파킨슨 질환 모델에서 신규화합물의 신경보호 효과 및 작용기전에 관한 연구
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Parkinson's disease (PD) is a neurodegenerative movement disorder characterized by a loss of nigral dopamine(DA)ergic neurons and motor impairments such as bradykinesia, rigidity and tremor. Oxidative stress and neuroinflammation are believed to be prominent contributors to the pathogenesis of PD. In this thesis, I tested a novel synthetic compound UHL-220 for its anti-oxidant and anti-inflammatory effects. UHL-220 showed high binding affinity to keap-1, a negative regulator of Nrf2, as assessed by surface plasmon resonance. UHL-220 increased the nuclear translocation of Nrf2, which is known to be involved in the regulation of antioxidant enzymes. UHL-220 also upregulated expression of heme oxygenase-1 (HO-1), NAD(P)H:quinone oxidoreductase1 (NQO1), GCLM and GCLC, whose gene products serve as cellular defenses against oxidative stress, in both DAergic neuronal CATH.a cells and BV2 microglial cells. UHL-220 was found to protect CATH.a cells from tetrahydrobiopterin (BH4)-induced damage. I also tested the effects of UHL-220 on activation of NF-?B, a transcription factor that controls expression of inflammatory genes. UHL-220 suppressed LPS-induced production of proinflammatory molecules in BV2 cells. UHL-220 significantly inhibited the nuclear translocation of NF-?B and phosphorylation and degradation of I?B that were induced by LPS. MAPK and TAK1 activation were suppressed by UHL-220. Besides, UHL-220 decreased phosphorylation of Tyr216 in GSK3? which is known to lead to Nrf2 degradation. In MPTP-induced mouse model of PD, oral administration of UHL-220 effectively prevented the degeneration of nigral DAergic neurons as assessed by TH immunohistochemistry. In addition, UHL-220 attenuated microglial activation in these animals as assessed by immunohistochemistry against the microglial marker Iba-1. UHL-220 also alleviated the PD-associated motor deficits as determined by hindlimb, rotarod and vertical grid tests. These results show that UHL-220 exerts a neuroprotective effect in PD models and thus, this compound may serve as a feasible therapeutic agent against neurodegeneration.