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1 스트레스硏究 : 第 19 卷第 2 號 2011 원저 트레드밀운동이당뇨유발흰쥐의기억력장애에미치는영향 * 경희대학교의과대학생리학교실, 경운대학교스포츠과학연구소 정선영 * ㆍ서진희 * ㆍ성윤희 * ㆍ김창주 * ㆍ김동제 ㆍ김대영 Effect of Treadmill Exercise on Memory Impairment in the Diabetic Rats Sun-Young Jung*, Jin-Hee Seo*, Yun-Hee Sung*, Chang-Ju Kim*, Dong-Je Kim, Dae-Young Kim *Department of Physiology, College of Medicine, Kyung Hee University, Seoul, Research Institute of Sport Science, Kyung Woon University, Gumi, Korea Diabetes mellitus (DM) is a metabolic disorder, and this disease is associated with degeneration and functional disorder of the nervous system. In the present study, we investigated the effects of treadmill exercise on memory, cell proliferation, and expressions of brain-derived neurotrophic factor (BDNF) and insulin-like growth factor 1 (IGF-1) in the hippocampus of the diabetic rats. Male Sprague-Dawley rats were used for this study. The animals were divided into four groups (n= 8 in each group): control group, exercise group, DM-induction group, DM-induction and exercise group. DM was induced by intraperitoneal injection of streptozotocin (50 mg/kg dissolved in 0.05 M citrate buffer, ph 4.5). The rats in the exercise groups were made to run on the treadmill for 30 min, five times a week for 6 weeks. For this study, step-down avoidance task, immunohistochemistry for 5-bromo-2'-deoxyuridine (BrdU), and western blot for BDNF and IGF-1 were performed. The present results showed that latency in the step-down avoidance task was decreased in the diabetic rats whereas treadmill exercise increased latency in the diabetic rats. Cell proliferation in the hippocampus was decreased in the diabetic rats, however treadmill exercise increased cell proliferation in the diabetic rats. The expressions of BDNF and IGF-1 protein in the hippocampus were decreased in the diabetic rats, in contrast, treadmill exercise increased the expressions of BDNF and IGF-1 in the diabetic rats. These results suggest that treadmill exercise may ameliorate DM-induced memory impairment by increasing cell proliferation through enhancing BDNF and IGF-1 expressions in the hippocampus. (Korean J Str Res 2011;19: ) Key Words: Dabetes mellitus, Treadmill exercise, Cell proliferation, Memory impairment, Hippocampus 서 론 책임저자 : 김대영, 경북구미시산동면인덕리 55 번지 , 경운대학교스포츠과학연구소 Tel: , cdps21@empal.com 접수 : 2011 년 5 월 15 일, 심사 : 2011 년 5 월 15 일게재승인 : 2011 년 5 월 20 일이논문은 2010 년정부재원 ( 교육과학기술부인문사회연구역량강화사업비 ) 으로한국연구재단의지원을받아연구되었음 (NRF G00095). 