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의학석사학위논문 백서의전뇌허혈모델에서유도고혈압에 의한신경학적영향 The effect of induced hypertension on neurological outcome in forebrain ischemia model in rats 2015 년 2 월 서울대학교대학원 의학과마취통증의학전공 한예름
초 록 서론 : 뇌에허혈손상이가해지는경우신경보호효과를얻을수있는처치들이다양하게연구되어왔다. 뇌허혈은대부분예측하지못한경우에발생하므로최근에는뇌졸중이발생한이후에적용할수있는처치에대한연구가활발하다. 뇌허혈후유도고혈압을적용한동물실험에서뇌혈류가개선되는등의효과가보고되었다. 하지만아직까지유도고혈압이신경보호효과를가져오는지세포수준에서검증된바는없다. 이연구에서는백서의전뇌허혈모델을이용하여유도고혈압이신경보호효과를가져오는지조직학적으로검증하고자하였다. 방법 : 체중 280-350 g의 Sprague-Dawley 수컷백서 20 마리를유도고혈압군과대조군에각 10마리씩무작위배정하였다. 양측총경동맥을겸자하고혈압이 30 mmhg가되도록채혈하여 8 분동안전뇌허혈을유발한후다시혈액을주입하고경동맥의겸자를풀었다. 유도고혈압군에서는재관류후 10 분동안평균동맥압을기저혈압보다 20 mmhg 이상유지되도록 phenylephrine 을 5 μg씩투여하였다. 실험 1 주일후해마 CA1 부위에서괴사된세포수와세포자멸사된세포수를관찰하였다. i
결과 : 전뇌허혈및재관류 1주일후괴사된세포를관찰하였을때생존세포수의비율이대조군에서는 26 ± 7%, 유도고혈압군에서는 35 ± 3% 였다. 생존세포의비율이대조군보다유도고혈압군에서유의하게높았다 (P = 0.004). 세포자멸사된세포수의비율은대조군에서 43 ± 19%, 유도고혈압군에서 57 ± 9% 로유의한차이가없었다 (P = 0.165). 결론 : 백서의전뇌허혈모델에서유도고혈압은단기적으로세포괴사를 감소시킴으로써신경보호효과를갖는다. 그러나세포자멸사과정에는 영향을미치지않는다. ---------------------------------------------------------------------------------------------------------- 주요어 : 전뇌허혈모델, 유도고혈압, 신경보호효과, 세포괴사, 세포자멸사학번 : 2013-21712 ii
목 차 초록 i 목차 iii 도표목록 iv 그림목록 v 서론 1 대상및방법 3 결과 6 고찰 11 참고문헌 15 초록 ( 영문 ) 19 iii
List of Tables Table 1. Physiological variables 10 minutes before and after ischemia/reperfusion 7 Table 2. Mean arterial blood pressure before and after ischemia/reperfusion... 8 iv
List of Figures Figure 1. Overview of the experimental process for forebrain ischemia and reperfusion...... 5 Figure 2. The percentage of viable cells in hippocampal Cornu Ammonis 1 region of rat seven days after transient forebrain ischemia... 9 Figure 3. The percentage of apoptotic cells in hippocampal Cornu Ammonis 1 region of rat seven days after transient forebrain ischemia..... 10 v
서 론 뇌에허혈손상이가해지는경우심각한합병증이발생할수있다. 이에신경보호효과가있는처치들이다양하게연구되어왔다 (1). 허혈성전처치와원격허혈성전처치또는수술중 sevoflurane의사용등이뇌보호에효과가있다고알려져있다 (2,3). 하지만임상적으로뇌허혈을미리예측할수있는경우는한계가있다. 뇌동맥류나대동맥수술등에서일시적으로동맥을결찰하는경우와같이미리대비할수있던경우가아니라면대부분의뇌졸중은사후처치가중요하다. 이러한이유로최근에는허혈손상후에시행하는처치의신경보호효과에대한연구들이많이이루어지고있다. 허혈성후처치 (4), 원격허혈성후처치 (5), 흡입마취제후처치 (6 8) 등많은연구가보고되고있으며유도고혈압을적용하려는연구도임상과동물실험을통해활발히이루어지고있다 (9). 국소뇌허혈모델에서허혈후유도고혈압을유지하였을때뇌혈류와산소화가개선되고뇌산소대사율이높아졌으며병리학적으로경색된뇌의부피도줄었다고보고되었다 (10). 국소적으로뇌허혈이발생한상황에서는허혈성반음영 (ischemic penumbra) 에유도고혈압을적용하여뇌혈류를개선하는것이뇌손상을줄이는효과가있다고볼수있다 (9,10). 전뇌허혈모델에서도유도고혈압이신경보호효과가있다고밝혀져있다. 모래쥐 (Gerbil) 의 1
