Reactive oxygen species in NMDA receptor-mediated glutamate neurotoxicity
Introduction
Excitatory amino acids (EEAs) such as glutamate are acknowledged as the primary neurotransmitters that mediate synaptic excitation in the vertebrate central nervous system (CNS). Glutamate satisfies the main criteria for classification as a neurotransmitter: presynaptic localization; specific release by physiological stimuli; identical action to the endogenous transmitter including response to antagonists; and the existence of mechanisms to terminate transmitter action rapidly [1]. In addition to its role in neurotransmission, glutamate can also act as a neurotoxin [2], [3]. Glutamate has been postulated to play an important role in the pathogenesis of the neuronal cell loss which is associated with several neurological disease states in the CNS. Thus, glutamate has a dual action on the CNS neurons, acting as an excitatory neurotransmitter at physiologic concentrations and as a neurotoxic substance when it is present in excess. Nitric oxide (NO), apparently identical to the endothelium-derived relaxing factor, is also formed in brain tissues and estimated to be a mediator of glutamate neurotoxicity [4], [5].
The actions of glutamate as an excitatory neurotransmitter are regulated by many other endogenous substances, such as inhibitory neurotransmitters and neuromodulators. Suppression of the control by those substances on glutamate-induced excitation causes severe dysfunction of the CNS activity. For example, convulsive drugs, which block the inhibitory actions of either GABA or glycine, are known to induce chronic and tonic convulsions, respectively. Therefore, excitatory actions of glutamate and other EAAs should receive tonic regulation by inhibitory neurotransmitters and neuromodulators to maintain normal neuronal activities in the CNS. Meanwhile, the cytotoxic effects of excitatory amino acids, including glutamate, have a crucial role in the pathogenesis of the neuronal degeneration. This suggests that neurons in the CNS are exposed to both the excitatory and cytotoxic effects of glutamate. Then, it is possible that the neurotoxic action of glutamate is also regulated by other endogenous substances in physiological and/or pathological conditions. In other words, certain neurotransmitters, neuromodulators or other endogenous substances may possess a neuroprotective action against glutamate cytotoxicity to promote cell survival in the CNS [6], [7], [8].
Section snippets
Role of NO and superoxide anion in glutamate neurotoxicity
Glutamate receptors are divided into two major subgroups; ionotropic receptors and metabotropic receptors. On pharmacological and physiological grounds, ionotropic receptors have been grouped into two subtypes: N-methyl-d-aspartate (NMDA) and non-NMDA receptors. The non-NMDA receptors are further divided into subgroups such as KA (kainate) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA). The NMDA receptor has been postulated to be the predominant route of glutamate neurotoxicity in
Neuroprotection by brain-derived neurotrophic factor (BDNF)
In search of endogenous substances having protective action against EAA, we found that BDNF prevented glutamate neurotoxicity in cultured cortical neurons derived from fetal rats [11], [12]. Cell viability was assessed using trypan blue exclusion. Activation of TrkB by BDNF leads to autophosphorylation for initiating its specific signal [13], [14]. In cortical cultures, induction of TrkB phosphorylation by BDNF (60 ng/ml) was rapid and persisted up to 24 h. TrkB tyrosine phosphorylation reached a
NMDA cytotoxicity in dopaminergic neurons in mesencephalic slice cultures
The main histopathological finding of Parkinson's disease is the selective degeneration of nigrostriatal dopamine neurons. It has been reported that dopamine neurons are susceptible to the cytotoxicity of excitatory amino acids: the application of NMDA was toxic to mesencephalic dopamine neurons in vivo and in vitro [16], [17], [18]. In vivo studies showed that the selective dopamine neuron death of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was blocked by NMDA antagonists [19], [20],
Conclusion
The soluble factors derived from target and/or non-target cells may regulate the elongation of mesencephalic dopamine fibers into the striatal tissue when the neurite outgrowth of dopamine neurons to the striatal slices occurred in contacting co-cultures with the striatum. This assumption is supported by the fact that the non-contacting co-cultures with the striatum did not show even the directional elongation of dopaminergic neurites toward the striatal part. The dopaminergic neurites failed
Acknowledgements
This study was supported in part by a Grant-in-aid from the Ministry of Education, Science, Sports and Culture, Japan. This study was also supported in part by a grant from the Smoking Research Foundation, Japan.
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An in vitro ischemic penumbral mimic perfusate increases NADPH oxidase-mediated superoxide production in cultured hippocampal neurons
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