The Redox Biology of Excitotoxic Processes: The NMDA Receptor, TOPA Quinone, and the Oxidative Liberation of Intracellular Zinc

Hong

et al. 2020

IJMS

Zinc is a trace metal ion in the central nervous system that plays important biological roles, such as in catalysis, structure, and regulation. It contributes to antioxidant function and the proper functioning of the immune system. In view of these characteristics of zinc, it plays an important role in neurophysiology, which leads to cell growth and cell proliferation. However, after brain disease, excessively released and accumulated zinc ions cause neurotoxic damage to postsynaptic neurons. On the other hand, zinc deficiency induces degeneration and cognitive decline disorders, such as increased neuronal death and decreased learning and memory. Given the importance of balance in this context, zinc is a biological component that plays an important physiological role in the central nervous system, but a pathophysiological role in major neurological disorders. In this review, we focus on the multiple roles of zinc in the brain.

Section: Friendmentioning

confidence: 99%

Zinc in the Brain: Friend or Foe?

Hong

et al. 2020

IJMS

“…To gain some further insight, we focused on two distinguishing features of the NMDARs and the nNOS (+) subpopulation. NMDARs are modulated by oxidizing and reducing agents, which decrease or potentiate the amplitude of receptor response to agonists, respectively (Aizenman et al, 1989(Aizenman et al, , 1990(Aizenman et al, , 2020. On the other hand, nNOS (+) neurons fail to generate ROS of mitochondrial origin following the activation of NMDARs (Canzoniero et al, 2013;Granzotto and Sensi, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…NMDAR ionic conductance can be modulated by oxidizing/reducing agents (Aizenman et al, 1989(Aizenman et al, , 1990(Aizenman et al, , 2020. We evaluated, in nNOS (+) and nNOS (-) neurons, NMDAR activity before and after pharmacological manipulation set to alter the redox status of the receptor (Fig.…”

Section: Compared To Nnos (-) Nnos (+) Neurons Show Reduced Nmdar-driven [Ca 2+ ] I Rises Following Receptor Reductionmentioning

confidence: 99%

Long-term dynamic changes of NMDA receptors following an excitotoxic challenge

Granzotto

D’Aurora

Bomba

et al. 2022

Preprint

Excitotoxicity is a form of neuronal death characterized by the sustained activation of N-methyl-D-aspartate receptors (NMDARs) triggered by the excitatory neurotransmitter glutamate. NADPH-diaphorase neurons [also known as nNOS (+) neurons] are a subpopulation of aspiny interneurons, largely spared following excitotoxic challenges. Unlike nNOS (-) cells, nNOS (+) neurons fail to generate reactive oxygen species in response to NMDAR activation, a key divergent step in the excitotoxic cascade. However, additional mechanisms underlying the reduced vulnerability of nNOS (+) neurons to NMDAR-driven neuronal death have not been explored. Using functional, genetic, and molecular analysis in striatal cultures, we demonstrate that nNOS (+) neurons possess distinct NMDAR properties. These specific features are primarily driven by the peculiar redox milieu of this subpopulation. In addition, we found that nNOS (+) neurons exposed to a pharmacological maneuver set to mimic chronic excitotoxicity alter their responses to NMDAR-mediated challenges. These findings suggest the presence of mechanisms providing long-term dynamic regulation of NMDARs that can have critical implications in neurotoxic settings.

“…Finally, Zn 2+ mobilization, by contributing to the activation of the CamKII/p38/syntaxin/calcineurin axis, promotes outward potassium (K + ) currents, a critical step in the production of neuronal apoptosis (Yu et al, 1997;McCord and Aizenman, 2013;Shah and Aizenman, 2014;Aizenman et al, 2020).…”

Section: Zinc As Neurotoxinmentioning

confidence: 99%

A Neurotoxic Ménage-à-trois: Glutamate, Calcium, and Zinc in the Excitotoxic Cascade

Granzotto

Canzoniero

Sensi

2020

Front. Mol. Neurosci.

Fifty years ago, the seminal work by John Olney provided the first evidence of the neurotoxic properties of the excitatory neurotransmitter glutamate. A process hereafter termed excitotoxicity. 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. Mechanisms linked to the overactivation of glutamatergic receptors involve an aberrant cation influx, which produces the failure of the ionic neuronal milieu. 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. Zinc is an essential element for neuronal functioning, but when dysregulated acts as a potent neurotoxin. 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. Finally, we summarize our work on the fascinating distinct properties of NADPH-diaphorase neurons. This neuronal subpopulation is spared from excitotoxic insults and represents a powerful tool to understand mechanisms of resilience against excitotoxic processes.