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Published on: May 4, 2020
Induction of ferroxidase enzymatic activity by copper reduces MPP+-evoked neurotoxicity in rats
Moisés Rubio-Osornio1, Sergio Montes, Yessica Heras-Romero
1Laboratorio de Enfermedades Neurodegenerativas, Instituto Nacional de Neurología y Neurocirugía, Manuel Velasco Suárez, Mexico.
Abstract:
Parkinson's disease (PD) is a neurodegenerative disorder characterized by decreased dopamine, intracellular inclusions (Lewy bodies) and brain iron deposits. PD has also been related with reduced ferroxidase activity, diminished antioxidant defenses and lipid peroxidation. Striatal injection of 1-methyl-4-phenylpyridinium (MPP(+)) into rodents reproduces the major biochemical characteristics of PD, including oxidative stress. Copper (Cu) plays an important role as prosthetic group of several proteins involved in iron metabolism and antioxidant responses, such as ceruloplasmin (Cp). In the present study, intraperitoneal CuSO4 injection (10μmol/kg) produced an insignificant increase of Cu content in striatum and midbrain (17.5% and 7%, respectively). After 10 and 11h, Cu induced 6- and 4-fold increase Cp mRNA in midbrain and striatum, respectively. Cu-supplement also produced a time-dependent increase ferroxidase activity in striatal tissue, reaching a maximum 16h after Cu treatment in midbrain; while, ferrous iron content diminished 18% in striatum and 8% in midbrain. In regard the PD model, we found that MPP(+) (10μg/8μL, intrastriatal), induced a significant (P<0.05) reduction of striatal ferroxidase activity; this effect was reverted by Cu pre-treatment 16h before MPP(+). Likewise, Cu-supplement prevented lipid fluorescent products formation in striatum, evaluated (P<0.01) 6h after MPP(+). In the long term, apomorphine-evoked circling behavior was evaluated 6 days after MPP(+) injury; Cu pre-treatment significantly reduced (P<0.05) the apomorphine-induced ipsilateral turns in MPP(+)-lesioned rats. These results suggest that Cu-induced expression of Cp could be an interesting scope against the deleterious effects of iron deposits in PD.
Insights
Copper supplementation can protect against Parkinson's disease (PD) effects by increasing ceruloplasmin (Cp) expression, which helps manage iron deposits and oxidative stress associated with PD.
Area of Science:
- Neuroscience
- Biochemistry
- Neuropharmacology
Background:
- Parkinson's disease (PD) is linked to dopamine deficiency, Lewy bodies, brain iron deposits, reduced ferroxidase activity, and oxidative stress.
- Copper (Cu) is crucial for iron metabolism and antioxidant proteins like ceruloplasmin (Cp).
- Rodent models using 1-methyl-4-phenylpyridinium (MPP(+)) mimic PD's biochemical characteristics, including oxidative stress.
Purpose of the Study:
- To investigate the neuroprotective effects of copper sulfate (CuSO4) supplementation in a rodent model of Parkinson's disease (PD).
- To determine if copper influences ceruloplasmin (Cp) expression, ferroxidase activity, and oxidative stress markers in the context of PD.
- To evaluate copper's ability to mitigate motor deficits induced by MPP(+) in rats.
Main Methods:
- Rodents were administered intraperitoneal copper sulfate (CuSO4) and/or intrastriatal 1-methyl-4-phenylpyridinium (MPP(+)).
- Measurements included copper and ceruloplasmin (Cp) mRNA levels, ferroxidase activity, and lipid peroxidation.
- Behavioral tests assessed motor function using apomorphine-induced circling behavior in MPP(+)-lesioned rats.
Main Results:
- Copper administration increased ceruloplasmin (Cp) mRNA and ferroxidase activity while decreasing ferrous iron content in the striatum and midbrain.
- Copper pre-treatment reverted the MPP(+)-induced reduction in striatal ferroxidase activity and prevented lipid peroxidation.
- Copper pre-treatment significantly reduced apomorphine-induced circling behavior in rats lesioned with MPP(+), indicating improved motor function.
Conclusions:
- Copper supplementation, by upregulating ceruloplasmin (Cp) expression, demonstrates potential neuroprotective effects against iron-related damage in Parkinson's disease (PD).
- Copper's ability to counteract oxidative stress and restore ferroxidase activity suggests a therapeutic role in managing PD.
- These findings highlight copper-induced ceruloplasmin as a promising target for mitigating the detrimental effects of iron dysregulation in PD.
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