당뇨병 (diabetes mellitus, DM) 은전세계적으로 2억 5천만명이상의환자가있으며, 매년 6백만명정도의증가추이를보이고있는대표적인만성질환이다 (Cole et al., 2007). 당뇨병은중추신경계 (central nervous system, CNS) 의변성및기능장애와도매우밀접한관련이있으며, 학습과기억력 175

2 스트레스硏究 : 제 19 권제 2 호 2011 의감소, 인지기능의손상및혈관성치매를촉진하는것으로알려져있다 (Beauquis et al., 2008; Biessels et al., 2008). 뇌의해마 (hippocampus) 영역은학습과기억을담당하는중추로서지속적인신경세포생성 (neurogenesis) 을통해인지기능을담당하기때문에다른부위의신경세포보다대사적요구량이높다 (Choeiri et al., 2005). 이러한이유로당뇨와같은만성대사장애시해마신경세포의활성, 특히인지기능이매우민감하게영향을받게된다 (Gispen et al., 2000). 최근동물모델연구에서당뇨로인한인지기능의감소는신경전구세포생성 (neural progenitor proliferation) 의억제에의한것으로밝혀졌다 (Zhang et al., 2008). 이러한신경세포생성의조절에중요한역할을하는것은해마에서발현되는신경영양인자 (neurotrophic factor) 인 brain-derived neurotrophic factor (BDNF) 와 insulin-like growth factor 1 (IGF-1) 이다 (Trejo et al., 2001; Achiron et al., 2008; Chan et al., 2008). BDNF는신경세포의생성과생존을조절하는중요한단백질로기억의형성과형성된기억을장기기억으로전환하는데필수적인요소이다 (Bekinschtein et al., 2008; Donovan et al., 2008). 또한중추신경계에서신경세포의분화및증식을조절하며성장중인신경세포의기능을유지하는데밀접하게관여한다 (Cotman et al., 2002). IGF-1은성장호르몬의여러가지작용들을매개하고신경전구세포의생존과분화에중요한역할을한다. IGF-1은뇌에서 amyloid의축적을예방할뿐만아니라해마신경세포의보호및신경세포생성을향상시키는중요한물질로알려져있다 (Carro et al., 2001; Lichtenwalner et al., 2006). 당뇨에의해 IGF-1와같은신경영양인자의감소는결과적으로신경세포생성의억제와인지기능의저하를유발하는원인이된다 (Zhang et al., 2008). 당뇨로인한중추신경계장애를개선하기위한다양한치료방법이시도되고있다. 특히비약물적치료의방안으로서운동은뇌질환의예방뿐만아니라뇌기능을향상시키고, 당뇨성신경병증 (diabetic neuropathy) 을개선하는데효과적인방안으로알려져있다 (Loimaala et al., 2003). 당뇨병에서신경세포생성의비율이낮게나타나지만, 규칙적인운동은신경세포생성과시냅스가소성 (synaptic plasticity) 을촉진하는것으로알려져있다 (Fontán-Lozano et al., 2007; Zhang et al., 2008). 특히운동이학습과기억력을담당하는해마치상회 (dentate gyrus) 에미치는영향에대한여러연구가수행되어왔다 (Lledo et al., 2006). Ding et al.(2006) 은쥐를대상으로자발적인달리기 (voluntary running) 가세포생성과생존을증가시킨다고보고하였고, Trejo et al. (2001) 도트레드밀운동이 IGF-1을통하여쥐의해마치상회 (dentate gyrus) 에서세포생성을증가시킨다고하였다. 또한운동은알츠하이머질환 (Alzheimer s disease) 이나노화쥐에서도인지능력과신경세포생성을증가시키는것으로보고되었다 (van Praag et al., 2005; Mirochnic et al., 2009). 