THALIPORPHINE DERIVATIVE IMPROVES FUNCTIONAL OUTCOME AND REDUCES ISCHEMIA/REPERFUSION INJURY VIA MULTIPLE MECHANISMS
碩士 === 國防醫學院 === 生理學研究所 === 96 === Focal cerebral ischemia-reperfusion (I/R) results in characteristic histopathological changes that manifest as a “necrotic core” in which cells die rapidly, and a surrounding “penumbra” region of variable size in which neurons die over an extended time period of da...
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ndltd-TW-096NDMC01160062015-11-30T04:02:35Z http://ndltd.ncl.edu.tw/handle/97661214216818180468 THALIPORPHINE DERIVATIVE IMPROVES FUNCTIONAL OUTCOME AND REDUCES ISCHEMIA/REPERFUSION INJURY VIA MULTIPLE MECHANISMS Thaliporphine衍生物藉由多重機制降低腦組織缺血/再灌流損傷及改善行為功能缺失 Hsu, Hui-Chi 許惠棋 碩士 國防醫學院 生理學研究所 96 Focal cerebral ischemia-reperfusion (I/R) results in characteristic histopathological changes that manifest as a “necrotic core” in which cells die rapidly, and a surrounding “penumbra” region of variable size in which neurons die over an extended time period of days to weeks. In this thesis, I used a rat model of focal cerebral I/R by microinjection of endothelin-1 (400 pmol in 20 μl saline) to right middle cerebral artery and unilateral ligation of common carotid artery. Cerebral ischemia, as evidenced by the decrease of the regional cerebral blood flow to 20~25% of the control, followed by 24 hr reperfusion (I/R24) produced stable and reproducible infarcts. Using this animal model we examined the effect of TM-1, which is a modified derivative of thaliporphine, on I/R-induced tissue injury and functional deficit. Our results indicated that TM-1 at the dose of 10 mg/kg (i.p), but a not 5 mg/kg dministered 20 min after I/R), significantly reduced the infarct volume following I/R 24. Motor asymmetry, evaluated by swing test (EBST) and modified neurological severity score (mNSS), resulted from I/R was also significantly improved by TM-1. I/R24 resulted in blood-brain-barrier (BBB) breakdown as evaluated br Evans blue extravasation and lipid peroxidation as revealed by malondialdehyde level resulted from I/R24 was significantly reduced by TM-1. TM-1 reduced levels of mRNA encoding for matrix metalloproteinase 9 (MMP-9) after I/R24. The potential mechanism underlying this neuroprotective effect was further stuied. Animals were subjected to I/R for various time intervals, and sacrificed after functional behavioral evaluations. Real-time reverse transcription-polymerase chain reaction (RT-PCR) indicated relative mRNA levels of endogenous protective proteins (HO-1, HSP27, eNOS and VEGF-) in the penumbra tissue. Relative mRNA levels of HO-1 and HSP27 in penumbra tissue increased after I/R and reached the maximum at 24 hr after I/R. TM-1 administration increased I/R-induced elevation of mRNA level of HO-1 and HSP27 in penumbra tissue at 24 hr after I/R. Relative mRNA levels of eNOS and VEGF- in penumbra tissue increased after I/R and reached the maximum at 12 hr after I/R. TM-1 administration potentiated I/R-induced elevation of mRNA levels of eNOS and VEGF-at I/R12. Levels of mRNA encoding for pro-apoptotic protein (Bax) and anti-apoptotic protein (Bcl-xL) in penumbra tissue increased after I/R and reached the maximum at 6 hr after I/R. We found that TM-1 attenated I/R-induced elevations of Bax m RNA levels while elevated levels of mRNA encoding for Bcl-xL was further increased by TM-1 treatment. Time course of mRNA expression for TNF-a , IL-1b and IL-6 indicated that the maximal levels of cytokine mRNA expression were after I/R6. TM-1 reduced levels of mRNA encoding for pro-inflammatory cytokine (TNF-, IL-1 and IL-6) after I/R6. TM-1 also supressed I/R-induced elevation of COX-2 and iNOS mRNAs which also peaked at I/R6. Taken together, post-treatment of TM-1 improved functional deficit and reduced extent of brain damage, with a concomitant increased mRNA expression of endogenous protective proteins (HO-1, HSP27, eNOS and VEGF-) and Bcl-xL, reduced mRNA expression of pro-inflammatory proteins (MMP9, TNF-, IL-1, IL-6, COX-2 and iNOS) and pro-apoptotic protein (Bax) in ischemic penumbra. These data suggests the neuroprotective effects of TM-1 in ischemic injury might be attributed to multiple mechanisms including upregulation of endogenous protective proteins, anti-inflammatory, antioxidant, and anti-apoptotic mechanisms. Wang, Jia-Yi 王家儀 2008 學位論文 ; thesis 91 zh-TW |
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碩士 === 國防醫學院 === 生理學研究所 === 96 === Focal cerebral ischemia-reperfusion (I/R) results in characteristic histopathological changes that manifest as a “necrotic core” in which cells die rapidly, and a surrounding “penumbra” region of variable size in which neurons die over an extended time period of days to weeks. In this thesis, I used a rat model of focal cerebral I/R by microinjection of endothelin-1 (400 pmol in 20 μl saline) to right middle cerebral artery and unilateral ligation of common carotid artery. Cerebral ischemia, as evidenced by the decrease of the regional cerebral blood flow to 20~25% of the control, followed by 24 hr reperfusion (I/R24) produced stable and reproducible infarcts. Using this animal model we examined the effect of TM-1, which is a modified derivative of thaliporphine, on I/R-induced tissue injury and functional deficit. Our results indicated that TM-1 at the dose of 10 mg/kg (i.p), but a not 5 mg/kg dministered 20 min after I/R), significantly reduced the infarct volume following I/R 24. Motor asymmetry, evaluated by swing test (EBST) and modified neurological severity score (mNSS), resulted from I/R was also significantly improved by TM-1. I/R24 resulted in blood-brain-barrier (BBB) breakdown as evaluated br Evans blue extravasation and lipid peroxidation as revealed by malondialdehyde level resulted from I/R24 was significantly reduced by TM-1. TM-1 reduced levels of mRNA encoding for matrix metalloproteinase 9 (MMP-9) after I/R24.
