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Neurotoxic mechanisms of 2,9‐dimethyl‐β‐carbolinium ion in primary dopaminergic culture
Author(s) -
Hamann Juliane,
Rommelspacher Hans,
Storch Alexander,
Reichmann Heinz,
Gille Gabriele
Publication year - 2006
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2006.03940.x
Subject(s) - dopaminergic , programmed cell death , neurotoxin , apoptosis , dopamine , microbiology and biotechnology , dopamine transporter , biology , mitochondrion , endogeny , neuroprotection , neurodegeneration , cell culture , chemistry , biochemistry , pharmacology , neuroscience , medicine , disease , genetics
β‐Carbolines are potential endogenous and exogenous neurotoxicants that may contribute to the pathogenesis of Parkinson's disease. The 2,9‐dimethyl‐β‐carbolinium ion (either 2,9‐dimethyl‐β‐norharmanium or 2,9‐Me 2 NH + ) was found to be neurotoxic in primary mesencephalic cultures and to be a potent inhibitor of mitochondrial complex I. However, the precise mechanisms of cell death remained obscure. Here, we investigated the mechanism of cell death in primary dopaminergic cultures of the mouse mesencephalon mediated by 2,9‐Me 2 NH + . The β‐carboline caused preferential death of dopaminergic neurones, which could not be attributed to cellular uptake via the dopamine transporter. Transient incubation with 2,9‐Me 2 NH + for 48 h caused a progressive deterioration in the morphology of dopaminergic neurones during a 5‐day recovery period and persistent damage to the overall culture. An increase in free radical production and caspase‐3 activity, as well as a decrease of respiratory activity, mitochondrial membrane potential and ATP content, contributed to toxicity and pointed to an apoptotic mode of cell death, although a significant quantity of cells dying via necrosis were present simultaneously. These data underline the preferential susceptibility of dopaminergic neurones to 2,9‐Me 2 NH + as a potent, oxidative stress generating neurotoxin.