운동이해마에서신경세포생성을촉진시키는것으로알려져있으나, 아직까지그기전은명확하게밝혀지지않았으며, 특히당뇨병에서운동이신경세포생성을증가시킬때신경성장인자인 BDNF와 IGF-1과의관련성에대해서는알려지지않았다. 본연구에서는당뇨유발흰쥐에서트레드밀운동이기억력에미치는영향을 BDNF와 IGF-1 의발현과관련지어신경세포생성의관점에서살펴봄으로써당뇨시뇌기능에미치는운동의효과를규명하고자한다. 재료및방법 1. 실험동물본실험에사용된동물은 Sprague-Dawley계 8주령 (254± 5.17 g) 수컷흰쥐 32마리를이용하였다. 실험기간동안모든쥐에게물과음식을자유롭게먹을수있도록하였고, 실험환경은온도 22±1 o C, 습도 60±3%, 명암 12시간 light/ dark cycle의자동조절을유지하였다. 집단은대조군 (control group), 운동군 (exercise group), 당뇨군 (DM-induction group), 당뇨운동군 (DM-induction and exercise group) 으로분류하였다 ( 각군 n=8). 2. 당뇨유도및 BrdU 투여방법대조군은생리식염수를복강주사하였고, 당뇨유발군은 streptozotocin (STZ; Sigma Chemical Co., St. Louis, MO, USA) 을 50 mg/kg의용량으로 10 mm citric buffer (ph 4.5) 용액에용해시킨후복강주사하여당뇨를유도하였다. 당뇨유발확인은 STZ 주사 3일후혈당측정 12시간전에먹이를제거하고, 꼬리정맥에서 50 μl 채혈하여공복혈당이 300 mg/dl 이상일때당뇨가유발된것으로간주하였다. 신경세포생성을확인하기위하여모든쥐들에게 5-bromo-2 -deoxyunridine (BrdU, Sigma Chemical Co., St. Louis, MO. USA) 를 50 mg/kg의용량으로 saline에용해시킨후, 쥐를희생시키기이틀전부터하루한번총 2회에걸쳐트레드밀운동시 176

3 정선영외 5 인 : 트레드밀운동이당뇨유발흰쥐의기억력장애에미치는영향 작 30분전에복강에주사하였다. 3. 트레드밀운동방법운동군은소형동물용트레드밀에서점증부하운동을실시하였다. 운동군에해당하는모든실험동물은경사도 0 o 에서처음 5분간은분당 3 m의속도로, 다음 5분간은분당 5 m의속도로, 그리고나머지 20분간분당 8 m의속도로하루 30분씩주 5회, 총 6주동안트레드밀달리기를실시하였다. 흰쥐에서위와같은트레드밀달리기의속도는저강도운동에해당되며해마의신경세포생성에있어서가장효과적인강도로보고된바있다 (Kim YP et al., 2003). 4. 수동회피검사 (step-down avoidance task) Step-down avoidance task는인지기능중기억능력 (memory capability) 을측정하기위한행동검사중하나이다. 실험동물들에게최초 7 25 cm platform (2.5 cm high) 에서 2분간안정을취하게하였다. Platform 위에놓인쥐들이평행하게놓인 1 cm 간격의스테인레스막대기 (42 25 cm) 로내려가네발이모두닿았을때흰쥐들에게 0.3 ma의전기자극을 2초간주어학습시킨뒤 2시간후동일한검사를실시하였다. 두번째검사에서흰쥐들이 platform에서스테인레스막대기로내려올때까지의경과시간 (latency time) 을측정하였다. 네발이모두닿는시간은최대 300초까지기록하였고, 300초를초과하는시간은모두 300초로간주하여기록하였으며, 이와같은검사방법과과정은 Kim H et al.(2007) 의선행연구에따라실시하였다. 5. 뇌적출및조직처리실험동물들은 Zoletile 50 R (10 mg/kg i.p.; Vibac Laboratories, Carros, France) 을복강내주사하여마취시킨후흉강을열고좌심실을통하여 50 mm 인산염완충식염수 (phosphate buffer saline, PBS) 를주입하고, 이후 50 mm 인산완충액에녹인 4% paraformaldehyde (PFA) 고정액을관류하였다. 관류고정후뇌를적출한다음고정액에담아서 4 o C에서 12시간후고정을실시하였다. 고정된뇌조직은 30% sucrose 용액에서 2 5일간침적시킨후 freezing microtome (Leica, Nussloch, Germany) 를이용하여 40 μm 두께의연속관상절편을제작하였다. 6. 면역조직화학검사해마에서의신경세포생성을정량화하기위해 BrdU 면 역조직화학법을시행하였다. 조직절편을 50 mm PBS로세척한후 0.5% Triton X-100에반응시켰다. Triton X-100을세척한후 65 o C에서 50% formamide와 2 standard saline citrate (SSC) 용액에서 2시간반응시켰다. 