Quercetin ameliorates glutamate toxicity-induced neuronal cell death by controlling calcium-binding protein parvalbumin

다국어 초록 (Multilingual Abstract)

Background: Glutamate is the main excitatory neurotransmitter. Excessive glutamate causes excitatory toxicity and increases intracellular calcium, leading to neuronal death. Parvalbumin is a calcium-binding protein that regulates calcium homeostasis. Quercetin is a polyphenol found in plant and has neuroprotective effects against neurodegenerative diseases.
Objectives: We investigated whether quercetin regulates apoptosis by modulating parvalbumin expression in glutamate induced neuronal damage.
Methods: Glutamate was treated in hippocampal-derived cell line, and quercetin or vehicle was treated 1 h before glutamate exposure. Cells were collected for experimental procedure 24 h after glutamate treatment and intracellular calcium concentration and parvalbumin expression were examined. Parvalbumin small interfering RNA (siRNA) transfection was performed to detect the relation between parvalbumin and apoptosis.
Results: Glutamate reduced cell viability and increased intracellular calcium concentration, while quercetin preserved calcium concentration and neuronal damage. Moreover, glutamate reduced parvalbumin expression and quercetin alleviated this reduction. Glutamate increased caspase-3 expression, and quercetin attenuated this increase in both parvalbumin siRNA transfected and non-transfected cells. The alleviative effect of quercetin was statistically significant in non-transfected cells. Moreover, glutamate decreased bcl-2 and increased bax expressions, while quercetin alleviated these changes. The alleviative effect of quercetin in bcl-2 family protein expression was more remarkable in non-transfected cells.
Conclusions: These results demonstrate that parvalbumin contributes to the maintainace of intracellular calcium concentration and the prevention of apoptosis, and quercetin modulates parvalbumin expression in glutamate-exposed cells. Thus, these findings suggest that quercetin performs neuroprotective function against glutamate toxicity by regulating parvalbumin expression.

참고문헌 (Reference)

1 Chen S, "Therapeutic effects of quercetin on inflammation, obesity, and type 2diabetes" 2016 : 9340637-, 2016

2 Takeuchi A, "The transmitter role of glutamate in nervous systems" 37 (37): 559-572, 1987

3 Maher P, "The role of monoamine metabolism in oxidative glutamate toxicity" 16 (16): 6394-6401, 1996

4 Smaili SS, "The role of calcium stores in apoptosis and autophagy" 13 (13): 252-265, 2013

5 Reyes-Farias M, "The anti-cancer effect of quercetin : molecular implications in cancer metabolism" 20 (20): 3177-, 2019

6 Schiavone S, "The NADPH oxidase NOX2 mediates loss of parvalbumin interneurons in traumatic brain injury : human autoptic immunohistochemical evidence" 7 (7): 8752-, 2017

7 Wu XJ, "Systematic investigation of quercetin for treating cardiovascular disease based on network pharmacology" 22 (22): 411-420, 2019

8 Zhang Z, "Roles of glutamate receptors in Parkinson's disease" 20 (20): 4391-, 2019

9 Deng W, "Role of metabotropic glutamate receptors in oligodendrocyte excitotoxicity and oxidative stress" 101 (101): 7751-7756, 2004

10 Park DJ, "Quercetin reduces ischemic brain injury by preventing ischemiainduced decreases in the neuronal calcium sensor protein hippocalcin" 430 : 47-62, 2020

11 Du G, "Quercetin protects rat cortical neurons against traumatic brain injury" 17 (17): 7859-7865, 2018

12 박동주 ; 강주빈 ; 파와드알리샤 ; 고필옥, "Quercetin attenuates the reduction of parvalbumin in middle cerebral artery occlusion animal model" 한국실험동물학회 37 (37): 74-81, 2021

13 Park DJ, "Quercetin attenuates neuronal cells damage in a middle cerebral artery occlusion animal model" 80 (80): 676-683, 2018

