我們認為，將入核訊息切除後，無入核訊息的胸腺前素(ProTNLS)可以抑制其促進發炎反應的能力，從而加強其對缺血性腦中風的療效。本實驗之第二部分我們以動物模式驗證本假說。暫時性缺血腦中風的大鼠接受ProT或ProTNLS 100g/kg靜脈注射治療。並和對照組比較。以腦壞死的體積,神經功能的損傷程度來評估該蛋白質的神經保護功能。各治療對發炎反應的影響以酵素免疫分析法評估促發炎性細胞激素(TNF-,MPO)及抗發炎細胞激素(IL-10)分泌量，及以組織免疫螢光染色來評估腦組織內微膠細胞(microglia)的活化來評估。也評估該治療對腦源性神經滋養因子(BDNF)的表現的影響。實驗結果發現，雖然ProT及ProTNLS 對缺血性腦中風都有治療效果，但ProTNLS較ProT有較好的保護效果。並且ProT治療將導致TNF-急遽上升，而ProTNLS治療則沒有這樣的現象。ProTNLS治療可以抑制基質金属蛋白酶(MMPs)及內微膠細胞的活化，顯示其有抗發炎效果。移除胸腺前素的入核訊息的確可以降低其促發炎作用並加強其療效。
本實驗以兩種不一樣的策略來發展缺血性腦中風的治療藥物。也揭示了免疫調節在缺血性腦中風多元治療扮演重要角色。本研究結果有助於後續發展缺血性腦中風治療藥物。

Multimodal therapy focusing on different targets is an important trend for developing therapy agents of ischemic stroke. Important strategies for multimodal therapy include: (1) Combination of established neuro-protective agents with distinct mechanisms. (2) Structure modification of a protein that is potentially neuroprotective to improve its therapeutic potency and decrease its detrimental effects. In this thesis, we tried to develop new therapies for ischemic stroke targeting on anti-necrosis and immunomodulation.
Inorganic magnesium ion (Mg2+) has potential to treat ischemic stroke by preventing the release of neurotransmitters and blocking N-methyl-D-asparate (NMDA)-coupled calcium channels, thereby inhibiting calcium entry into the neurons. However, large bolus dosage carries the risk of cardiovascular depression. To decrease the effective therapeutic dose and adverse effects of MgSO4, combination with other drugs targeting on the downstream pathophysiologic events is a reasonable consideration. Anti-inflammatory agents, such as cyclooxygenase-2 inhibitor, are also promising agents for treatment of ischemic stroke. In the first part of this thesis, we tested the synergism of MgSO4 and nimesulide at half their usual dose. The neuro-protective effects of three protocols, MgSO4 alone, nimesulide alone, and a combination of both, were compared. Inflammatory markers, such as cyclooxygenase-2, myeloperoxidase, prostaglandin E2 were examined to evaluate the impact of individual treatment on post-ischemic inflammation. Our results demonstrated that combination treatment group showed a significant decrease in infarction volume and neurological severity score. Low dose MgSO4 or nimesulide showed no significant neuroprotection. There was also significant suppression of cyclooxygenase-2, prostaglandin E2, myeloperoxidase, and caspase-3 expressions in the combination treatment group, suggesting that the combination of the two drugs improved the neuroprotective effects of each individual drug. MgSO4 and nimesulide have synergistic effects on ischemia-reperfusion insults.
Prothymosin-α (ProT) has shown its neuroprotective effect for ischemic insults by shifting necrotic cell death to apoptosis. However, ProT also has pro-inflammatory activity that may enhance ischemic injury. C-terminal of ProT contains its nuclear localizing signal (NLS) and most potent immunostimulatory signal. We hypothesized that delete NLS from ProT (ProTNLS) can attenuate its pro-inflammatory effect and improve the therapeutic effect on treatment of ischemic stroke. In second part of this thesis, we evaluated the therapeutic effect of ProT and ProTNLS on transient ischemic stroke, with special focus on immunomodulatory effects of ProTNLS on post-ischemic inflammation after transient middle cerebral artery occlusion. Therapeutic outcomes of ProT and ProTNLS on ischemic brain injury were evaluated by morphological and functional outcome evaluations. The impact of treatments on the post-ischemic inflammation was also evaluated. Expression of inflammatory cytokines, Tumor necrosis factor alpha (TNF-α), matrix metallopeptidase (MMPs) 2 and 9, myeloperoxidase (MPO), and interleukin-10 (IL-10) were examined by enzyme-linked immunosorbent assay or gelatin zymography. Immunohistochemistry for antigens indicating activation of microglia, Iba-1 and CD68, were used to evaluate the activation of microglia. Our results showed that while both ProT and ProTΔNLS reduce infarction volume and improve functional outcome, ProTΔNLS provides the best therapeutic outcome. ProT increases TNF-α but decreases IL-10 secretion after ischemic injury, reflecting its pro-inflammatory activity. ProTΔNLS suppresses expression of TNF-α, MPO and activity of MMPs in ischemic brain tissue. It also suppresses activation of microglia in penumbral cortex. These data demonstrated that deletion of NLS from ProT may attenuate post-ischemic inflammation and enhance the neuroprotective effects of ProT.
Immunomodulation is an important target for treatment of ischemic stroke. In this thesis, we showed immunomodulation can work synergistically with potential neuroprotective agents to decrease effective therapeutic dose, improve therapeutic effects and decrease adverse side effects. Immunomodulation is an important part in multimodal treatments for ischemic stroke

