초록 ▼

본 연구과제는 이미 사용중인 약물의 다양한 기능을 이용하여 뇌졸중에의 치료 가능성을 보기 위한 것임.
뇌경색 동물모델에서 PPAR-γ agonist인 Rosiglitazone의 신경보호작용에 대한 연구를 진행하여 위 약물의 뇌세포 보호효과와 신경 혈관 재생 효과를 증명하고 기전을 알아 내었으며, Angiotensin II 수용체 억제 약물인 Telmisartan을 이용하여 뇌출혈에서의 신경 보호 효과를 조사하여, Telmisartan의 PPAR-γ receptor의 기능 항진 작용을 이용하여 뇌출혈과 연관된 뇌손상을 막음을 입

본 연구과제는 이미 사용중인 약물의 다양한 기능을 이용하여 뇌졸중에의 치료 가능성을 보기 위한 것임.
뇌경색 동물모델에서 PPAR-γ agonist인 Rosiglitazone의 신경보호작용에 대한 연구를 진행하여 위 약물의 뇌세포 보호효과와 신경 혈관 재생 효과를 증명하고 기전을 알아 내었으며, Angiotensin II 수용체 억제 약물인 Telmisartan을 이용하여 뇌출혈에서의 신경 보호 효과를 조사하여, Telmisartan의 PPAR-γ receptor의 기능 항진 작용을 이용하여 뇌출혈과 연관된 뇌손상을 막음을 입증하였음.
Histone deacetylase 억제제인 Valproic acid의 뇌출혈에서의 치료효과를 연구하여, 치료기전을 병인과 연관지어 연구하였음.
이미 임상에서 널리 쓰이며 안전성이 확인된 FDA 공인 약물들에서 뇌졸중에서의 치료효과를 입증함의로써 보다 임상진입에 용이할 것으로 기대되며, 본 연구의 main purpose인 bench to bedside로의 전략에 충실하기 위해, 본 연구 결과를 이용하여 조속한 시기에 임상시험을 진행할 예정임.

Abstract ▼

The cerebral infarction and hemorrhage share the common cascade of pathomechanism related to the cell death, although differ in the view of initial triggering factors. There are many researches that try to intercept the specific part of this cascade, however if the one step is blocked, the other cel

The cerebral infarction and hemorrhage share the common cascade of pathomechanism related to the cell death, although differ in the view of initial triggering factors. There are many researches that try to intercept the specific part of this cascade, however if the one step is blocked, the other cell death promoting sequence are started from different part. So, we aimed to develop the diverse functional agents which blocks various sites involving cascade all at once.
First we showed the anti-inflammatory action and improved functional recovery of endothelial cells through increasing production of eNOS by vascular endothelium when peroxismal proliferator-activated receptors (PPARs) agonist, rosiglitazone, known anti-diabetic agent was administrated. Based on this finding, we show the neuroprotectiveandangiogeniceffect of rosiglitazone through PPAR-r activation in the focal cerebral ischemia. This is demonstrated by ischemic lesional volume reduction on the 2,3,5- triphenyltetrazolium chloride (TTC) staining and functional neurological improvement by modified limb placing test (MLPT). Interestingly, the rosiglitazone have been used so many years safely for human anti-diabetic treatment that the people thought this medication was so safe to try clinical use for the cerebral ischemia immediately. Second, we showed the therapeutic effect of Telmisartan, the anti-hypertensive agent, in the cerebral hemorrhage animal model using rat collagenase. The administration of Telmisartan could induce the early functional recovery, lasting to five weeks, and show the decrease of hemorrhage volume, the size of perihematomal edema, the number of OX-$42^{+}$ microglia, $MPO^{+}$ neutrophil. These facts revealed that the telmisartan could reduce the activation of inflammatory cells around hematoma. Also, the expression of the inflammatory cytokine including TNF-alpha, COX-2, and the number of $TUNEL^{+}$ cell - the indication or cell death, are decreased. The anti-inflammatory, anti-apoptotic, anti-oxidant effects of Telmisartan are explained by the increased expression of eNOS which involves in the neuroprotective mechanism in the cerebral infarction. and by the decreased production of superoxide which involves in the oxidative cell damage. In addition, we suggested the neuroprotective effect of valproic acid, the well-known. anti-convulsant, in the cerebral hemorrhage animal model. The valproic acid could decrease the size of hemorrhage and the extent of cerebral atrophy in the rodent model, using rat collagenase, and the early functional recovery also was demonstrated. The number of inflammatory cells and the expression of cytokine/chemokine. reflecting the perihematomal inflammation were both decreased. The expression of proapoptotic proteins was decreased. This facts indicated that the neuroprotective effect of valproic acid could have several anti-inflammatory and anti-apoptotic constituents by direct suppression of HDAC.
In this study, we showed the several productive results. We proved the therapeutic effect in the cerebrovascular disease of well-known agents used for the other human diseases safely for a long time, so that we could design the clinical trials of above agents more easily. This fact has the significance to decrease the social costs of stroke, and can contribute to development of more common, safe, and sustainable therapeutics. Finally this study leads to several academic accomplishments though publication of numerous papers, to development of medical industries, to cultivate the investigators, to development the new medical therapeutics of stroke.

목차 Contents

• 표지...1
• 제출문...3
• 3. 보고서 요약서...4
• 4. 요약문(한글)...5
• 5. 요약문(영문)...6
• 6. 연구 성과 실적 및 향후 계획 ...7
• 7. 참여연구원 현황표...10
• II. 총괄연구과제 연구결과...11
• 1. 연구개발과제의 배경 및 필요성...12
• 1.1. 연구개발과제의 배경...12
• 2. 국내외 기술개발 현황...15
• 2.1. 전반적인 다기능약물개발의 연구현황과 산업화 전망...15
• 2.2. PPAR-γ (Peroxisome proliferater-activated receptor-γ) agonist의 약리작용과 심혈관계 보고효과...15
• 2.3. Anglotensin II 수용체 억제제와 뇌졸중 연구현황과 전망...17
• 2.4. 기타 다기능 약물 개발 현황 현황과 뇌졸중 치료제로서의 전망...19
• 3. 연구개발과제의 추진체계...20
• 4. 연구개발수행 내용 및 결과...21
• 4.1. 연구의 내용 및 방법...21
• 4.2. 연구의 결과...25
• 4.3. 연구성과...32
• 5. 목표달성도 및 관련분야 기여도...36
• 5.1. 총괄연구개발과제의 목표달성도...36
• 5.2. 관련분야 기여도...37
• 6. 향후 연구성과 추진 계획...38
• 7. 연구개발결과의 파급효과...38
• 7.1. 기술적 파급효과...38
• 7.2. 경제.산업적 파급효과...39
• 7.3. 사회적 파급효과...39
• 8. 연구개발결과의 활용계획...40
• 8.1. 연구개발결과의 활용계획 및 추가연구의 필요성...40
• 9. 연구개발과정에서 수집한 해외과학기술정보...40
• 10. 참고문헌...41
• IV. 첨부서류...45
• 1. 자체평가의견서...46