Astaxanthin Counteracts Excitotoxicity and Reduces the Ensuing Increases in Calcium Levels and Mitochondrial Reactive Oxygen Species Generation

Abstract

Astaxanthin (ASX) is a carotenoid pigment with strong antioxidant properties. We have reported previously that ASX protects neurons from the noxious effects of amyloid-β peptide oligomers, which promote excessive mitochondrial reactive oxygen species (mROS) production and induce a sustained increase in cytoplasmic Ca2+ concentration. These properties make ASX a promising therapeutic agent against pathological conditions that entail oxidative and Ca2+ dysregulation. Here, we studied whether ASX protects neurons from N-methyl-D-aspartate (NMDA)-induced excitotoxicity, a noxious process which decreases cellular viability, alters gene expression and promotes excessive mROS production. Incubation of the neuronal cell line SH-SY5Y with NMDA decreased cellular viability and increased mitochondrial superoxide production; pre-incubation with ASX prevented these effects. Additionally, incubation of SH-SY5Y cells with ASX effectively reduced the basal mROS production and prevented hydrogen peroxide-induced cell death. In primary hippocampal neurons, transfected with a genetically encoded cytoplasmic Ca2+ sensor, ASX also prevented the increase in intracellular Ca2+ concentration induced by NMDA. We suggest that, by preventing the noxious mROS and Ca2+ increases that occur under excitotoxic conditions, ASX could be useful as a therapeutic agent in neurodegenerative pathologies that involve alterations in Ca2+ homeostasis and ROS generation.

Ginsenoside Rg1 attenuates cerebral ischemia-reperfusion injury due to inhibition of NOX2-mediated calcium homeostasis dysregulation in mice

“…It was reported that excessive mitochondrial ROS could induce a sustained increase of [Ca 2+ ] i . And antioxidants could prevent the increase of [Ca 2+ ] i and attenuated NMDA-induced neuronal damage [ 43 ]. Moreover, oxidative stress is also reported to lead to an increase of [Ca 2+ ] i released from the endoplasmic reticulum (ER) [ 44 ].…”

Astaxanthin as a Novel Mitochondrial Regulator: A New Aspect of Carotenoids, beyond Antioxidants

“…Oxidative stress disturbs intracellular Ca 2+ homeostasis, resulting in excessive Ca 2+ efflux from the endoplasmic reticulum and an influx into mitochondria, which subsequently triggers mitochondrial membrane permeabilization, loss of mitochondrial membrane potential, and the release of mitochondrial pro-apoptotic factors [ 81 ]. It has been widely reported that AX prevents the ROS-induced Ca 2+ influx into mitochondria, protects against mitochondrial dysfunction, and inhibits apoptosis [ 82 , 83 , 84 , 85 , 86 , 87 , 88 ]. The role of AX in modulating mitochondrial-mediated activation of apoptosis is beyond the scope of this review.…”

“…The receptors of adiponectin are AdipoR1 and AdipoR2, which are expressed at different levels in different tissues, and are involved in the regulation of glucose and fatty acid metabolism, mainly through the activation of Ca 2+ signaling, AMPK/SIRT1, and PPARα signaling pathways [ 165 ]. It has been reported that AX has an inhibitory effect on Ca 2+ signaling, which is mainly involved in ROS [ 83 , 85 , 86 , 87 , 88 ], but its effect on Ca 2+ /calmodulin-dependent protein kinase β (CaMKKβ), which is involved in the activation of AMPK [ 166 ] is still unknown. Thus, to summarize what is currently known, oxidative stress decreases the amount of adiponectin and its receptors.…”

Misfolded protein oligomers induce an increase of intracellular Ca2+ causing an escalation of reactive oxidative species

“…This interaction results in the disruption of cell membranes, compromising its ability to maintain cellular homeostasis, and promoting two important early biochemical changes. The first is the uncontrolled increase in cytosolic calcium (Ca 2+ ) levels flowing from the extracellular space into the cytosol [7][8][9][10][11][12][13][14], and the second is the accumulation of reactive oxygen species (ROS) [10,11,15,16].…”

“…Other Ca 2+ channels that seem to be involved in the Aβ-induced flux of Ca 2+ ions are the transient receptor potential melastatin 2 (TRPM2) [23], the voltage-dependent Ca 2+ channels (VDCCs) [24], and the transient receptor potential A1 (TRPA1) [25]. Another relevant early biochemical change resulting from the interaction of Aβ oligomers with cell membranes is oxidative stress, which is associated with the accumulation of ROS in the cytosol [10,11,15,16] and represents an important determinant in AD pathogenesis [26,27]. The elevation of ROS is caused by the activation of the oxidative metabolism to respond to the intracellular Ca 2+ increase induced by the oligomers and the consequent increased need for ATP by the Ca 2+ pumps, that try to restore the normal levels of intracellular Ca 2+ [10,28].…”