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Excitotoxicity: an Organized Crime at the Cellular Level

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Excitotoxicity: an Organized Crime at the Cellular Level Research Article iMedPub Journals JOURNAL OF NEUROLOGY AND NEUROSCIENCE 2017 http://www.imedpub.com ISSN 2171-6625 Vol. 8 No. 3: 193 DOI: 10.21767/2171-6625.1000193 Excitotoxicity: An Organized Crime at Manuel Velasco1*, Joselyn Rojas-Quintero2, The Cellular Level Mervin Chávez-Castillo3,4, Milagros Rojas3, Jordan Bautista3, Abstract María Sofía Martínez3, 3 Excitotoxicity is a form of neuronal death induced by increased Glutamate Juan Salazar , 3 (Glu) signaling which has been implicated in the pathophysiology of a myriad of Rafael Mendoza , neuropsychiatric conditions, such as dementia, motor disorders and epilepsy, Valmore Bermúdez3,5 among many others. The molecular mechanisms underlying excitotoxicity involve alterations of Glu and ionic calcium metabolism, Glu receptor –particularly 1 Department of Pharmacology, “JM N-Methyl-D-Aspartate receptors (NMDARs)– and Glu transporter functioning, Vargas” Medical School, Central activation of downstream enzymes including phospholipases and proteases, and University of Venezuela, Caracas, activation of pro-apoptotic mechanisms such as the conformation of mitochondrial Venezuela permeability pores and release of pro-apoptotic factors. Different mechanisms 2 Division of Pulmonary and Critical appear to be more relevant in distinct acute or chronic contexts. Knowledge of Care Medicine, Brigham and Women’s these aspects has propelled use of NMDAR antagonists such as memantine in the Hospital, Harvard Medical School, therapeutic management of disorders where excitotoxicity is prominent. In this Boston, MA review, we explore the current views on the neurobiological and clinical aspects of 3 Endocrine and Metabolic Diseases excitotoxicity, presenting this process as a complex organized crime at the cellular Research Center. School of Medicine. level. University of Zulia. Maracaibo, Venezuela Keywords: Excitotoxicity; Glutamate; NMDA receptors; Memantine; Cell death 4 Maracaibo Psiquiatric Hospital. Faculty of Medicine. University of Zulia. Maracaibo, Venezuela Received: June 08, 2017; Accepted: June 24, 2017; Published: June 28, 2017 5 Advanced Frontier Studies Research Group (ALEF), Simón Bolívar University, Cúcuta, Colombia Introduction Excitotoxicity is a form of neuronal death caused by hyperactivity of excitatory amino acids –mainly Glutamate (Glu)-in the mammal *Corresponding author: Manuel Velasco Central Nervous System (CNS) [1]. This activity leads to an excessive cellular influx of ions, particularly calcium, causing the activation of [email protected] proteases, phospholipases and endonucleases [2]. MD, MSc, PhD. Department of Pharmacology, The neurotoxic effects of Glu were first identified in reports by “JM Vargas” Medical School, Central University Lucas and Newhouse in 1957 [3], with studies in mouse retina of Venezuela, Caracas, Venezuela. samples in which after parenteral administration of L-Glutamate, damage to the inner layers of the retina was observed, manifested as partial necrosis of the ganglionic and inner nuclear cells. In Tel: +58 212 5619871 the 1960s, further studies emerged on this neurotransmitter and others, such as γ-aminobutyric acid (GABA). The term “excitotoxin” was coined to designate excitatory amino acids Citation: Velasco M, Rojas-Quintero J, with neurotoxic effects [4]; and Glu was discovered to be involved Chávez-Castillo M, Rojas M, Bautista J, in calcium release after cell depolarization [5]. Later, during the et al. (2017) Excitotoxicity: An Organized 1970s, the glutamate-glutamine cycle was first described, and Crime at The Cellular Level. J Neurol Glu was found to be reabsorbed by glia cells following its release Neurosci. Vol. 8 No. 3: 193 to the synaptic cleft. Here, it is converted back to glutamine which returns to the synaptic terminals, where is converted back to Glu by the glutaminase enzyme [6]. © Under License of Creative Commons Attribution 3.0 License | This article is available in: www.jneuro.com 1 JOURNAL OF NEUROLOGYARCHIVOS AND NEUROSCIENCE DE MEDICINA 2017 ISSNISSN 2171-6625 1698-9465 Vol. 8 No. 3: 193 Excitotoxicity is a complex process that has been associated in excitotoxicity [20]. In the CNS, Glu is mainly synthesized from with an important number of pathologic conditions with great endogenous precursors, chiefly α-ketoglutarate, a metabolite clinical relevance. These include hypoxic-ischemic states [7], from the Krebs Cycle [21]. However, the majority of Glu utilized hypoglycemia [8], status epilepticus [9], neurodegenerative in synapses derives from the recycling of this molecule in a diseases [1], head trauma [10], as well as with multiple other dynamic pool maintained through the glutamate-glutamine cycle neuropsychiatric