반응완료후 2 SSC로세척한후 37 o C에서 2 N HCl에반응시켰다. 반응이끝나면바로 100 mm sodium borate, ph 8.5로세척한후 50 mm PBS 로재세척하였다. 이과정이끝난조직은자유부유 (free-floating) 법을사용하여면역조직화학염색을시행하였다. 항체와반응하기전에 50 mm PBS에 10% horse serum과 1% bovine serum albumin (BSA) 를함유한차단용액으로한시간동안반응시켰다. BrdU 항체 (Boehringer Mannheim, Germany) 를 50 mm PBS에 0.5% BSA와 0.5% sodium azide를함유한일차항체용액에 1 : 600의비율로희석한후 24시간동안반응시켰다. 50 mm PBS로세척한후, biotinylated anti-mouse IgG를 50 mm PBS에 0.3% Triton X-100을함유한이차항체용액에 1:200의비율로희석한후 1시간동안반응시켰다. 50 mm PBS로세척한후, HRP avidine-biotin complex (Vector Laboratories, Burlingame, CA, USA) 에서 1시간동안반응시켰다. 50 mm PBS로세척한후, 50 mm Tris 완충액에과산화수소와 3,3 -diaminobenzidine tetrahydrochloride (DAB) 를함유하는발색제로발색반응을실시한다음세척하였다. BrdU 항체로면역조직반응을시행한조직을 neuronal nuclei (NeuN) 항체 (Chemicon International, Temecula, CA, USA) 로 1 : 2,000 으로희석한후위와같이반응시켰다. 이후 avidine-biotin complex에서반응시키고, 발색이완료된조직은탈수과정을거쳐 Permount R (Fischer Scientific, Pittsburg, PA, USA) 로봉입하였다. BrdU 양성세포수를광학현미경 (BX-51, Olympus, Tokyo, Japan) 을이용하여관찰하여해마치상회부위의과립세포층단위면적 (mm 2 ) 당으로정량적분석을실시하였다. 7. 단백질발현측정해마의 BDNF와 IGF-1의단백질발현을측정하기위해 western blotting 분석을실시하였다. 적출된해마를 1 x PBS 로씻어낸후에, 50 mm HEPES (ph 7.5), 150 mm NaCl, 10% glycerol, 1% Triton X-100, 1.5 mm magnesium chloride hexahydrate, 1 mm ethyleneglycol-bis-(β-aminoethyl ether)-n, N'-tetraacetic acid (EGTA), 1 mm phenylmethylsulfonyl fluoride (PMSF), 2 μg/ml leupeptin, 1 μg/ml pepstatin, 1 mm sodium ortho vanadate와 100 mm sodium floride를포함하고있는 lysis buffer로용해시킨후, 단백질을추출하고원심분리하여그 177

스트레스硏究 : 제 19 권제 2 호 2011 상층액을취하여단백질을정량하였다. 이와같이추출된단백질을 SDS-polyacrylamide gels로전기영동시킨후, nitrocellulose membrane (Schleicher & Schuell GmbH, Dassel, Germany) 으로전사시켰다.

Cruz Biotech) 로반응시켰다. 이후 BDNF의 2차 antibody로 anti-rabbit antibody (1 : 5,000; Santa Cruz Biotech), IGF-1은 anti-goat antibody (1 : 5,000; Santa Cruz Biotech) 를이용하였다.

인지기능중기억력을검사하기위하여 step-down avoidance task를실시하여다음과같은 latency time을얻었다. 대조군이 271.83±10.09초, 운동군은 296.33±3.66초, 당뇨군은 145.50±7.86초, 그리고당뇨운동군은 260.00±19.14초를나타내었다 (Fig. 1). 본실험의결과, 당뇨유발흰쥐의기억력이대조군에비하여감소되었다.

0 통계프로그램을이용하여각항목에대한평균과표준오차 (standard error mean, SEM) 를산출하였다. 각집단간차이검증은일원변량분석 (one-way ANOVA) 을이용하였으며, 사후검정은 Duncan's post hoc test를실시하였다. 유의수준은 p<0.05 로설정하였다. 결 과 1.

