Postsynaptic mechanisms of excitotoxicity: Involvement of postsynaptic density proteins, radicals, and oxidant molecules.
ABSTRACT Traditional models of neuronal excitotoxicity focused on the overactivation of receptors such as the ionotropic N-methyl-D-aspartate (NMDA)-subtype glutamate receptor. Recent developments have shifted focus to downstream neurotoxic signaling molecules with exciting implications to specific strategies for treating excitotoxic disorders. This review outlines these developments and introduces newly emerging evidence implicating the involvement of the melastatin subfamily in anoxic neuronal death. Both of these converge on the production of reactive oxygen species (ROS), including superoxide, nitric oxide (NO) and the oxidant peroxynitrite.
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ABSTRACT: Hippocampal CA1 neurons are particularly sensitive to ischemic damage, such as experienced following cardiac arrest and cardiopulmonary resuscitation. In recent years transient receptor potential M2 (TRPM2) channels have been identified as mediators of ischemic damage. We previously demonstrated that neuroprotective strategies targeting TRPM2 channels preferentially protect male cortical neurons from ischemic injury both in vitro and in vivo. It is important to determine the role of TRPM2 in ischemic injury of hippocampal neurons as this population of neurons are particularly sensitive to ischemic injury and are therapeutic targets. Here we report significantly decreased neuronal cell death following in vitro ischemia preferentially in male hippocampal neurons using TRPM2 inhibitors or knockdown of TRPM2 expression. Electrophysiological characterization of sex-stratified cultures shows similar levels of functional TRPM2 channel expression in male and female hippocampal neurons under basal conditions. In contrast, recordings made during reperfusion following in vitro ischemia revealed that TRPM2 channels are activated only in male neurons, resulting in rapid and complete depolarization. These findings provide strong evidence for TRPM2 as a target for protection against cerebral ischemia in male brain and helps define a molecular cell death pathway that is differentially engaged in male and female neurons.Neuroscience Letters 10/2012; 530(1). DOI:10.1016/j.neulet.2012.09.044 · 2.06 Impact Factor
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ABSTRACT: Traumatic brain injury (TBI) is a major health and socioeconomic problem throughout the world. It is a complicated pathological process that consists of primary insults and a secondary insult characterized by a set of biochemical cascades. The imbalance between a higher energy demand for repair of cell damage and decreased energy production led by mitochondrial dysfunction aggravates cell damage. At the cellular level, the main cause of the secondary deleterious cascades is cell damage that is centred in the mitochondria. Excitotoxicity, Ca2+ overload, reactive oxygen species (ROS), Bcl‐2 family, caspases and apoptosis inducing factor (AIF) are the main participants in mitochondria‐centred cell damage following TBI. Some preclinical and clinical results of mitochondria‐targeted therapy show promise. Mitochondria‐ targeted multipotential therapeutic strategies offer new hope for the successful treatment of TBI and other acute brain injuries.British Journal of Pharmacology 10/2012; 167(4). DOI:10.1111/j.1476-5381.2012.02025.x · 4.99 Impact Factor
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ABSTRACT: BACKGROUND AND PURPOSE: Increasing evidence shows the dysregulation of glutamate transmission in both multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), the animal model of MS. A clear hallmark of EAE is an increased glutamate transmission associated with the up-regulation of AMPA receptors. However, little is known about the role of NMDA receptors (NMDAR) in the synaptic modifications induced by EAE. EXPERIMENTAL APPROACH: The contribution of NMDARs in the alterations of glutamate transmission and disease severity in EAE mice was assessed by means of neurophysiological, morphological, western blot, metabolic and clinical score evaluations. KEY RESULTS: Our results showed the appearance in EAE of an NMDAR-dependent increase of glutamate release, associated with dramatic activation of the astroglia. Presynaptic NMDARs became overactive during EAE, playing a positive role in modulating synaptic glutamate release in a way dependent on voltage-gated sodium channels. By means of NAD(P)H autofluorescence analysis, we also found that EAE has a glutamate and NMDAR-dependent dysfunction of mitochondrial activity, which is known to contribute to the neurodegenerative damage of MS and EAE. Furthermore, pharmacological blockade of NMDARs in vivo resulted in an amelioration of both synaptic transmission defects and of the clinical disease course of EAE mice, while EAE induced in mice with a genetically enhanced NMDAR signaling had opposite effects. CONCLUSIONS AND IMPLICATIONS: Our data, showing both sensitization of NMDARs and their involvement in the progression of the EAE disease, support pharmacological impairment of NMDAR signalling as a candidate to neuroprotection strategy in MS.British Journal of Pharmacology 08/2012; DOI:10.1111/j.1476-5381.2012.02178.x · 4.99 Impact Factor