Mild Hyperhomocysteinemia Causes Anxiety-like Behavior and Brain Hyperactivity in Rodents: Are ATPase and Excitotoxicity by NMDA Receptor Overstimulation Involved in this Effect?
Animals
Anxiety
Brain
/ metabolism
Dizocilpine Maleate
/ pharmacology
Glutamate-Ammonia Ligase
/ metabolism
Glutamic Acid
/ metabolism
Homocysteine
Hyperhomocysteinemia
/ complications
Male
Rats
Rats, Wistar
Receptors, N-Methyl-D-Aspartate
/ metabolism
Rodentia
/ metabolism
Sodium-Potassium-Exchanging ATPase
/ metabolism
Sucrose
/ metabolism
Anxiety disorders
Cell survival
Glutamate homeostasis
Mild hyperhomocysteinemia
N-Methyl-D-Aspartate
Receptors
Sodium–Potassium-exchanging ATPase
Journal
Cellular and molecular neurobiology
ISSN: 1573-6830
Titre abrégé: Cell Mol Neurobiol
Pays: United States
ID NLM: 8200709
Informations de publication
Date de publication:
Nov 2022
Nov 2022
Historique:
received:
07
10
2020
accepted:
18
07
2021
pubmed:
30
7
2021
medline:
18
10
2022
entrez:
29
7
2021
Statut:
ppublish
Résumé
Mild hyperhomocysteinemia is a risk factor for psychiatric and neurodegenerative diseases, whose mechanisms between them are not well-known. In the present study, we evaluated the emotional behavior and neurochemical pathways (ATPases, glutamate homeostasis, and cell viability) in amygdala and prefrontal cortex rats subjected to mild hyperhomocysteinemia (in vivo studies). The ex vivo effect of homocysteine on ATPases and redox status, as well as on NMDAR antagonism by MK-801 in same structures slices were also performed. Wistar male rats received a subcutaneous injection of 0.03 µmol Homocysteine/g of body weight or saline, twice a day from 30 to 60th-67th days of life. Hyperhomocysteinemia increased anxiety-like behavior and tended to alter locomotion/exploration of rats, whereas sucrose preference and forced swimming tests were not altered. Glutamate uptake was not changed, but the activities of glutamine synthetase and ATPases were increased. Cell viability was not altered. Ex vivo studies (slices) showed that homocysteine altered ATPases and redox status and that MK801, an NMDAR antagonist, protected amygdala (partially) and prefrontal cortex (totally) effects. Taken together, data showed that mild hyperhomocysteinemia impairs the emotional behavior, which may be associated with changes in ATPase and glutamate homeostasis, including glutamine synthetase and NMDAR overstimulation that could lead to excitotoxicity. These findings may be associated with the homocysteine risk factor on psychiatric disorders development and neurodegeneration.
Identifiants
pubmed: 34324129
doi: 10.1007/s10571-021-01132-0
pii: 10.1007/s10571-021-01132-0
doi:
Substances chimiques
Receptors, N-Methyl-D-Aspartate
0
Homocysteine
0LVT1QZ0BA
Glutamic Acid
3KX376GY7L
Sucrose
57-50-1
Dizocilpine Maleate
6LR8C1B66Q
Glutamate-Ammonia Ligase
EC 6.3.1.2
Sodium-Potassium-Exchanging ATPase
EC 7.2.2.13
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2697-2714Subventions
Organisme : Conselho Nacional de Desenvolvimento Científico e Tecnológico
ID : Edital Universal (Proc. 401507/2016)
Organisme : Conselho Nacional de Desenvolvimento Científico e Tecnológico
ID : INCT (EN 465671/2014-4)
Organisme : Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul
ID : PRONEX (16/2551-0000465-0)
Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Références
Arteni NS, Pereira LO, Rodrigues AL et al (2010) Lateralized and sex-dependent behavioral and morphological effects of unilateral neonatal cerebral hypoxia-ischemia in the rat. Behav Brain Res 210:92–98. https://doi.org/10.1016/j.bbr.2010.02.015
doi: 10.1016/j.bbr.2010.02.015
pubmed: 20156487
Bailey KR, Crawley JN (2009) Anxiety-Related Behaviors in Mice. In: Buccafusco JJ (ed) Methods of Behavior Analysis in Neuroscience., 2nd edition. Boca Raton (FL): CRC Press/Taylor & Francis, Boca Raton (FL)