4 스트레스硏究 : 제 19 권제 2 호 2011 상층액을취하여단백질을정량하였다. 이와같이추출된단백질을 SDS-polyacrylamide gels로전기영동시킨후, nitrocellulose membrane (Schleicher & Schuell GmbH, Dassel, Germany) 으로전사시켰다. 이렇게전사된 membrane을 blocking 한후에, mouse β-actin antibody (1 : 1,000; Santa Cruz Biotech, Santa Cruz, CA, USA), rabbit BDNF antibody (1 : 1,000; Santa Cruz Biotech), goat IGF-1 antibody (1 : 500; Santa Cruz Biotech) 로반응시켰다. 이후 BDNF의 2차 antibody로 anti-rabbit antibody (1 : 5,000; Santa Cruz Biotech), IGF-1은 anti-goat antibody (1 : 5,000; Santa Cruz Biotech) 를이용하였다. Western blotting의결과는 enhanced chemiluminescence (ECL) detection system (Amersham Pharmacia Biothech GmbH, Freiburg, Germany) 을이용하여 film 발색을통해확인하였다. 인지기능중기억력을검사하기위하여 step-down avoidance task를실시하여다음과같은 latency time을얻었다. 대조군이 ±10.09초, 운동군은 ±3.66초, 당뇨군은 ±7.86초, 그리고당뇨운동군은 ±19.14초를나타내었다 (Fig. 1). 본실험의결과, 당뇨유발흰쥐의기억력이대조군에비하여감소되었다. 트레드밀운동은당뇨유발흰쥐의기억력을증가시켰다. 트레드밀운동은정상흰쥐에서도기억력을증가시켰으나통계학적유의성은없었다. 2. 운동이당뇨유발쥐의해마신경세포생성에미치는영향해마치상회부위의 BrdU 양성세포는대조군이 ± 8. 자료처리본실험에서측정된결과들은 SPSS version 14.0 통계프로그램을이용하여각항목에대한평균과표준오차 (standard error mean, SEM) 를산출하였다. 각집단간차이검증은일원변량분석 (one-way ANOVA) 을이용하였으며, 사후검정은 Duncan's post hoc test를실시하였다. 유의수준은 p<0.05 로설정하였다. 결 과 1. 운동이당뇨유발쥐의기억력에미치는영향 Fig. 1. Effect of exercise on memory in the diabetic rats. (A) Control group, (B) exercise group, (C) DM-induction group, (D) DM-induction and exercise group. The data are represented as the mean±sem. a p<0.05 compared to the control group. b p<0.05 compared to the DM-induction group. Fig. 2. Effect of exercise on neurogenesis in the diabetic rats. (A) Control group, (B) exercise group, (C) DM-induction group, (D) DM-induction and exercise group. Upper panel: photomicrographs of BrdU-positive cells in the hippocampus. A scale bar represents 100 μm. Low panel: the mean number of BrdU-positive cells. The data are represented as the mean±sem. a p<0.05 compared to the control group. b p<0.05 compared to the DM-induction group. 178

