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Graduate School of Ajou University
Department of Neuroscience and Technology Course
3. Theses(Master)
신경질환에서 산화적 손상의 바이오마커 탐색과 중재요법 연구
- Alternative Title
- Gyeong Joon Moon
- Author(s)
- 문경준
- Alternative Author(s)
- Gyeong Joon Moon
- Advisor
- 곽병주
- Department
- 일반대학원 신경과학기술과정
- Publisher
- The Graduate School, Ajou University
- Publication Year
- 2009-02
- Language
- eng
- Keyword
- Stroke; Biomarker; Proteomics; CSF; Oxidative stress; albumin
- Alternative Abstract
- Oxidative stress plays a major role in tissue damage under pathological conditions and has been targeted for pharmacological prevention of nerve cell injury in a number of neurological diseases including stroke, Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS). Unfortunately, although necessary for the development of new drugs, useful diagnostic biomarkers of oxidative stress for neurological diseases are not yet available. In the first part of the current study, we demonstrated that protein alterations in cerebral spinal fluid (CSF) of stroke patients, including expression and post-translational modifications such as oxidation, were investigated using two-dimensional electrophoresis (2-DE). Protein oxidation was detected with immunoblotting using 2, 4-dinitrophenylhydrazine (2, 4-DNPH) and anti-DNP antibody. In the CSF proteins of stroke patients, approximately 48 spots were altered after the onset of stroke, including alpha-1-acid glycoprotein, alpha-1-microglobulin, vitamin D-binding protein precursor (DBP), beta-actin, transthyretin, and complement C4. In addition, human serum albumin (HSA) was a major oxidized protein found after stroke in CSF. Albumin is well known as an endogenous anti-oxidant in the blood. We suggest that albumin provided protection against reactive oxygen species, preventing neuronal cell death in the CA1 region following 10 min of transient forebrain ischemia. We also found that the function of albumin as an ROS scavenger could be changed by modification of its oxidation status in vivo. A second issue that also needs consideration regarding development of new CNS drugs concerns the ability of various compounds to cross the blood-brain barrier (BBB). In several clinical trials, antioxidant drugs such as vitamin E have shown no beneficial effect because an effective therapeutic concentration could not be achieved in the brain. The BBB penetration rate is intimately associated with success of CNS targeted drug development. Pharmacokinetics and pharmacodynamics studies on the target organ are very important in the process of drug development. In second part of this study, we studied the pharmacokinetics and pharmacodynamics of a new drug candidate, AAD-2004, which has been proposed as having antioxidant properties capable of targeting neurodegenerative diseases. LC-MS was first used to validate pharmacokinetics and pharmacodynamics analysis of AAD-2004. This compound reduced oxidative stress products such as nitrotyrosine and 8-OHdG in ALS mice. Moreover, it showed maximal effects at Cmax = ~ 2.12 μg/ml and AUC = ~3.92 μg.hr/ml in blood that could realistically be expected to achieve more than effective dose in the brain.
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