14 Yang EJ, "Protective effects of onion-derived quercetin on glutamate-mediated hippocampal neuronal cell death" 9 (9): 302-308, 2013

15 Sakanashi Y, "Possible use of quercetin, an antioxidant, for protection of cells suffering from overload of intracellular Ca2+ : a model experiment" 83 (83): 164-169, 2008

16 Kao JP, "Photochemically generated cytosolic calcium pulses and their detection by fluo-3" 264 (264): 8179-8184, 1989

17 Heizmann CW, "Parvalbumin, an intracellular calcium-binding protein; distribution, properties and possible roles in mammalian cells" 40 (40): 910-921, 1984

18 Ruden JB, "Parvalbumin interneuron vulnerability and brain disorders" 46 (46): 279-287, 2021

19 Gupta K, "NMDA receptor-dependent glutamate excitotoxicity in human embryonic stem cell-derived neurons" 543 : 95-100, 2013

20 Lugon MD, "Mechanisms of nicotinic modulation of glutamatergic neuroplasticity in humans" 27 (27): 544-553, 2017

21 Fukui M, "Mechanism of glutamate-induced neurotoxicity in HT22mouse hippocampal cells" 617 (617): 1-11, 2009

22 Koh PO, "Ischemic injury decreases parvalbumin expression in a middle cerebral artery occlusion animal model and glutamate-exposed HT22 cells" 512 (512): 17-21, 2012

23 Sanderson TH, "Insulin blocks cytochrome c release in the reperfused brain through PI3-K signaling and by promoting Bax/Bcl-XL binding" 106 (106): 1248-1258, 2008

24 Liu X, "Induction of apoptotic program in cell-free extracts : requirement for dATP and cytochrome c" 86 (86): 147-157, 1996

25 Stout AK, "Glutamate-induced neuron death requires mitochondrial calcium uptake" 1 (1): 366-373, 1998

26 Hu NW, "Glutamate receptors in preclinical research on Alzheimer's disease : update on recent advances" 100 (100): 855-862, 2012

27 Peng S, "Glutamate receptors and signal transduction in learning and memory" 38 (38): 453-460, 2011

28 Choi DW, "Glutamate neurotoxicity in cortical cell culture is calcium dependent" 58 (58): 293-297, 1985

29 Rueda CB, "Glutamate excitotoxicity and Ca2+-regulation of respiration : Role of the Ca2+ activated mitochondrial transporters(CaMCs)" 1857 (1857): 1158-1166, 2016

30 Zhou Y, "Glutamate as a neurotransmitter in the healthy brain" 121 (121): 799-817, 2014

31 Girard F, "Gene expression analysis in the parvalbuminimmunoreactive PV1 nucleus of the mouse lateral hypothalamus" 34 (34): 1934-1943, 2011

32 Oyama Y, "Flow-cytometric estimation on glutamate-and kainateinduced increases in intracellular Ca2+ of brain neurons : a technical aspect" 728 (728): 121-124, 1996

33 Havsteen B, "Flavonoids, a class of natural products of high pharmacological potency" 32 (32): 1141-1148, 1983

34 Berridge MJ, "Dysregulation of neural calcium signaling in Alzheimer disease, bipolar disorder and schizophrenia" 7 (7): 2-13, 2013

35 Baimbridge KG, "Calcium-binding proteins in the nervous system" 15 (15): 303-308, 1992

36 Szydlowska K, "Calcium, ischemia and excitotoxicity" 47 (47): 122-129, 2010

37 Marambaud P, "Calcium signaling in neurodegeneration" 4 (4): 20-, 2009

38 Hockenbery D, "Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death" 348 (348): 334-336, 1990

39 Oltval ZN, "Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programed cell death" 74 (74): 609-619, 1993

40 Annunziato L, "Apoptosis induced in neuronal cells by oxidative stress : role played by caspases and intracellular calcium ions" 139 (139): 125-133, 2003

41 Arif SH, "A Ca(2+)-binding protein with numerous roles and uses : parvalbumin in molecular biology and physiology" 31 (31): 410-421, 2009