Baird L, Dinkova-Kostova AT (2011) The cytoprotective role of the Keap1-Nrf2 pathway. Arch Toxicol 85:241–272. https://doi.org/10.1007/s00204-011-0674-5
doi: 10.1007/s00204-011-0674-5
pubmed: 21365312
Bandelow B, Michaelis S (2015) Epidemiology of anxiety disorders in the 21st century. Dialogues Clin Neurosci 17:327–335
doi: 10.31887/DCNS.2015.17.3/bbandelow
Belleau EL, Pedersen WS, Miskovich TA et al (2018) Cortico-limbic connectivity changes following fear extinction and relationships with trait anxiety. Soc Cogn Affect Neurosci 13:1037–1046. https://doi.org/10.1093/scan/nsy073
doi: 10.1093/scan/nsy073
pubmed: 30137604
pmcid: 6204483
Bhatia P, Singh N (2015) Homocysteine excess: Delineating the possible mechanism of neurotoxicity and depression. Fundam Clin Pharmacol 29:522–528. https://doi.org/10.1111/fcp.12145
doi: 10.1111/fcp.12145
pubmed: 26376956
Blanke ML, Vandongen AMJ (2009) Activation Mecanisms of the NMDA Receptor. In: Van Dongen A (ed) Biology of the NMDA Receptor. CRC Press/Taylor & Francis, Boca Raton (FL), pp 1–24
Boldyrev AA (2005) Homocysteinic acid causes oxidative stress in lymphocytes by potentiating toxic effect of NMDA. Bull Exp Biol Med 140:33–37. https://doi.org/10.1007/s10517-005-0404-1
doi: 10.1007/s10517-005-0404-1
pubmed: 16254614
Bradford M (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254
doi: 10.1016/0003-2697(76)90527-3
Browne RW, Armstrong D (1998) Reduced glutathione and glutathione disulfide. Methods Mol Biol 108:347–352
pubmed: 9921543
Carageorgiou H, Sideris AC, Messari I et al (2008) The effects of rivastigmine plus selegiline on brain acetylcholinesterase, (Na+, K+)-, Mg2+- ATPase activities, antioxidant status, and learning performance of aged rats. Neuropsychiatr Dis Treat 4:687–699
doi: 10.2147/NDT.S3272
Chan K, Delfert D, Junger K (1986) A direct colorimetric assay for Ca2+-stimulated ATPase activity. Anal Biochem 157:375–380
doi: 10.1016/0003-2697(86)90640-8
Choudhury S, Borah A (2015) Activation of NMDA receptor by elevated homocysteine in chronic liver disease contributes to encephalopathy. Med Hypotheses 85:64–67. https://doi.org/10.1016/j.mehy.2015.03.027
doi: 10.1016/j.mehy.2015.03.027
pubmed: 25881985
Chung K, Chiou H, Chen Y (2017) Associations between serum homocysteine levels and anxiety and depression among children and adolescents in Taiwan. Sci Rep. https://doi.org/10.1038/s41598-017-08568-9
doi: 10.1038/s41598-017-08568-9
pubmed: 29255146
pmcid: 5735100
Clarke R (2011) Homocysteine, B vitamins, and the risk of cardiovascular disease. Clin Chem 57:1201–1202. https://doi.org/10.1373/clinchem.2011.164855
doi: 10.1373/clinchem.2011.164855
pubmed: 21666070
Crema L, Schlabitz M, Tagliari B et al (2010) Na+, K+-ATPase activity is reduced in Amygdala of rats with chronic stress-induced anxiety-like behavior. Neurochem Res 35:1787–1795. https://doi.org/10.1007/s11064-010-0245-9
doi: 10.1007/s11064-010-0245-9
pubmed: 20717721
da Silva FF, de Ferreira AP, O, Ribeiro LR, et al (2016) The impact of previous physical training on redox signaling after traumatic brain injury in rats: A behavioral and neurochemical approach. J Neurotrauma 33:1317–1330. https://doi.org/10.1089/neu.2015.4068
doi: 10.1089/neu.2015.4068
pubmed: 26651029
de Arnaiz GR, L, Ordieres MGL, (2014) Brain Na+, K+-ATPase activity in aging and disease. Int J Biomed Sci 10:85–102
de Wyse AT, S, Streck EL, Worm P, et al (2000) Preconditioning prevents the inhibition of NA+, K+-ATPase activity after brain ischemia. Neurochem Res 25:971–975. https://doi.org/10.1023/A:1007504525301
doi: 10.1023/A:1007504525301
Diehl LA, Pereira NDSC, Laureano DP et al (2014) Contextual fear conditioning in maternal separated rats: The amygdala as a site for alterations. Neurochem Res 39:384–393. https://doi.org/10.1007/s11064-013-1230-x
