초록 ▼

- 합성된 aspirin의 유사체 70 여종 중 흥분성 신경독성, 산화적 독성, 아연 독성에 의한 신경세포 사멸에 대한 보호효과가 뛰어난 합성물을 선별.
- AJ-000과 최종적으로 선별되 Neu2000은 낮은 농도에서 산화적 독성을 억제하는 효과를 지니며 아연 독성을 억제하고 흥분성 신경독성을 억제하는 기전으로는 NMDA rceptor에 대해 low-affinity, fast-fast dissociation 특성을 지니고 있으므로 기존의 NMDA receptor들 보다 뛰어난 안정성을 지님.
-New2000은 허혈성 뇌

- 합성된 aspirin의 유사체 70 여종 중 흥분성 신경독성, 산화적 독성, 아연 독성에 의한 신경세포 사멸에 대한 보호효과가 뛰어난 합성물을 선별.
- AJ-000과 최종적으로 선별되 Neu2000은 낮은 농도에서 산화적 독성을 억제하는 효과를 지니며 아연 독성을 억제하고 흥분성 신경독성을 억제하는 기전으로는 NMDA rceptor에 대해 low-affinity, fast-fast dissociation 특성을 지니고 있으므로 기존의 NMDA receptor들 보다 뛰어난 안정성을 지님.
-New2000은 허혈성 뇌손상, 척수손상모델, ALS 모델, 노화코델, PD 모델에서 신경세표 사멸보호에 대한 탁월한 효과 나타냄.
- 5 종의 서로다은 trangenic cassettes를 갖는 총 58 마리의 founder lines 을 생산하여 Swedish 및 London mutation을 동시에 갖는 APP-Tg와 London mutation을 갖는 C99-Tg 계열이 Passive aviodance, Motis Water maze등의 검사에서 <노화에 따른 인지기능의 결함>을 보임.
-AD moouse 에게 Neu2000을 장기간 복용하였을 때 인지기능이 정상 마우스에 준하는 수준으로 회복.

Abstract ▼

Excitotoxicity and oxidative stress has been shown to be majot mechanism in brain disease imcluding hypoxic-ischemia, Alzheimer's disease, and Parkinson's disease. Hence, if compounds are developed that prevent concurrently excitotoxicity and oxidative stress, this may provide beneficial effect on b

Excitotoxicity and oxidative stress has been shown to be majot mechanism in brain disease imcluding hypoxic-ischemia, Alzheimer's disease, and Parkinson's disease. Hence, if compounds are developed that prevent concurrently excitotoxicity and oxidative stress, this may provide beneficial effect on brain disease. We found that anti-inflammatory drug sulfasalzine act as a N-methyl-D-aspartate (NMDA) antagonist and atioxidant. However, because sulfasalazine need to increase in potency and efficacy against excitotoxicity and ocidative stress, we derived 2-Hydrocy-5-2,3,5,6-tetrafluoro -4 trifluoromethyl-benzylamino)-benzoic acid (Neu 2000) from sulfasalazine. New2000 attenuated markedly NMDA- and free redical- induced neurotoxicity in cortical cultures, and also reduced nerronal death and ROS production following transient cerebral ischemia in adult rat. In addition, Neu2000 reduced neuronal death and improved the physiological function following flobal ischemia, traumatic spinal cord injury, animal models of Parkinson's disease, Amyotrophic lateral Sclerosis (ALS) or aging.
Alzheir's disease (AD) is the most common cause of senile dementia. AD is associated with $\beta$-amyyloid ($A\beta$ plaque, neurofibrillary tangles, and lar-scale neuronal cell loss.We generated our own AD animal models, two transgenic (Tg) mouse lines that expressed the human amyloid precursor protein (APP751.swe, V717F; APP_Tg) or C-terminal 99 amino acids (C99.V717F;C99-Tg). Both APP-Tg and CT-Tg mice showed expression of transgene products, APP or C99 proteins, respectively, in brain. ERK, JNK and c-jun, known as potential signaling events linked to the AD pathogenesis, were significantly activated in the cortes of APP-Tg or C99-Tg mice at 12 mouth of age. In additions, increased tau phosphorylation was observed in APP-Tg or V99-Tg mice. Although APP-Tg and C99-Tg mice that we generated do not manifest complete histological pathogenesis of AD, or AD mice do appear to be good models to evaluate the AD-related pahtogenesis of JNK activation, tau phosphrylation, inlammatory response and cognitive deficits. We tested whether Neu2000 could be an effective means to rescue behavioral deficits of AD models, APP-Tf or C99-Tg moce. Oral administration of Neu2000 (10mg/kg/day) for 4-6 months notably rescue the behavioral deficits displaye by APP-Tg or C99-Tg mice in Morris water maze test and in passive avoidance test.

목차 Contents

• 제1장 연구개발과제의 개요...9
• 제2장 국내외 기술개발 현황...11
• 제3장 연구개발수행 내용 및 결과...16
• 제4장 목표달성도 및 관련분야에의 기여도...78
• 제5장 연구개발결과의 활용계획...82
• 제6장 연구개발과정에서 수집한 해외과학기술정보...83
• 제7장 참고문헌...85