Cytosolic zinc accumulation contributes to excitotoxic oligodendroglial death

Abstract

Dyshomeostasis of cytosolic Zn(2+) is a critical mediator of neuronal damage during excitotoxicity. However, the role of this cation in oligodendrocyte pathophysiology is not well understood. The current study examined the contribution of Zn(2+) deregulation to oligodendrocyte injury mediated by AMPA receptors. Oligodendrocytes loaded with the Zn(2+)-selective indicator FluoZin-3 responded to mild stimulation of AMPA receptors with fast cytosolic Zn(2+) rises that resulted from intracellular release, as they were not blocked by the extracellular Zn(2+) chelator Ca-EDTA. Pharmacological experiments suggested that AMPA-induced Zn(2+) mobilization depends on cytosolic Ca(2+) accumulation, arises from mitochondria and protein-bound pools, and is triggered by mechanisms that do not involve the generation of reactive oxygen species. Moreover, intracellular Zn(2+) rises resulting from AMPA receptor activation seem to be promoted by Ca(2+)-dependent cytosolic acidification. Addition of the cell-permeable Zn(2+) chelator TPEN significantly reduced mitochondrial membrane depolarization, reactive oxygen species production, and cell death by sub-maximal activation of AMPA receptors both in vitro and in situ, suggesting that Zn(2+) deregulation is an important mediator of oligodendrocyte excitotoxicity. These data provide evidence that strategies aimed at maintaining Zn(2+) homeostasis may be useful for the treatment of disorders in which excitotoxicity is an important trigger of oligodendroglial death.

Erythropoietin Protects Retinal Cells in Diabetic Rats Through Upregulating ZnT8 via Activating ERK Pathway and Inhibiting HIF-1α Expression

“…Therefore, ZnT8 reduction would cause intracellular zinc accumulation. Even though zinc plays a vital role in many biological processes, 58,59 elevated zinc ion is toxic to neurons, glia, and other cells, [60][61][62] and has been reported to result in the overproduction of reactive oxygen species, cell cycle arrest at G2/M phases, disrupted homeostasis of calcium in photoreceptors, and thus it induces cell death. 63 Hence, it is easy to believe that the reduced ZnT8 expression in the retinal cells under hypoxia could lead to overload of intracellular zinc, and then cell death.…”

Demyelination as a rational therapeutic target for ischemic or traumatic brain injury

“…Blockade of this receptor reduces oligodendrocyte death in vivo (Tekkok and Goldberg, 2001) and in vitro (McDonald et al, 1998). Recent work further suggests that Zn 2+ dysregulation is important in AMPA-induced excitotoxicity (Mato et al, 2013). The activation of AMPA receptors results in the cytosolic accumulation of Ca 2+ , which in turn induces Zn 2+ mobilization and accumulation in the cytosol (Mato et al, 2013).…”

“…Recent work further suggests that Zn 2+ dysregulation is important in AMPA-induced excitotoxicity (Mato et al, 2013). The activation of AMPA receptors results in the cytosolic accumulation of Ca 2+ , which in turn induces Zn 2+ mobilization and accumulation in the cytosol (Mato et al, 2013). Excessive Zn 2+ is known to activate ERK1/2 signal transduction cascades and induce oligodendrocyte death in a poly[ADP]-ribose polymerase 1 (PARP-1)-dependent manner (Baxter et al, 2014; Domercq et al, 2013).…”

White matter injury: Ischemic and nonischemic

“…Damage to WM as a consequence of hypoxic-ischemic injury occurs in lesions such as periventricular leukomalacia in the neonatal period, stroke and cardiac arrest in adults, as well as in vascular dementia in the aging brain (Matute et al, 2013). Damage to WM as a consequence of hypoxic-ischemic injury occurs in lesions such as periventricular leukomalacia in the neonatal period, stroke and cardiac arrest in adults, as well as in vascular dementia in the aging brain (Matute et al, 2013).…”