Abstract
Memory impairment has been shown to be associated with glutamate (Glu) excitotoxicity, homocysteine (Hcy) accumulation, and oxidative stress. We hypothesize that Glu and Hcy could damage neuronal cells, while astaxanthin (ATX) could be beneficial to alleviate the adverse effects. Using PC12 cell model, we showed that Glu and Hcy provoked a huge amount of reactive oxygen species (ROS) production, causing mitochondrial damage at EC50 20 and 10 mm, respectively. The mechanisms of action include: (1) increasing calcium influx; (2) producing ROS; (3) initiating lipid peroxidation; (4) causing imbalance of the Bcl-2/Bax homeostasis; and (5) activating cascade of caspases involving caspases 12 and 3. Conclusively, the damages caused by Glu and Hcy to PC12 cells can be alleviated by the potent antioxidant ATX.
Highlights
Glutamate is the most well-known excitatory neurotransmitter, occurring in over 50% of nervous tissues [1]; it is involved in the process of learning, cognition, and neurodegeneration [2]
PC12 cells were found to be more susceptible to Hcy than Glu, with susceptibilities of 3.4%/mM and 1.3%/mM, respectively, at 48 h of incubation (Figure 1c,d)
-overload can lead to increased generation of oxygen inducing the opening of the mitochondrial permeability transition pore and causing neuronal reactive f reactiveoxygen oxygen species(ROS)
Summary
Glutamate is the most well-known excitatory neurotransmitter, occurring in over 50% of nervous tissues [1]; it is involved in the process of learning, cognition, and neurodegeneration [2]. Excess extracellular glutamate level could induce brain lesions, neuronal death, and other pathological changes in several organs associated with endocrine function; this pathway is called excitotoxicity, which was coined by Olney (1969) [4]. During the development process for Alzheimer’s disease (AD), excessive activated extracellular glutamate receptors prompt changes in ion channels and signaling systems [5,6,7]. Hcy induced calcium influx, depolarization of mitochondrial membrane potential, and changes of Bcl-2 and Bcl-xL in the PC12 cell model [15]. We hypothesize that Glu and Hcy may cooperatively attack the glutamate receptor; whether ATX can effectively issue its protective effect against the neurotoxicity induced by cotreatment with these two ligands is still unclear.
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