Copper induced oxidation of serotonin: analysis of products and toxicity

Abstract

Serotonin is a major neurotransmitter that controls many functions, ranging from mood and behaviour through to sleep and motor functions. The non-enzymatic oxidation of serotonin is of significant importance as some oxidation products are considered to be neurotoxic. An interaction between copper and serotonin has been suggested by symptoms observed in a number of neurodegenerative diseases such as Wilson's and Prion diseases. Using PC12 cells as a model of neuronal cells, we show that the interaction between copper and serotonin is toxic to undifferentiated cells. The toxicity is largely due to reactive oxygen species as cell death is significantly reduced in the presence of the antioxidant mannitol.Differentiation of the PC12 cells also confers resistance to the oxidative process. In vitro oxidation of serotonin by copper results in the eventual formation of a coloured pigment, thought to be a melanin-like polymeric species. Using spectroscopic methods we provide evidence for the formation of a single intermediate product. This dimeric intermediate was identified and characterized as 5,5¢-dihydroxy-4,4¢-bitryptamine. These results indicate that copper structurally alters serotonin and this process may play a role in copper related neurodegenerative diseases.

Protective Actions of the Vesicular Monoamine Transporter 2 (VMAT2) in Monoaminergic Neurons

“…Injection of 5,6-dihydroxytryptamine or 5,7-dihydroxytryptamine destroys serotonin neurons, and it has been suggested that serotonin can be oxidized to these compounds in vivo [186][187][188]. Experimental evidence suggests that in Alzheimer's disease and disorders of copper storage, serotonin oxidation produces 4,5-dihydroxytryptamine which further oxidizes to compounds that inhibit acetylcholine esterase and cause oxidative stress [189][190][191][192]. Furthermore, the production of neurotoxic oxidation products of cytosolic serotonin has been proposed as a possible mechanism of methamphetamine neurotoxicity in these neurons [187,191,193].…”

Carnosine Protects Against the Neurotoxic Effects of a Serotonin-Derived Melanoid

“…Differentiation of PC12 cells confers almost complete resistance to serotonin-derived dimers and polymers that were produced under oxidizing conditions with copper ions, whereas undifferentiated cells show decreased survival with serotonin/Cu 2? (1 mM/66 lM) [10]. With SH-SY5Y cells, the undifferentiated phenotype is more susceptible to toxicity induced by either 6-hydroxydopamine or 1-methyl-4-phenyl-pyridinium ion as compared with the differentiated cell type [18], further suggesting a survival benefit associated with differentiation.…”

“…Other studies have shown that differentiation of cells can provide protection against toxicity induced by other agents such as Cu 2? -oxidized serotonin [10] and dopaminergic toxins [18]. Differentiation of PC12 cells confers almost complete resistance to serotonin-derived dimers and polymers that were produced under oxidizing conditions with copper ions, whereas undifferentiated cells show decreased survival with serotonin/Cu 2?…”

“…Serotonin has been increasingly recognized as crucial for memory and cognition [9], suggesting that localized depletion of serotonin may contribute to POCD symptomatology. Serotonin forms higher order structures in an oxidizing environment that in addition to depleting serotonin levels may generate side products that are neurotoxic [10,11]. We previously observed that serotonin reacts with acrolein [7], which is a lipid peroxidation 3-carbon fragment that accumulates in aging [12] and plays a role in substantia nigra pathology [13].…”

Redox Mechanism of Neurotoxicity by a Serotonin–Acrolein Polymeric Melanoid

“…Experiments using rat pheochromocytoma cells provide evidence that melanoid-like compounds derived from serotonin are toxic (Jones et al 2007). In addition, mannitol, an antioxidant, prevents cell death, suggesting a freeradical mechanism of toxicity.…”