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Differential effects of dopamine melanin on norharman-induced toxicity in PC12 cells
A Ostergren1, N G Lindquist, E B Brittebo
1Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
Abstract:
The food contaminant norharman structurally resembles MPTP a compound that selectively damages pigmented brain areas. Both compounds are sequestered and retained in melanin-containing neurons. The aim of the study was to examine whether intracellular melanin can modulate the toxicity of norharman in melanin-loaded PC12 cells. Dopamine melanin protected against norharman-induced upregulation of grp78, activation of caspase 3 and necrosis at low concentrations (5 and 50 microM). In contrast, at a high conentration (500 microM) there was a significantly increased expression of grp78, hsp90 and caspase 3 and a disassociation of melanin aggregates leading to dispersal of granules to swollen neurite terminals. In human populations, a long-term low-level exposure to toxicants with a high affinity to melanin will probably result in accumulation in melanin-containing neurons in vivo. Our data suggest that accumulation of a neurotoxicant in melanin-loaded cells may lead to increased cell stress, apoptotic signaling and disassociation of melanin aggregates.
Insights
Melanin accumulation in neurons can protect against the neurotoxicant norharman at low doses. However, high norharman concentrations cause cell stress and damage in melanin-loaded cells.
Area of Science:
- Neuroscience
- Toxicology
- Cell Biology
Background:
- Norharman, a food contaminant, shares structural similarities with MPTP, a known neurotoxin.
- Both norharman and MPTP accumulate in melanin-containing neurons, suggesting a potential role for melanin in neurotoxicity.
Purpose of the Study:
- To investigate how intracellular melanin influences the toxicity of norharman.
- To assess the protective or detrimental effects of melanin on norharman-induced cellular damage in PC12 cells.
Main Methods:
- Utilized melanin-loaded PC12 cells to model melanin-containing neurons.
- Administered varying concentrations of norharman to assess cellular responses.
- Measured key indicators of cell stress, apoptosis, and necrosis, including grp78, caspase 3, and hsp90 expression.
Main Results:
- Low concentrations (5 and 50 microM) of norharman showed reduced toxicity in melanin-loaded cells, with dopamine melanin providing protection.
- High norharman concentration (500 microM) led to increased expression of grp78, hsp90, and caspase 3.
- High norharman exposure caused melanin aggregate dissociation and dispersal into neurites, indicating cellular damage.
Conclusions:
- Intracellular melanin can modulate norharman toxicity, offering protection at lower levels.
- High-level exposure to norharman in melanin-rich environments can paradoxically increase neurotoxic effects and trigger apoptotic pathways.
- Findings suggest potential risks associated with long-term exposure to melanin-binding toxicants in human populations.