5 정선영외 5 인 : 트레드밀운동이당뇨유발흰쥐의기억력장애에미치는영향 3.93개 /mm 2, 운동군은 ±11.98개 /mm 2, 당뇨군은 67.94± 4.57개 /mm 2, 그리고당뇨운동군은 ±6.87개 /mm 2 로나타났다 (Fig. 2). 본실험의결과, 당뇨유발흰쥐의해마치상회에서신경세포생성이억제되었다. 트레드밀운동은당뇨유발흰쥐에서신경세포생성을증가시켰으며정상흰쥐에서도신경세포생성을증가시켰다. 3. 운동이당뇨유발쥐의해마 BDNF 발현에미치는영향본연구에서해마의 BDNF 단백질발현을측정하기위해 western blotting으로정량적분석을한결과, 대조군에서의 BDNF 발현을 1.00으로하였을때, 운동군이 1.17±0.45, 당뇨군은 0.62±0.06, 그리고당뇨운동군은 0.71±0.03으로나타났다 (Fig. 3). 본실험의결과당뇨유발흰쥐의해마에서 BDNF 발현이억제되었다. 트레드밀운동은당뇨유발흰쥐의 BDNF 발현을증가시켰으며정상흰쥐에서도 BDNF 발현을증가시켰다. 4. 운동이당뇨유발쥐의해마 IGF-1 발현에미치는영향본연구에서해마의 IGF-1 단백질발현을측정하기위해 western blotting으로정량적분석을한결과, 대조군에서의 IGF-1 발현을 1.00으로하였을때, 운동군이 1.35±0.06, 당뇨군은 0.59±0.05, 그리고당뇨운동군은 0.76±0.03으로나타났다 (Fig. 4). 본실험의결과, 당뇨유발흰쥐의해마에서 IGF-1의발현이억제되었다. 트레드밀운동은당뇨유발흰쥐의 IGF-1 발현을증가시켰으며정상흰쥐에서도 IGF-1 발현을증가시켰다. 고찰당뇨는만성염증과산화스트레스를유발하여신경세포사멸을촉진하고, 신경세포생성과시냅스가소성을억제하여뇌기능장애를유발한다 (MacLullich et al., 2008). 당뇨병동물모델의경우해마에서의신경세포생성이억제되 Fig. 3. Effect of exercise on BDNF level in the hippocampus. (A) Control group, (B) exercise group, (C) DM-induction group, (D) DM-induction and exercise group. Upper panel: Representative expression of the protein level of BDNF and β-actin in the hippocampus. Low panel: Relative BDNF expression in the hippocampus. The data are represented as the mean±sem. a p<0.05 compared to the control group. b p<0.05 compared to the DM-induction group. Molecular weights of BDNF=14 kda, β-actin=42 kda. Fig. 4. Effect of exercise on IGF-1 level in the hippocampus. (A) Control group, (B) exercise group, (C) DM-induction group, (D) DM-induction and exercise group. Upper panel: Representative expression of the protein level of IGF-1 and β-actin in the hippocampus. Low panel: Relative IGF-1 expression in the hippocampus. Data are expressed as a percentage of control group. The data are represented as the mean±sem. a p<0.05 compared to the control group. b p<0.05 compared to the DM-induction group. Molecular weights of IGF-1=17 kda, β-actin=42 kda. 179

6 스트레스硏究 : 제 19 권제 2 호 2011 고, 해마기능의감퇴로인하여학습능력과기억형성에장애를유발하는것으로알려져있다 (Biessels et al., 1998; Kamal et al., 2000). 본연구에서는당뇨로인해감소된기억력에운동의효과를관찰하기위하여 step-down avoidance task를실시하였다. 본연구의결과기억력은당뇨에의해유의하게감소하였고, 트레드밀달리기에의해유의하게증가하는것으로나타났다. 이러한결과는당뇨로인해저하된기억력이트레드밀달리기를통하여증가되었으며, 결과적으로당뇨환자에서트레드밀달리기에의하여학습된기억을보다오랫동안유지할수있는가능성을보여주었다. 많은임상연구들에서당뇨병환자들의기억력과인지기능손상이보고되었으며 (Stewart et al., 1999; Ryan et al., 2000), 운동은퇴행성뇌질환으로유발되는치매와같은인지기능의손상을지연혹은개선하는데효과가있는것으로알려져있다 (Laurin et al., 2001). 