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(Stroke. 2007;38:661.)
© 2007 American Heart Association, Inc.

Glutamate-Independent Calcium Toxicity: Introduction

Glutamate-Independent Calcium Toxicity

Introduction

Lucio Annunziato, MD; Mauro Cataldi, MD, PhD; Giuseppe Pignataro, PhD; Agnese Secondo, PhD Pasquale Molinaro, PhD

From the Division of Pharmacology, Department of Neuroscience, University of Naples "Federico II", Naples, Italy.

Correspondence to Lucio Annunziato, MD, Division of Pharmacology, Department of Neuroscience, School of Medicine, "Federico II" University of Naples, Via S. Pansini 5, 80131 Naples, Italy. E-mail lannunzi@unina.it

An extract of the first 250 words of the full text is provided, because this article has no abstract.

It is widely accepted that a critical factor in determining neuronal death during cerebral ischemia is the progressive accumulation of intracellular Na⁺ ([Na⁺]_i) and Ca²⁺ ([Ca²⁺]_i) ions, which can precipitate necrosis and apoptosis of vulnerable neurons. Whereas the detrimental action of [Na⁺]_i increase is attributable to both cell swelling and microtubular disorganization—2 phenomena that lead to cell necrosis¹—a change in [Ca²⁺]_i has been shown to be a key factor in ischemic brain damage, for it modulates several death pathways, including oxidative and nitrosative stress, mitochondrial dysfunction, and protease activation.

Reassessment of the Excitotoxicity Theory: Criticism to the Paradigm

Since Olney’s seminal work firstly suggested that excitatory aminoacids could elicit neurotoxicity,² a large amount of work has been accumulated showing that glutamate extracellular concentrations briskly rise during acute brain injury, thus triggering an influx of Ca²⁺ and Na⁺ ions into neurons through ionotropic glutamate receptor subtypes. This evidence has led to the elaboration of the paradigm of glutamate excitotoxicity that explained ischemic neuronal cell death as a mere consequence of Na⁺ and Ca²⁺ influx through glutamate receptors.³ Although this theory has been guiding basic research in the field of neurodegeneration for almost 3 decades, more recently it has become the object of serious criticism and reassessment. What has aroused such skepticism among researchers has been the fact that although first, second, and third generation glutamate receptor antagonists have long yielded promising results in animal models of brain ischemia, they have failed to elicit a neuroprotective action in stroke and traumatic brain injury in . . . [Full Text of this Article]