Quercetin's Effects on Glutamate Cytotoxicity

Abstract

The potentially therapeutic effects of the naturally abundant plant flavonoid quercetin have been extensively studied. An extensive body of literature suggests that quercetin's powerful antioxidant effects may relate to its ability to treat disease. Glutamate excitotoxicity occurs when a neuron is overstimulated by the neurotransmitter glutamate and causes dysregulation of intracellular calcium concentrations. Quercetin has been shown to be preventative against many forms of neuronal cell death resulting from glutamate excitotoxicity, such as oncosis, intrinsic apoptosis, mitochondrial permeability transition, ferroptosis, phagoptosis, lysosomal cell death, parthanatos, and death by reactive oxygen species (ROS)/reactive nitrogen species (RNS) generation. The clinical importance for the attenuation of glutamate excitotoxicity arises from the need to deter the continuous formation of tissue infarction caused by various neurological diseases, such as ischemic stroke, seizures, neurodegenerative diseases, and trauma. This review aims to summarize what is known concerning glutamate physiology and glutamate excitotoxic pathophysiology and provide further insight into quercetin's potential to hinder neuronal death caused by cell death pathways activated by glutamate excitotoxicity. Quercetin's bioavailability may limit its use clinically, however. Thus, future research into ways to increase its bioavailability are warranted.

Keywords: excitotoxicity; glutamate; reactive nitrogen species; reactive oxygen species.

Figure 1

Structure of Glutamate.

Figure 2

Diagram of the main effects of glutamate toxicity leading to the different forms of neuronal death. Abbreviations: NMDAR, NMDA receptor; AMPAR/KR, AMPA receptor/kainate receptor; x_c⁻, glutamate/cysteine antiporter; Ca²⁺, calcium; CytoC release, cytochrome c release; PARP-1, Poly [ADP-ribose] polymerase 1.

Figure 3

Structure of Quercetin.

Figure 4

Diagram of quercetin’s neuroprotective properties against calcium-induced apoptotic mechanisms and LMP that are activated during GE. Green arrows indicate activation, and red arrows indicate inhibition. Abbreviations: Glu, glutamate; NMDAR, NMDA receptor; AMPAR, AMPA receptor; KR, kainate receptor; Ca²⁺, calcium; Qu, quercetin; CytoC, cytochrome c; Apaf-1, apoptotic protease activating factor 1; BH3, BH3-only proteins, MMP, mitochondrial membrane permeabilization; LMP/LCD, lysosomal membrane permeabilization/lysosomal cell death.

Figure 5

Diagram of quercetin’s neuroprotective properties against oxidative damage from ROS/RNS, ferroptosis, and mitochondrial membrane permeabilization that occurs during GE. Green arrows indicate activation, and red arrows indicate inhibition. Abbreviations: Glu, glutamate; NMDAR, NMDA receptor; AMPAR, AMPA receptor; KR, kainate receptor; Qu, quercetin; CytoC, cytochrome c; MMP, mitochondrial membrane permeabilization; MPTP, mitochondrial permeability transition pores; ROS, reactive oxygen species; NO, nitric oxide; SOD1/2, superoxide dismutase 1 or 2; CAT, catalase; HO-1, heme oxidase 1; NQO1, NADPH dehydrogenase quinone-1; Nrf2, nuclear factor erythroid 2-related factor 2; FR, Fenton Reaction; Xc⁻; cystine/glutamate exchanger; Cys, cysteine; GSH, glutathione; GPX4, glutathione peroxidase 4; ATP, adenosine triphosphate.

Figure 6

Diagram of quercetin’s neuroprotective properties against parthanatos and phagoptosis, which are activated during GE. Green arrows indicate activation, and red arrows indicate inhibition. Abbreviations: Glu, glutamate; NMDAR, NMDA receptor; AMPAR, AMPA receptor; KR, kainate receptor; Ca²⁺, calcium; Qu, quercetin; NO, nitric oxide; PS, phosphatidylserine; PARP-1, Poly [ADP-ribose] polymerase 1.