disorders, such as substance abuse and [22]. In this purport, Excitatory Amino Acid Transporters (EAAT) – withdrawal disorders, major depression and schizophrenia subtypes EAAT1 and EAAT2-located in astrocyte membranes, may [11-13]. In view of the prominent role excitotoxicity plays in withdraw Glu from the synaptic cleft, ending synaptic signaling. these conditions, and the potential therapeutic implications of Once in the cytoplasm of astrocytes, Glu is converted back to this phenomenon in the management of these disorders, the glutamine through glutamine synthase, and then released to the purpose of this article is to summarize current molecular and extracellular space in this inactive form, which may be recaptured neurobiological views on the pathophysiology of excitotoxicity, by presynaptic terminals. It is here where glutamine might be conceived as a crime or murder of neuronal cells. reconverted to Glu by mitochondrial glutaminase, effectively returning Glu back to its place of origin, where it can be reutilized The Synapse: Scene of The Crime as a NT [23]. Neuronal impulses are transmitted through synapses, the sites Therefore, the glutamine-glutamate cycle is essential, as it where the axon of a presynaptic neuron comes into proximity reduces the requirement of de novo synthesis of Glu from the with a postsynaptic excitable cell. Synapses might be electrical Krebs Cycle and regulates Glu activity through EAATs, thus or chemical. In the former, postsynaptic and presynaptic favoring neuronal energetic stability [24]. membranes form communicating junctions, which act as high Glu excess may have multiple origins, reflecting the different conductance ionic bridges [14]. However, almost all synapses in conditions that share excitotoxicity as a common mechanism. the human CNS are of chemical nature. In this type of synapses, These include energetic homeostasis disruptions secondary to a molecule released by the presynaptic terminal –also called a hypoxic-ischemic states and hypoglycemic states in the CNS [25]. neurotransmitter (NT) – mediates the activation of the target cell These conditions interrupt the supply of oxygen and glucose to the [15]. neurons, which results in disruption of oxidative phosphorylation in the mitochondria, reducing ATP levels. Although there are Once the NT is released into the synaptic cleft, it may bind to alternative substrates to glucose, such as glycogen, lactate and receptors in the postsynaptic membrane. In general, the basic fatty acids, oxygen is irreplaceable in mitochondrial oxidative structure of these receptors includes a ligand-binding site phosphorylation. Therefore, hypoxic-ischemic states stimulate and an active site. Ionotropic receptors allow ionic diffusion glycogen catabolism, leading to the accumulation of protons and after being activated by the NT, which causes a change in their lactate, and therefore, to rapid intracellular acidification and an structure to a channel-like conformation [16]. Depending on the even greater decrease in ATP availability [26]. ion transported through these channels, an ionotropic receptor might be excitatory if it favors the travel of cations, mainly sodium; or inhibitory, if it favors the travel of anions, mainly chloride. Conversely, metabotropic receptors initiate diverse intracellular signaling cascades through second messengers, which in turn trigger an excitatory or inhibitory net effect [17]. Indeed, the structural and functional characteristics of the postsynaptic receptors determine the excitatory or inhibitory nature of the synapses. Figure 1 illustrates this process. Activation of postsynaptic receptors results in excitatory or inhibitory modifications to the membrane potential of the target cell; which may be enhanced by spatial or temporal summation. Figure 1 The axon of the presynaptic neuron is filled with Changes in the membrane potential lead to depolarization or mitocondria and Glu vesicles (Glu). When depolarization hyperpolarization of the target cell [18]. To this end, the neuron occurs, Ca2+ voltaje-dependent channels play a pivotal must reach a minus negative voltage of -45 mV from a basal role in the cytoskeleton contractile machine, which potential of -65 mV in order to be depolarized and activate allows the coupling od synaptobrevin ((located in the the voltage dependent calcium channels that will trigger the vesicular membrane) with syntaxin (located in the subsequent synapsis [19]. celular membrane). Therefore, both membranes fuse together and Glu exocytosis occurs into the synaptic cleft. Here, Glu finds its postsynaptic receptors and Glutamate, Receptors and Calcium: The once it has fulfilled its function the remaining Glu will Criminals be recycled through amino acid excitatory transporters (EAAT) located in astrocytes and later, through Glutamate: Intellectual author enzymatic
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