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과당 이인산의 대뇌피질 신경세포 보호작용
- Alternative Title
- Protective roles of fructose-1, 6-bisphosphate in cortical neuronal death
- Author(s)
- 박지영
- Alternative Author(s)
- Park. Jee-Young
- Advisor
- 백은주
- Department
- 일반대학원 신경과학기술과정
- Publisher
- The Graduate School, Ajou University
- Publication Year
- 2006-02
- Language
- eng
- Alternative Abstract
- NMDA induces neuronal excitability by stimulating various signaling pathways, and hyperactivation of NMDA receptor primarily causes neuronal death following such as stroke, seizure and neurodegenerative disease. Fructose-1, 6-bisphosphate (FBP), an intermediate of glucose metabolism, is known to show neuroprotective effect in various animal models including brain ischemia. Up to the present, however, the intracellular signaling pathways for FBP-induced neuroprotection, in particular, in pure cortical neuron culture system, have not been clearly elucidated. In this study, I investigated whether FBP can protect pure cortical neurons from NMDA excitotoxicity, and if so, whether its protective effect is associated with modulation of intracellular signaling molecules such as MAPKs, reactive oxygen sepsis (ROS), cyclooxygenase-2 (COX-2) and prostaglandins (PGs). To examine the effect of FBP on neuronal excitotoxicity, cortical neurons were treated with NMDA in the presence or absence of FBP (1-20 mM) and cell death was estimated by lactate dehydrogenase (LDH) release and neuronal cell loss. After 24 h of NMDA treatment, significant increase in LDH release and remarkable loss of neuronal count were observed, and this neuronal death was almost completely blocked by 10 ？？M FBP. It was also found that ROS level in neurons was increased and MMP (mitochondrial membrane potential) was decreased after 4-8 h of NMDA treatment, and that these alterations were completely reversed by FBP. To examine the intracellular signaling pathways for FBP-induced neuroprotection, the effects of FBP on MAPKs activation (phosphorlation) were examined by western blotting. Phosphorylation of p38 MAPK and ERK were increased by NMDA, and these activated MAPKs were, at least partially, inhibited by treatment with FBP. Both the neuroprotective effect and the ROS-lowering effect of FBP were significantly blocked by either p38MAPK inhibitor SB203580 or ERK inhibitor PD98059. To investigate additional potential candidate involved in the mechanism of FBP-induced neuroprotection, the effect of FBP on NMDA-induced COX-2 expression and PGE2 production, which are known to be potent inflammatory mediators in response to various noxious stimuli in brain. Unexpectedly, this study showed that cortical neuronal cells had little level of COX-2 protein and mRNA expression and PGE2 production even in the presence of NMDA. Moreover, arachidonic acid (AA)-induced PGE2 release in neurons remained unaltered even in the presence of various COX inhibitors, suggesting an existence of COX-independent PGE2 releasing system in AA-treated neurons. As expected, COX-independent PGs called isoprostane were observed in pure cortical neurons and cell free media. Moreover, both the neuronal death and the PGE2 release induced by AA were inhibited by FBP, which might be act through regulating an auto-oxidation from AA to PGs. From the results in this study, it is suggested that FBP protects neurons against NMDA-induced cell death through down-regulation of free radical production mediated by activation of p38 MAPK/ERK pathway, and through down-regulation of COX-independent PG-like compounds, such as lipid-peroxidation products.
- Fulltext
- Appears in Collections:
- Graduate School of Ajou University > Department of Medicine > 3. Theses(Master)
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