전뇌허혈모델에서재관류후유도고혈압을유지하였을때개체생존율이증가하고뇌부종이감소하며뇌혈류와뇌산소대사율이증가한다고보고되었다 (11). Ishikawa 등 (12) 도백서의한쪽경동맥을일시적으로결찰한후유도고혈압을적용하였을때뇌부종이악화되지않으며뇌혈류가증가하고뇌경색부위의부피도줄었다고보고하였다. 하지만아직까지세포수준에서유도고혈압이허혈후뇌손상에미치는영향에대해연구된바는없다. 이에본연구에서는백서의전뇌허혈모델에서재관류후유도고혈압을유지하였을때신경손상에미치는효과를조직검사를통하여알아보고자하였다. 2
대상및방법 본연구는서울대학교동물실험윤리위원회의승인을받은후진행하였다. 체중 280-350 g의 Sprague-Dawley 수컷백서 20 마리를대상으로하였고유도고혈압군과대조군에각 10 마리를무작위배정하였다. 모든실험용백서들은 12 시간간격으로명암이조절되는사육실에서물과사료를자유로이먹게하였다. 시술전에는 12-16 시간을금식시키되수분섭취는자유롭게하였다. 측두근육에체온유지용바늘을삽입한후가온과냉각을통하여체온을 37.5 로유지하였다. 혈압관찰과혈액검사를위하여꼬리동맥에동맥로를확보하였다. 베타딘으로피부를소독한후멸균처치된수술도구를이용하여우측내경정맥과양측총경동맥을확보하였다. 우측내경정맥에는약제투여와탈혈을위하여실리콘카테터를삽입하였고양측총경동맥은겸자할수있도록노출시킨후실을걸어두었다. 내경정맥을통하여혈압이 30 mmhg 가될때까지혈액을뽑고양측총경동맥을겸자하여전뇌허혈을유발하였다. 8 분동안뇌허혈상태를유지한후에다시혈액을주입하고경동맥의겸자를풀었다. 대조군에서는재관류후다른처치는하지않았으며유도고혈압군에서는재관류후 10 분동안평균동맥압을기저혈압보다 20 mmhg 이상유지되도록 phenylephrine 을 5 μg씩투여하였다 (Figure 1). 이모든과정이끝나면절개부위를봉합한후한시간뒤백서가깨어날수있도록마취를유지하였다. 1 주일후에백서를생리식염수 100 ml 와 3
10% 포르말린 200 ml 로관류하여희생시키고밤사이냉장보관하였다. 다음날뇌를적출하여포르말린으로고정한후관상면절단으로얻은해마부위의뇌절편에 hematoxylin and eosin(h&e) 염색과 terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end labeling(tunel) 염색을시행하였다. H&E 염색을시행한해마 Cornu Ammonis(CA) 1 조직을광학현미경 400배배율로관찰하여온전한세포와괴사된세포수를평가하였다. 핵이둥글고핵소체가뚜렷한세포는살아있던것으로보았고, 핵농축, 핵파괴, 핵용해, 세포질호산구증가증등을보이는경우괴사된세포로보았다. TUNEL 염색을시행한조직도광학현미경 400배배율로관찰하였다. TUNEL 양성반응을보이는세포는세포자멸사된것으로보았고음성반응을보이는세포는살아있던것으로판단하였다. 전체세포수에대한괴사된세포수와세포자멸사된세포수의비율을계산하였다. 모든수치는평균과표준편차로나타내었다. 두군의생리학적변수는반복분산분석법 (repeated measures analysis of variance) 을이용하여분석하였고조직학적검사는 Mann-Whitney 법을사용하여분석하였다. p 값이 0.05 미만인경우에유의한것으로판단하였다. 4
Figure 1. Overview of the experimental process for forebrain ischemia and reperfusion Group Surgical preparation Ischemia Reperfusion and administration of drugs Control (n=10) Surgical preparation Occlusion Reperfusion Induced Hypertension (n=10) Surgical preparation Occlusion Reperfusion and intermittent phenylephrine injection 5