또한운동은당뇨로인한신경세포생성의억제를경감시켜, BrdU 양성세포수를증가시키는것으로보고되었다 (Lee HH et al., 2005; Beauquis et al., 2006; Chae CH et al., 2009). 본연구에서도선행연구와마찬가지로당뇨유발에의해 BrdU 양성세포수가유의하게감소하였으며, 운동은이러한 BrdU 양성세포수의감소를억제하는데효과적인것으로나타났다. 즉, 당뇨에의하여해마치상회에서신경세포생성이감소되었으나트레드밀달리기에의하여신경세포생성이증가되었다. 트레드밀달리기의신경세포생성작용은정상쥐에서도나타났다. 이는당뇨에의해신경세포생성이감소하며, 운동은정상뿐만아니라당뇨시에도신경세포생성을증가시킴을의미한다. 운동을통한신경세포생성은신경영양인자를매개로하여촉진되며, 그중대표적인인자가 BDNF이다. BDNF 발현의증가는신경세포생성을향상시키며생성된신경세포의생존을촉진시키고, 반대로 BDNF 발현의결핍은신경세포의생성과생존율을감소시킨다 (Chan et al., 2008). BDNF는신경의성장과분화를유도하고신경손상시이의재생에관여하며, 특히운동이신경계에미치는영향을측정하는지표로도사용되고있다 (Cotman et al., 2002). 운동으로인한 BDNF 단백질증가효과에대해 Soya et al.(2007) 은저강도트레드밀운동을통해흰쥐해마의 BDNF mrna와 BDNF 단백질발현이증가하였음을보고하였다. Aguiar et al.(2008) 은트레드밀달리기를통해해마 BDNF 단백질을 70% 까지증가시켰다고보고하였다. 또한 Wu et al.(2008) 은 5주간의트레드밀달리기가 BDNF의증가를통해신경세포의생성과생존을향상시킨것으로보고하였다. 본연구에서해마에서 BDNF 단백질발현은당뇨에의하여유의하게감소하였고, 트레드릴달리기에의해유의하게증가하는것으로나타났다. 트레드밀달리기의 BDNF 발현증가작용은정상쥐에서도나타났다. 이는당뇨에의해 BDNF 단백질발현이감소하며, 운동은정상에서뿐만아니라당뇨에서도 BDNF 단백질발현을증가시킴을의미한다. BDNF의발현에영향을미치는중요한요인으로작용하는것중하나가 IGF-1이다 (Carro et al., 2000). IGF-1은간과뇌등의여러조직에서생성되며 (Holzenberger et al., 2003), 신경의성장과분화에관여하고, 운동에의하여발현이증가한다 (Markowska et al., 1998). 운동에의해증가된 IGF-1는신경보호작용을나타내며또한 BDNF의발현을촉진하는것으로알려져있다 (Carro et al., 2000). 그러나당뇨와같은대사성질환에서운동이뇌의 IGF-1에미치는영향은아직규명되지않았다. Carro et al.(2001) 은외부적으로 IGF-1을처치하였을때, 신경보호효과와더불어신경세포생성을촉진한다고보고하였다. 설치류의해마에서 IGF-1은신경세포생성을자극하는것으로알려져있다 (Anderson et al., 2002). 운동이뇌에미치는많은긍정적효과들은이러한 IGF-1과같은신경성장인자들에의해매개되는것으로제시되고있다 (Cotman et al., 2002). 즉운동은 IGF-1을증가시켜뇌기능을향상시키는것으로보고되었다 (Trejo et al., 2001; Ma, 2008). 본연구에서해마 IGF-1 단백질발현은당뇨군에서유의하게감소하였고, 트레드밀달리기에의하여유의하게증가하는것으로나타났다. 트레드밀달리기의 IGF-1 발현증가작용은정상쥐에서도나타났다. 이는당뇨에의해 IGF-1 단백질발현이감소하며, 운동은정상에서뿐만아니라당뇨에서도 IGF-1 단백질발현을증가시킴을의미한다. 본연구의결과당뇨와같은대사성질환에서트레드밀달리기는 IGF-1과 BDNF와같은신경영양인자의분비를향상시킴으로서, 신경세포생성을증가시켜당뇨에의한기억력의감퇴를경감시킨것으로알수있었다. 따라서트레드밀운동은당뇨에의하여유발된기억력감퇴에도움이되는것으로생각된다. 180

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8 스트레스硏究 : 제 19 권제 2 호 2011 exercise and its biological mechanisms on brain health. Neurosci. Bull. 24: MacLullich AM, Seckl JR (2008) Diabetes and cognitive decline: are steroids the missing link? Cell Metab. 