The potential mechanism underlying this neuroprotective effect was further stuied. Animals were subjected to I/R for various time intervals, and sacrificed after functional behavioral evaluations. Real-time reverse transcription-polymerase chain reaction (RT-PCR) indicated relative mRNA levels of endogenous protective proteins (HO-1, HSP27, eNOS and VEGF-) in the penumbra tissue. Relative mRNA levels of HO-1 and HSP27 in penumbra tissue increased after I/R and reached the maximum at 24 hr after I/R. TM-1 administration increased I/R-induced elevation of mRNA level of HO-1 and HSP27 in penumbra tissue at 24 hr after I/R. Relative mRNA levels of eNOS and VEGF- in penumbra tissue increased after I/R and reached the maximum at 12 hr after I/R. TM-1 administration potentiated I/R-induced elevation of mRNA levels of eNOS and VEGF-at I/R12. Levels of mRNA encoding for pro-apoptotic protein (Bax) and anti-apoptotic protein (Bcl-xL) in penumbra tissue increased after I/R and reached the maximum at 6 hr after I/R. We found that TM-1 attenated I/R-induced elevations of Bax m RNA levels while elevated levels of mRNA encoding for Bcl-xL was further increased by TM-1 treatment. Time course of mRNA expression for TNF-a , IL-1b and IL-6 indicated that the maximal levels of cytokine mRNA expression were after I/R6. TM-1 reduced levels of mRNA encoding for pro-inflammatory cytokine (TNF-, IL-1 and IL-6) after I/R6. TM-1 also supressed I/R-induced elevation of COX-2 and iNOS mRNAs which also peaked at I/R6. Taken together, post-treatment of TM-1 improved functional deficit and reduced extent of brain damage, with a concomitant increased mRNA expression of endogenous protective proteins (HO-1, HSP27, eNOS and VEGF-) and Bcl-xL, reduced mRNA expression of pro-inflammatory proteins (MMP9, TNF-, IL-1, IL-6, COX-2 and iNOS) and pro-apoptotic protein (Bax) in ischemic penumbra. These data suggests the neuroprotective effects of TM-1 in ischemic injury might be attributed to multiple mechanisms including upregulation of endogenous protective proteins, anti-inflammatory, antioxidant, and anti-apoptotic mechanisms.
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author2 |
Wang, Jia-Yi |
author_facet |
Wang, Jia-Yi Hsu, Hui-Chi 許惠棋 |
author |
Hsu, Hui-Chi 許惠棋 |
spellingShingle |
Hsu, Hui-Chi 許惠棋 THALIPORPHINE DERIVATIVE IMPROVES FUNCTIONAL OUTCOME AND REDUCES ISCHEMIA/REPERFUSION INJURY VIA MULTIPLE MECHANISMS |
author_sort |
Hsu, Hui-Chi |
title |
THALIPORPHINE DERIVATIVE IMPROVES FUNCTIONAL OUTCOME AND REDUCES ISCHEMIA/REPERFUSION INJURY VIA MULTIPLE MECHANISMS |
title_short |
THALIPORPHINE DERIVATIVE IMPROVES FUNCTIONAL OUTCOME AND REDUCES ISCHEMIA/REPERFUSION INJURY VIA MULTIPLE MECHANISMS |
title_full |
THALIPORPHINE DERIVATIVE IMPROVES FUNCTIONAL OUTCOME AND REDUCES ISCHEMIA/REPERFUSION INJURY VIA MULTIPLE MECHANISMS |
title_fullStr |
THALIPORPHINE DERIVATIVE IMPROVES FUNCTIONAL OUTCOME AND REDUCES ISCHEMIA/REPERFUSION INJURY VIA MULTIPLE MECHANISMS |
title_full_unstemmed |
THALIPORPHINE DERIVATIVE IMPROVES FUNCTIONAL OUTCOME AND REDUCES ISCHEMIA/REPERFUSION INJURY VIA MULTIPLE MECHANISMS |
title_sort |
thaliporphine derivative improves functional outcome and reduces ischemia/reperfusion injury via multiple mechanisms |
publishDate |
2008 |
url |
http://ndltd.ncl.edu.tw/handle/97661214216818180468 |
work_keys_str_mv |
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