Penicillamine increases free copper and enhances oxidative stress in the brain of toxic milk mice.
Wilson disease (WD) is characterized by the accumulation of copper arising from a mutation in the ATP7B gene. Penicillamine (PA) makes 10-50% of the patients with neurologic symptoms neurologically worse at the early stage of administration. The aim of this study was to determine how the copper meta...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2012-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3357430?pdf=render |
| _version_ | 1811205581746208768 |
|---|---|
| author | Ding-Bang Chen Li Feng Xiao-Pu Lin Wei Zhang Fu-Rong Li Xiu-Ling Liang Xun-Hua Li |
| author_facet | Ding-Bang Chen Li Feng Xiao-Pu Lin Wei Zhang Fu-Rong Li Xiu-Ling Liang Xun-Hua Li |
| author_sort | Ding-Bang Chen |
| collection | DOAJ |
| description | Wilson disease (WD) is characterized by the accumulation of copper arising from a mutation in the ATP7B gene. Penicillamine (PA) makes 10-50% of the patients with neurologic symptoms neurologically worse at the early stage of administration. The aim of this study was to determine how the copper metabolism changes and whether the change impairs the brain of toxic milk (tx) mice, an animal model of WD, during the PA administration. The free copper and protein-bound copper concentrations in the serum, cortex and basal ganglia of tx mice with PA administration for 3 days, 10 days and 14 days, respectively, were investigated. The expression of copper transporters, ATP7A and CTR1,was analyzed by real-time quantitative PCR, immunofluorescence and Western blot. Then SOD, MDA and GSH/GSSG were detected to determine whether the oxidative stress changed correspondingly. The results revealed the elevated free copper concentrations in the serum and brain, and declined protein-bound copper concentrations in the brain of tx mice during PA administration. Meanwhile, transiently increased expression of ATP7A and CTR1 was observed generally in the brain parenchyma by immunofluorescence, real-time quantitative PCR and Western blot. Additionally, ATP7A and CTR1 were observed to locate mainly at Golgi apparatus and cellular membrane respectively. Intense staining of ATP7A in the choroid plexus was found in tx mice on the 3rd and 10th day of PA treatment, but rare staining of ATP7A and CTR1 in the blood-brain barrier (BBB). Decreased GSH/GSSG and increased MDA concentrations were also viewed in the cortex and basal ganglia. Our results suggested the elevated free copper concentrations in the brain might lead to the enhanced oxidative stress during PA administration. The increased free copper in the brain might come from the copper mobilized from brain parenchyma cells but not from the serum according to the ATP7A and CTR1 expression analysis. |
| first_indexed | 2024-04-12T03:34:47Z |
| format | Article |
| id | doaj.art-b8cf70287f8b4762acec8906b1128dc4 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-12T03:34:47Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-b8cf70287f8b4762acec8906b1128dc42022-12-22T03:49:28ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0175e3770910.1371/journal.pone.0037709Penicillamine increases free copper and enhances oxidative stress in the brain of toxic milk mice.Ding-Bang ChenLi FengXiao-Pu LinWei ZhangFu-Rong LiXiu-Ling LiangXun-Hua LiWilson disease (WD) is characterized by the accumulation of copper arising from a mutation in the ATP7B gene. Penicillamine (PA) makes 10-50% of the patients with neurologic symptoms neurologically worse at the early stage of administration. The aim of this study was to determine how the copper metabolism changes and whether the change impairs the brain of toxic milk (tx) mice, an animal model of WD, during the PA administration. The free copper and protein-bound copper concentrations in the serum, cortex and basal ganglia of tx mice with PA administration for 3 days, 10 days and 14 days, respectively, were investigated. The expression of copper transporters, ATP7A and CTR1,was analyzed by real-time quantitative PCR, immunofluorescence and Western blot. Then SOD, MDA and GSH/GSSG were detected to determine whether the oxidative stress changed correspondingly. The results revealed the elevated free copper concentrations in the serum and brain, and declined protein-bound copper concentrations in the brain of tx mice during PA administration. Meanwhile, transiently increased expression of ATP7A and CTR1 was observed generally in the brain parenchyma by immunofluorescence, real-time quantitative PCR and Western blot. Additionally, ATP7A and CTR1 were observed to locate mainly at Golgi apparatus and cellular membrane respectively. Intense staining of ATP7A in the choroid plexus was found in tx mice on the 3rd and 10th day of PA treatment, but rare staining of ATP7A and CTR1 in the blood-brain barrier (BBB). Decreased GSH/GSSG and increased MDA concentrations were also viewed in the cortex and basal ganglia. Our results suggested the elevated free copper concentrations in the brain might lead to the enhanced oxidative stress during PA administration. The increased free copper in the brain might come from the copper mobilized from brain parenchyma cells but not from the serum according to the ATP7A and CTR1 expression analysis.http://europepmc.org/articles/PMC3357430?pdf=render |
| spellingShingle | Ding-Bang Chen Li Feng Xiao-Pu Lin Wei Zhang Fu-Rong Li Xiu-Ling Liang Xun-Hua Li Penicillamine increases free copper and enhances oxidative stress in the brain of toxic milk mice. PLoS ONE |
| title | Penicillamine increases free copper and enhances oxidative stress in the brain of toxic milk mice. |
| title_full | Penicillamine increases free copper and enhances oxidative stress in the brain of toxic milk mice. |
| title_fullStr | Penicillamine increases free copper and enhances oxidative stress in the brain of toxic milk mice. |
| title_full_unstemmed | Penicillamine increases free copper and enhances oxidative stress in the brain of toxic milk mice. |
| title_short | Penicillamine increases free copper and enhances oxidative stress in the brain of toxic milk mice. |
| title_sort | penicillamine increases free copper and enhances oxidative stress in the brain of toxic milk mice |
| url | http://europepmc.org/articles/PMC3357430?pdf=render |
| work_keys_str_mv | AT dingbangchen penicillamineincreasesfreecopperandenhancesoxidativestressinthebrainoftoxicmilkmice AT lifeng penicillamineincreasesfreecopperandenhancesoxidativestressinthebrainoftoxicmilkmice AT xiaopulin penicillamineincreasesfreecopperandenhancesoxidativestressinthebrainoftoxicmilkmice AT weizhang penicillamineincreasesfreecopperandenhancesoxidativestressinthebrainoftoxicmilkmice AT furongli penicillamineincreasesfreecopperandenhancesoxidativestressinthebrainoftoxicmilkmice AT xiulingliang penicillamineincreasesfreecopperandenhancesoxidativestressinthebrainoftoxicmilkmice AT xunhuali penicillamineincreasesfreecopperandenhancesoxidativestressinthebrainoftoxicmilkmice |