Dopamine protects neurons against glutamate-induced excitotoxicity

Abstract

Glutamate excitotoxicity is responsible for neuronal death in acute neurological disorders including stroke, trauma and neurodegenerative disease. Loss of calcium homeostasis is a key mediator of glutamate-induced cell death. The neurotransmitter dopamine (DA) is known to modulate calcium signalling, and here we show that it can do so in response to physiological concentrations of glutamate. Furthermore, DA is able to protect neurons from glutamate-induced cell death at pathological concentrations of glutamate. We demonstrate that DA has a novel role in preventing delayed calcium deregulation in cortical, hippocampal and midbrain neurons. The effect of DA in abolishing glutamate excitotoxicity can be induced by DA receptor agonists, and is abolished by DA receptor antagonists. Our data indicate that the modulation of glutamate excitotoxicity by DA is receptor-mediated. We postulate that DA has a major physiological function as a safety catch to restrict the glutamate-induced calcium signal, and thereby prevent glutamate-induced cell death in the brain. Signal transduction within the central nervous system (CNS) is mediated by specific neurotransmitters, whose properties have been studied in detail for several decades. Besides their role in signal transduction, neurotransmitters have been implicated in neurotoxicity.Neurotoxicity in the mammalian CNS has been linked to glutamate (e.g. see review by Choi 1 ). Glutamate-induced excitotoxicity has been implicated in neuronal cell death that follows periods of acute neuronal injury as anoxia and reperfusion, and it has been proposed that similar processes may contribute to the neuronal injury in neurodegenerative diseases such as motor neuron disease (for review, see Shaw et al. 2 ) and Alzheimer's disease (e.g. see Schubert and Piasecki 3 ).Neuronal delayed Ca 2 þ accumulation (delayed calcium deregulation, DCD) and mitochondrial membrane depolarization in response to glutamate is a requirement for the progression to cell death 1,4-6 . Exposure of neurons in culture to excitotoxic levels of glutamate results in an initial transient increase in cytosolic calcium concentration [Ca 2 þ ] c followed by a delayed sustained rise in [Ca 2 þ ] c (DCD), which coincides with a profound collapse of mitochondrial membrane potential and is believed to be an initial trigger for neuronal death. 7,8 Exposure of neurons in culture to glutamate causes selective neuronal cell death that can be effectively blocked by application of inhibitors of glutamate receptors. 9 However, glutamate antagonists are significantly less effective against neuronal death in vivo when applied to brain following periods of anoxia and reperfusion and clinical trials of N-methyl-Daspartic acid (NMDA) receptor antagonists remained unsuccessful, suggesting some additional mechanisms apply in the whole brain compared with primary neuronal cultures. 10,11 A possible explanation for this might be an interaction with other neurotransmitters in the brain, modulating glutamate toxicity in vivo.One of the major emer...

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“…Zebrafish brain was also capable synthesizing dopamine, known as protectant against toxic effect of glutamate (Vaarmann et al, 2013;Holzschuh et al, 2001). One or all together may operate to reverse condition back to basal, thus, Bax, Bcl-2, and caspase-3 decreased, reached normal level in 24h MSG treated embryos, 5 days postcessation of MSG.…”

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