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Reduced levels of catalase activity potentiate MPP+-induced toxicity: comparison between MN9D cells and CHO cells
S Hussain1, B S Hass, W Slikker
1Neurochemistry Laboratory, Division of Neurotoxicology, National Center for Toxicological Research/FDA Jefferson, AR 72079, USA.
Abstract:
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been shown to be toxic by inducing oxygen free radicals in the mammalian nervous system, especially in the nigrostriatal dopaminergic system. The present study was designed to compare the toxic effects of MPP+, the active metabolite of MPTP, in MN9D neuronal cells that exhibit relatively low levels of catalase activity, as compared to CHO cells, which exhibit high levels of catalase activity. The survival of the MN9D cells in the presence of 250 microM MPP+ was less than 10%, whereas CHO cells exhibited 70% survival at the same concentration of MPP+. The ED50 values of MPP+ in MN9D and CHO cell lines were 60-600 microM, respectively. MN9D cells contain less catalase, an enzyme believed to be involved in the detoxification of free radicals compared to CHO cells. The catalase activity was 2 Units/mg protein in MN9D cells and 30 U/mg protein in CHO cells. The catalase activity in CHO cells increased with increasing MPP+ concentrations from 100-500 microM, however, it decreased at 1 mM MPP+. In contrast, catalase activity in MN9D remained the same at all MPP+ concentrations. When the CHO cells were pre-treated with 10-25 mM 3-aminotriazole (3-AT), which inhibits catalase activity, and exposed to MPP+ at various concentrations, they became susceptible to MPP+. It is evident from these data that the differential susceptibility to MPP+ in these two cell lines are due to differences in catalase activity. In addition, the inhibition of constituentive catalase activity in CHO cells by 3-AT treatment enhances their susceptibility. In conclusion, the study demonstrates that catalase activity represents an important defence mechanism in MPTP-induced toxicity.
Insights
Catalase activity protects against 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity. Cells with low catalase are more vulnerable to MPP+, the active MPTP metabolite, highlighting catalase
Area of Science:
- Neuroscience
- Toxicology
- Cell Biology
Background:
- 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces neurotoxicity via free radicals.
- MPTP's active metabolite, MPP+, targets the nigrostriatal dopaminergic system.
- Catalase is an enzyme involved in free radical detoxification.
Purpose of the Study:
- To compare the toxicity of MPP+ in cell lines with differing catalase activity.
- To investigate the role of catalase in cellular defense against MPP+.
Main Methods:
- Comparing survival rates of MN9D (low catalase) and CHO (high catalase) cells exposed to MPP+.
- Measuring catalase activity in both cell lines under varying MPP+ concentrations.
- Assessing MPP+ susceptibility in catalase-inhibited CHO cells using 3-aminotriazole (3-AT).
Main Results:
- MN9D cells showed <10% survival with 250 microM MPP+, while CHO cells had 70% survival.
- ED50 values for MPP+ were 60 microM in MN9D and 600 microM in CHO cells.
- Inhibiting catalase in CHO cells with 3-AT significantly increased their susceptibility to MPP+.
Conclusions:
- Differential susceptibility to MPP+ is directly linked to cellular catalase activity.
- Catalase activity is a crucial defense mechanism against MPTP-induced neurotoxicity.
- Targeting catalase may offer therapeutic strategies for MPTP-related neurodegeneration.