결 과 전뇌허혈및재관류전후에동맥혈 ph, 동맥혈이산화탄소및산소분압, 혈색소, 혈당값을측정하였다. 측정한값들은대조군과유도고혈압군에서유의한차이가없었다 (Table 1). 허혈전대조군과유도고혈압군에서측정한평균동맥압은각각 83 ± 9 mmhg, 81 ± 9 mmhg로유의한차이가없었다. 전뇌허혈및재관류 2 분후부터대조군에서는평균동맥압이허혈전과비슷한수준으로유지되었으며유도고혈압군에서는기저혈압보다 20 mmhg 높은수준으로유지되었다 (Table 2). 총 20 마리의백서중일시적인전뇌허혈후 1주일까지사망한백서는없었다. 전뇌허혈및재관류 1 주일후 H&E 염색을하여해마 CA1 부위조직을관찰하였을때생존세포수의비율이대조군에서는 26 ± 7%, 유도고혈압군에서는 35 ± 3% 였다. 생존세포의비율이대조군보다유도고혈압군에서유의하게높았다 (P = 0.004)(Figure 2). TUNEL 양성반응을보이는세포수의비율은대조군에서 43 ± 19%, 유도고혈압군에서 57 ± 9% 로유의한차이가없었다 (P = 0.165)(Figure 3). 6
Table 1. Physiological variables 10 minutes before and after ischemia/reperfusion ph PaCO 2 PaO 2 Hemoglobin Blood (mmhg) (mmhg) (g/dl) glucose (mg/dl) Control before 7.32 ±.03 48 ± 5 320 ± 41 13.9 ± 1.2 124 ± 23 after 7.34 ±.05 47 ± 5 336 ± 45 13.4 ± 0.7 IHT before 7.34 ±.04 46 ± 6 326 ± 30 13.6 ± 0.8 132 ± 21 after 7.33 ±.09 42 ± 7 305 ± 47 12.1 ± 2.4 Data are expressed as mean ± SD. Abbreviation: IHT = induced hypertension 7
Table 2. Mean arterial blood pressure before and after ischemia/reperfusion Control Before 83 ± 9 1 min 67 ± 14 2 min 78 ± 16 3 min 83 ± 19 After ischemia/reperfusion 4 5 6 7 min min min min 84 85 85 85 ± 20 ± 19 ± 17 ± 16 8 min 86 ± 17 9 min 86 ± 19 10 min 84 ± 16 Induced hypertension 81 ± 9 91 ± 15 102 ± 15 115 ± 22 111 ± 17 129 ± 17 126 ± 19 127 ± 14 120 ± 14 121 ± 16 108 ± 12 Data are expressed as mean ± SD(mmHg). 8
Figure 2. The percentage of viable cells in hippocampal Cornu Ammonis 1 region of rat seven days after transient forebrain ischemia The viable cells stained with hematoxylin and eosin staining(magnification: x 400) were more in the induced hypertersion group than in the control group(p = 0.004). Data are expressed as mean ± SD. 9
Figure 3. The percentage of apoptotic cells in hippocampal Cornu Ammonis(CA) 1 region of rat seven days after transient forebrain ischemia The CA1 region was stained with TUNEL and observed at 400x magnification thereafter. There was no difference in the number of apoptotic cells between the induced hypertension group and the control group(p = 0.165). Data are expressed as mean ± SD. Abbreviation: TUNEL = terminal deoxynucleotidyl transferase-mediated uridine 5'- triphosphate-biotin nick end labeling 10