7: Markowska AL, Mooney M, Sonntag WE (1998) Insulin-like growth factor-1 ameliorates age-related behavioral deficits. Neuroscience 87: Mirochnic S, Wolf S, Staufenbiel M et al. (2009) Age effects on the regulation of adult hippocampal neurogenesis by physical activity and environmental enrichment in the APP23 mouse model of Alzheimer disease. Hippocampus 19: Ryan CM, Geckle MO (2000) Circumscribed cognitive dysfunction in middle-aged adults with type 2 diabetes. Diabetes Care 23: Soya H, Nakamura T, Deocaris CC et al. (2007) BDNF induction with mild exercise in the rat hippocampus. Biochem. Biophys. Res. Commun. 13: Stewart R, Liolitsa D (1999) Type 2 diabetes mellitus, cognitive impairment and dementia. Diabet. Med. 16: Trejo JL, Carro E, Torres-Aleman I (2001) Circulating insulin-like growth factor I mediates exercise-induced increases in the number of new neurons in the adult hippocampus. J. Neurosci. 21: van Praag H, Shubert T, Zhao C et al. (2005) Exercise enhances learning and hippocampal neurogenesis in aged mice. J. Neurosci. 25: Wu CW, Chang YT, Yu L et al. (2008) Exercise enhances the proliferation of neural stem cells and neurite growth and survival of neuronal progenitor cells in dentate gyrus of middle-aged mice. J. Appl. Physiol. 105: Zhang WJ, Tan YF, Yue JT et al. (2008) Impairment of hippocampal neurogenesis in streptozotocin treated diabetic rats. Acta. Neurol. Scand. 117: = 국문초록 = 당뇨병은대사성질환으로신경계의퇴행및기능이상을유발한다. 본연구의목적은당뇨유발흰쥐에서트레드밀운동이기억력과신경세포생성, 그리고 brain-derived neurotrophic factor (BDNF) 와 insulin-like growth factor 1 (IGF-1) 단백질발현에미치는영향을살펴보고자하였다. 본실험에사용된동물은 8 주령수컷흰쥐 32 마리를이용하였다. 집단은대조군, 운동군, 당뇨군, 당뇨운동군으로구분하였으며, 집단별 8 마리씩배치하였다. 당뇨는 streptozotocin 을이용하여유발하였으며, 운동군에해당하는실험동물은경사도 0 o 에서하루 30 분씩주 5 회, 총 6 주동안저강도운동을실시하였다. 본연구의결과당뇨유발흰쥐의해마에서 BDNF 와 IGF-1 의발현이감소되었고, 신경세포생성이억제되어기억력의장애를나타내었다. 트레드밀운동은당뇨유발흰쥐에서 BDNF 와 IGF-1 의발현을증가시켰고, 신경세포생성이향상되어기억력의장애가감소되었다. 본실험을통하여트레드밀운동은 BDNF 와 IGF-1 의발현을증가시켜신경세포생성을향상시킴으로써당뇨에의한기억력의감퇴를경감시킴을알수있었다. 따라서트레드밀운동은당뇨에의하여유발된기억력감퇴에도움이되는것으로생각된다. 중심단어 : 뇨병, 트레드밀운동, 신경세포생성, 기억장애, 해마 182

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( )Kju269.hwp 만성세균성전립선염모델흰쥐에서 의항염효과 Anti-inflammatory Effect of Lycopene on Chronic Bacterial Prostatitis Rat Model Cho Hwan Yang, Dong Wan Sohn, Yong-Hyun Cho From the Department of Urology, The Catholic University