In the central nervous system, glutamate is a major excitable neurotransmitter responsible for many cellular functions. However, excessive levels of glutamate induce neuronal cell death via oxidative stress during acute brain injuries as well as chronic neurodegenerative diseases. The present study was conducted to examine the effect of tetrahydrocurcumin (THC), a major secondary metabolite of curcumin, and its possible mechanism against glutamate-induced cell death. We prepared THC using curcumin isolated from Curcuma longa (turmeric) and demonstrated the protective effect of THC against glutamate-induced oxidative stress in HT22 cells. THC abrogated glutamate-induced HT22 cell death and showed a strong antioxidant effect. THC also significantly reduced intracellular calcium ion increased by glutamate. Additionally, THC significantly reduced the accumulation of intracellular oxidative stress induced by glutamate. Furthermore, THC significantly diminished apoptotic cell death indicated by annexin V-positive in HT22 cells. Western blot analysis indicated that the phosphorylation of mitogen-activated protein kinases including c-Jun N-terminal kinase, extracellular signal-related kinases 1/2, and p38 by glutamate was significantly diminished by treatment with THC. In conclusion, THC is a potent neuroprotectant against glutamate-induced neuronal cell death by inhibiting the accumulation of oxidative stress and phosphorylation of mitogen-activated protein kinases.Molecules 2020, 25, 144 2 of 10 neurodegenerative diseases [3,4]. Earlier studies showed that an excessive release of glutamate in the extracellular region provoked the accumulation of intracellular ROS by depletion of intracellular glutathione levels through blocking cysteine uptake [5]. The presence of an antioxidant, such as flavonoids or N-acetylcysteine, strongly prevented ROS-induced neuronal cell death [6,7].The use of natural antioxidants for scavenging free radicals and maintaining homeostasis contributes to alleviating neuronal dysfunction [8]. Typically, natural compounds are multiple-target molecules found mainly in microorganisms and plants and exhibit strong antioxidant activity [8,9]. Phenolic compounds from natural sources also exhibit various beneficial effects in cancer, inflammation, and neurodegenerative disorders [9]. This broad spectrum of biological or pharmacological activities has made phytochemicals suitable candidates for treating multifactorial diseases, such as neurodegenerative diseases [10,11]. However, there are also several concerns regarding their poor bioavailability, stability and safety, which must be resolved before effective therapeutics can be developed.Mitogen-activated protein kinases (MAPKs), known as a family of serine/threonine protein kinases, are well-identified biological molecules involved in glutamate-induced oxidative neuronal cell death. MAPKs are related to multiple cellular functions including differentiation, proliferation, cell survival, inflammation, and cell death [12]. The presence of excessive glutam...