고 찰 본연구에서는백서의전뇌허혈모델에서재관류후약물을이용하여혈압을높이면신경보호효과가나타나는지조직학적으로검증하고자하였다. 전뇌허혈및재관류 1 주일후에백서의해마 CA1 조직을관찰하였을때괴사된세포수는유도고혈압군에서유의하게적었고세포자멸사된세포수는두군사이에차이가없었다. 본연구에서유도고혈압이신경보호효과를보인것은혈압을높임으로써뇌혈류량이증가하였기 (11) 때문으로생각된다. 뇌허혈후에는뇌혈관의자동조절능이소실되면서 (13) 뇌혈류량이혈압에민감하게영향받게된다. Hosomi 등 (11) 은전뇌허혈후유도고혈압을적용했을때개체의생존율이증가하고뇌부종이감소하며뇌혈류와뇌산소대사율이증가했다고보고한바있다. 그러나신경세포의생존에도영향이미치는지까지알아보지는않았다. 유도고혈압을적용하여뇌경색의범위를줄였다고조직학적으로결과를보고한연구들 (10,12,14) 도있다. 그러나이연구들도국소뇌허혈모델에서육안으로뇌경색된부분의크기를비교한것으로세포수준에서신경보호효과를밝히지는못했다. 본연구에서는전뇌허혈모델을대상으로허혈에가장취약하여선택적으로손상되는해마 CA1 부위 (15) 에서생존세포의수를직접관찰하였다. 이를통해허혈후혈압을높게유지하여뇌혈 11
류를개선하는것이뇌세포의생존율을높인다는것을확인할수있었다. 또한세포괴사와세포자멸사된세포를모두살펴봄으로써유도고혈압이 각세포사멸기전에다르게영향을미친다는점도밝힐수있었다. 본연구에서세포자멸사된세포수는유도고혈압을적용한군과대조군에서차이가없었다. sevoflurane의뇌보호효과를본기존의연구에서도뇌허혈후세포괴사는감소하였지만세포자멸사는차이가없는것으로보고하였다 (3). 이는세포자멸사의기전과관계된것으로보인다. 뇌허혈후에는활성산소와면역학적기전으로인해세포자멸사에이르는신호전달경로가활성화되어신경세포손상이일어나게되며재관류후에는활성산소가급증하고이러한손상기전이더활성화된다 (16). 특히활성산소는양성되먹임기전으로활성산소생성과신호전달경로를더욱증폭시키는것으로알려져있다 (17). 유도고혈압으로뇌혈류량을증가시켜도이러한활성산소의생성이나세포자멸사에이르는신호전달경로에는영향을미치지못하는것으로보인다. 전뇌허혈모델은심정지나부정맥, 출혈성쇼크등으로뇌허혈이발생하는경우를잘반영한다 (18). 본연구를비롯하여전뇌허혈모델에서유도고혈압이신경보호효과가있다는보고는있지만 (11), 아직임상에서일시적심정지후발생하는뇌허혈손상을줄이기위해유도고혈압을적용해본연구는없다. 심정지후저체온을유도하는것이신경학적결과를개선한다고보고된 (19,20) 이후치료적저체온을적용하도록권고해왔으나 (21) 최근 12
Nielsen 등 (22) 은저체온과정상체온으로유지한군에서신경학적결과에차이가없는것으로보고하였다. 한편, 유도고혈압을뇌졸중환자에게적용하여신경보호효과를본임상연구는많이시행되었다. 아직대규모의무작위임상시험은없지만여러연구결과들에따르면뇌졸중이발생한후고혈압을유발했을때적어도단기간동안은신경학적증상이개선되며비교적안전하다고알려져있다 (9). 뇌졸중발생후유도고혈압을적용하여영상의학적으로저관류되는영역을줄였을때신경행동학적결과에이득이있다는보고 (23) 도같은맥락으로볼수있다. 추후근거를더모으면심정지및자발순환회복후에유도고혈압을적용하는것이신경보호효과가있는지에대해서도연구해볼수있을것으로생각한다. 유도고혈압은 10분정도유지하였다. 기존의연구에따르면유도고혈압기간이짧은편이뇌부종을줄인다 (18). 또한고혈압을약한정도로유발하는것이생존율을높이고뇌부종을줄인다고 (11) 하여혈압은기저혈압보다 20mmHg 높였다. 본연구에는여러한계가있다. 첫째, 본연구는일주일후에뇌보호효과가있는지에대해서만관찰하였다. 장기간에걸쳐효과가있는지에대해서도추가연구가필요할것으로생각된다. 특히해마 CA1 부위는허혈후세포가서서히손상되므로 (24,25) 장기결과가단기간본결과와다를가능성을배제할수없다. 둘째, 뇌파나뇌혈류를감시하지않아뇌허혈과재관류가의도한대로일어났는지실험적으로확인하지는못했다. 그러나이미기존 13
연구들로부터백서에서양측총경동맥을결찰하고저혈압을유발하면피질 과해마부위를포함한전뇌부위에완전허혈을거의유발할수있다는것 이잘알려져있다 (26). 결론적으로백서의전뇌허혈모델에유도고혈압을적용하면 1주일후시점에괴사된세포수는감소한다. 그러나세포자멸사된세포수는유도고혈압을적용해도차이가없다. 유도고혈압은세포괴사를줄임으로써신경보호효과를가져온다. 14