Table of Contents 
Chapter 1. Introduction	1
1.1	Pathophysiology of ischemic stroke	1
1.1.1 Mechanisms of necrotic cell death	1
1.1.2 Mechanisms of programmed cell death	3
1.1.3 Post-ischemic inflammation	4
1.2	Current status in treatment of ischemic stroke	5
1.3	Magnesium is a potential neuroprotective agent for ischemic injuries	7
1.4	COX-2 inhibitor is a potential neuroprotective agent for ischemic injuries	8
1.5	Prothymosin-α is a potential neuroprotective agent for ischemic injuries	9
1.6	Thesis aims	11
Aim 1: Studies on treatment of transient ischemic stroke using combined MgSO4 and nimesulide regimen.	12
Aim 2:  Studies on treatment of transient ischemic stroke using ProTNLS.	13
Chapter 2. Synergistic effects of magnesium sulfate and nimesulide on treatment of transient ischemic stroke	14
2.1 Background and aims	14
2.2 Materials and methods	15
Animals	15
Middle cerebral artery occlusion	16
Drugs	17
Experimental groups	17
Neurobehavioral testing	17
Infarct volume assessment	18
Evaluation of cerebral edema	19
Western blotting	19
Enzyme linked immunosorbent assay	20
Brain sections preparation	20
Immunohistochemistry	21
Image analysis and cell counting	21
Statistical analysis	22
2.3 Results	23
Changes of LDF signal and body temperature during MCAO and reperfusion	23
Table 2-1. Changes of LDF signal and temperature during MCAO and reperfusion.	23
Effect of combined MgSO4 and nimesulide treatment on infarct volume	24
Effect of MgSO4 and nimesulide treatment on post-ischemia brain edema	24
Figure 2-1. Effect of combined MgSO4 and nimesulide on infarct volume and brain edema	25
Effect of combined MgSO4 and nimesulide treatment on functional outcome	26
Figure 2-2. Effect of combined treatment on functional outcome after tMCAO.	26
Effect of MgSO4 and nimesulide treatments on COX-2 expression in the inner boundary zone of infarction	27
Effects of combined treatment on suppressing COX-2 expression in the brain tissue	27
Figure 2-3. Effect of combined MgSO4 and nimesulide on COX-2 expression 72 hours after ischemia-reperfusion injury.	28
Effect of combined treatment on PGE2 expression after ischemic infarction	29
Figure 2-4. ELISA of PGE2 expression in brain 72 hours after ischemic-reperfusion injury.	30
Effect of combined treatment on MPO expression	30
Figure 2-5. Effect of combined MgSO4 and nimesulide on MPO expression 72 hours after ischemia-reperfusion injury	31
Caspase-3 expression in brain tissue	32
Figure 2-6. Effect of combined MgSO4 and nimesulide on Caspase-3 expression 72 hours after ischemia-reperfusion injury.	33
2.4 Discussions	35
Chapter 3. ProTNLS enhance neuroprotective effect of ProT	40
3.1 Background and aims	40
3.2 Materials and methods	42
Protein preparation	42
Experimental Paradigm	43
Middle cerebral artery occlusion	43
Infarct volume assessment	44
Neuro-behavioral testing	45
Rotarod test	46
Protein assay	46
Gelatin zymography for MMP-2 and MMP-9	47
Brain sections preparation	47
Immunofluorescent stains	48
Image analysis and cell counting	48
Statistical analysis	49
3.3 Results	50
ProTNLS and ProT decrease infarction volume after ischemia/reperfusion injury	50
Figure 3-1. Infarction volume 72 h after ischemia/reperfusion injury evaluated by TTC staining.	50
ProTNLS and ProT improved functional recovery after ischemia/reperfusion injury	51
Figure 3-2. Functional outcome 24 h and 72 h after ischemia/reperfusion injury with different treatment evaluated NSS and rotarod performance	52
ProTNLS attenuate expression of TNF-α induced by ProT but promote secretion of IL-10	53
Figure 3-3. Expression of TNF-α 24 h after ischemia/reperfusion injury with different treatment.	54
Figure 3-4. Impact of ProT treatment on IL-10 expression with different treatment.	54
ProTNLS decreased expression of activated of MMP-2 and MMP-9 72 h after ischemia/reperfusion injury	55
Figure 3-5. Expression of activated MMP-2 and MMP-9 24 and 72 h after ischemia/reperfusion injury with different treatment.	56
ProTNLS suppressed expression of MPO 72 h after ischemia/reperfusion injury	57
Figure. 3-6. Expression of MPO 72 h after ischemia/reperfusion injury with different treatment.	57
ProTNLS can suppress activation of microglia after ischemic/reperfusion injury	58
Figure 3-7. Immunofluorescent stains for activated microglia at 24 h after tMCAO with different treatments.	59
ProTNLS stimulate the expression of BDNF	60
Figure 3-8. Expression of BDNF 72 h after ischemia/reperfusion injury with different treatment.	60
3.4 Discussions	61
Chapter 4. Conclusions and prospect	66
4.1 Experimental results	66
Magnesium sulfate and nimesulide have synergistic effects on rescuing brain damage after temporary focal ischemia	66
Deletion of nuclear localizing signal attenuates pro-inflammatory activity of Prothymosin-alpha and enhances its neuroprotective effect on transient ischemic stroke	66
Thesis conclusions	67
Prospect	68
References:	70
                                    

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