In the review, we provide a brief overview of the role of Zn 2+ in the brain and discuss its neurotoxic properties and how they intertwine with the excitotoxic cascade. Zinc (Zn 2+) is, for instance, a VIP guest. However, Ca 2+ is not alone, and other cations find a way to participate in the death banquet. The NMDAR-driven Ca 2+ overload is, in fact, a mandatory step in the process as most of the downstream mechanisms of the cascade, like the generation of reactive oxygen species (ROS of mitochondrial and non-mitochondrial origin), or reactive nitrogen species (RNS), the concurrent mitochondrial dysfunction, metabolic impairment, as well as the activation of necrotic/apoptotic pathways, are all Ca 2+-dependent processes ( Lee et al., 1999 Lai et al., 2014 Bano and Ankarcrona, 2018 Choi, 2020 Swanson and Wang, 2020). The construct posits that excitotoxic neuronal death is primarily mediated by the glutamate-driven activation of N-methyl-D-aspartate receptors (NMDARs) and the subsequent toxic intraneuronal accumulation of calcium (Ca 2+). These studies have also helped provide support for the excitotoxic cascade hypothesis ( Zivin and Choi, 1991 Choi, 2020). Only riluzole and memantine, two drugs that target glutamate-driven neuronal death, have been approved for the treatment of ALS and AD, respectively.Īlthough, most of the preclinical findings failed “the bench to bed” translation, this experimental evidence has significantly helped dissect the molecular underpinnings of excitotoxicity. These approaches have been found promising in preclinical models ( Lee et al., 1999) but failed in clinical trials ( Lee et al., 1999 Ikonomidou and Turski, 2002 Chamorro et al., 2016 Choi, 2020). In that regard, the targeting of upstream mechanisms of glutamate-driven neurotoxicity has produced, in the late 80s, an early wave of enthusiasm and fueled a level of optimism that has not been corroborated in the following years. Evidence accumulated in the past four decades indicates that excitotoxicity is a critical contributor to the neuronal demise occurring upon acute and chronic neurological conditions, like stroke, Alzheimer’s disease (AD), Huntington’s disease (HD), Amyotrophic Lateral Sclerosis (ALS), and Parkinson’s disease (PD) ( Mehta et al., 2013).Īlthough, 50 years have passed since the first description of glutamate’s neurotoxic activity ( Olney, 1969), therapeutic strategies set at counteracting these processes have been only partially exploited. This neuronal subpopulation is spared from excitotoxic insults and represents a powerful tool to understand mechanisms of resilience against excitotoxic processes.Įxcitotoxicity is a form of neuronal death triggered by excessive and/or sustained exposure to the amino acid glutamate, the primary excitatory neurotransmitter in the brain. Finally, we summarize our work on the fascinating distinct properties of NADPH-diaphorase neurons. In this review, we discuss the ionic changes and downstream effects involved in the glutamate-driven neuronal loss, with a focus on the role exerted by zinc. Zinc is an essential element for neuronal functioning, but when dysregulated acts as a potent neurotoxin. In this context, zinc, the second most abundant metal ion in the brain, is a key but still somehow underappreciated player of the excitotoxic cascade. Mechanisms linked to the overactivation of glutamatergic receptors involve an aberrant cation influx, which produces the failure of the ionic neuronal milieu. Since then, glutamate-driven neuronal death has been linked to several acute and chronic neurological conditions, like stroke, traumatic brain injury, Alzheimer’s, Parkinson’s, and Huntington’s diseases, and Amyotrophic Lateral Sclerosis. A process hereafter termed excitotoxicity. Fifty years ago, the seminal work by John Olney provided the first evidence of the neurotoxic properties of the excitatory neurotransmitter glutamate.
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