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Abstract Introduction: Many treatment for cerebral ischemic injury have been studied for neuroprotection. Recently, it s been actively studied to treat after ischemic insult rather than before or during ischemia because it usually occurs unexpectedly. Induced hypertension after cerebral ischemia/reperfusion is known for improving cerebral blood flow and others in animal model. The effect of induced hypertension on neuroprotection, however, remain unproved at the cellular level. This study is to investigate histopathologically whether the induced hypertension has neuroprotective effect in forebrain ischemia model in rats. Methods: Twenty Sprague-Dawley rats weighted 280-350 g were randomly assigned to induced hypertension group(n = 10) or control group(n = 10). Forebrain ischemia was induced by clamping bilateral common carotid arteries and drawing blood to decreasing mean arterial blood pressure to 30 mmhg for 8 minutes. The transient ischemia was followed by reperfusion by declamping the arteries and transfusing autologous blood. In induced hypertension group, phenylephrine 5 μg at a time was administered to maintain mean arterial blood pressure greater than 20 mmhg above baseline for 10 minutes. One week later, necrotic and apoptotic cells in hippocampal CA1 region were quantified. Results: The mean percentage of viable cells in hippocampal CA1 region was increased in the induced hypertension group than in the control group(35 ± 3% vs. 26 ± 7%, P = 19
0.004). However, there was no significant difference in the ratio of apoptotic cells between both groups(57 ± 9% vs. 43 ± 19%, P = 0.165). Conclusions: Induced hypertension has neuroprotective effect in forebrain ischemia model in rats in the short term by reducing neuronal cell necrosis. Induced hypertension, however, does not affect apoptosis. ---------------------------------------------------------------------------------------------------------- Keywords: forebrain ischemia model, induced hypertension, neuroprotective effect, necrosis, apoptosis Student number: 2013-21712 20