doi: 10.1007/s11064-013-1230-x
pubmed: 24368626
dos Santos AQ, Nardin P, Funchal C et al (2006) Resveratrol increases glutamate uptake and glutamine synthetase activity in C6 glioma cells. Arch Biochem Biophys 453:161–167. https://doi.org/10.1016/j.abb.2006.06.025
doi: 10.1016/j.abb.2006.06.025
pubmed: 16904623
dos Santos TM, Siebert C, Federizzi M et al (2019) Chronic mild Hyperhomocysteinemia impairs energy metabolism, promotes DNA damage and induces a Nrf2 response to oxidative stress in rats brain. Cell Mol Neurobiol. https://doi.org/10.1007/s10571-019-00674-8
doi: 10.1007/s10571-019-00674-8
pubmed: 30949917
dos Santos TM, Kolling J, Siebert C et al (2017) Effects of previous physical exercise to chronic stress on long-term aversive memory and oxidative stress in amygdala and hippocampus of rats. Int J Dev Neurosci 56:58–67. https://doi.org/10.1016/j.ijdevneu.2016.12.003
doi: 10.1016/j.ijdevneu.2016.12.003
pubmed: 28039090
Esnafoglu E, Yaman E (2017) Vitamin B12, folic acid, homocysteine and vitamin D levels in children and adolescents with obsessive compulsive disorder. Psychiatry Res 254:232–237. https://doi.org/10.1016/j.psychres.2017.04.032
doi: 10.1016/j.psychres.2017.04.032
pubmed: 28477545
Finkelstein JD (2007) Metabolic regulatory properties of S-adenosylmethionine and S-adenosylhomocysteine. Clin Chem Lab Med 45:1694–1699. https://doi.org/10.1515/CCLM.2007.341
doi: 10.1515/CCLM.2007.341
pubmed: 17963455
Foo K, Blumenthal L, Man HY (2012) Regulation of neuronal bioenergy homeostasis by glutamate. Neurochem Int 61:389–396. https://doi.org/10.1016/j.neuint.2012.06.003
doi: 10.1016/j.neuint.2012.06.003
pubmed: 22709672
pmcid: 3430810
Ganapathy PS, White RE, Ha Y et al (2011) The role of N-methyl-D-aspartate receptor activation in homocysteine-induced death of retinal ganglion cells. Investig Ophthalmol vis Sci 52:5515–5524. https://doi.org/10.1167/iovs.10-6870
doi: 10.1167/iovs.10-6870
Green LC, Wagner DA, Glogowski J et al (1982) Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids. Anal Biochem 126:131–138. https://doi.org/10.1016/0003-2697(82)90118-X
doi: 10.1016/0003-2697(82)90118-X
pubmed: 7181105
Grigor’yan GA, Gulyaeva N V, (2017) Modeling depression in animals : Behavior as the basis for the methodology, assessment criteria, and classification. Neurosci Behav Physiol 47:204–216. https://doi.org/10.1007/s11055-016-0386-7
doi: 10.1007/s11055-016-0386-7
Ikeda K, Onaka T, Yamakado M et al (2003) Degeneration of the amygdala/piriform cortex and enhanced fear/anxiety behaviors in sodium pump alpha2 subunit (Atp1a2)-deficient mice. J Neurosci 23:4667–4676
doi: 10.1523/JNEUROSCI.23-11-04667.2003
Izquierdo I, Furini CRG, Myskiw JC (2016) Fear memory. Physiol Rev 96:695–750. https://doi.org/10.1152/physrev.00018.2015
doi: 10.1152/physrev.00018.2015
pubmed: 26983799
Jendricko T, Andelko V, Grubisic-llic M et al (2009) Progress in Neuro-Psychopharmacology & Biological Psychiatry Homocysteine and serum lipids concentration in male war veterans with posttraumatic stress disorder. Prog Neuro-Psychopharmacology Biol Psychiatry 33(33):134–140. https://doi.org/10.1016/j.pnpbp.2008.11.002
doi: 10.1016/j.pnpbp.2008.11.002
John CS, Sypek EI, Carlezon WA et al (2015) Blockade of the GLT-1 transporter in the central nucleus of the amygdala induces both anxiety and depressive-like symptoms. Neuropsychopharmacol 40:1700–1708. https://doi.org/10.1038/npp.2015.16
doi: 10.1038/npp.2015.16
Kim HK, Nunes PV, Oliveira KC et al (2016) Neuropathological relationship between major depression and dementia: A hypothetical model and review. Prog Neuro-Psychopharmacology Biol Psychiatry 67:51–57. https://doi.org/10.1016/j.pnpbp.2016.01.008
doi: 10.1016/j.pnpbp.2016.01.008
Kim MJ, Loucks R, a, Palmer AL, et al (2011) The structural and functional connectivity of the amygdala: From normal emotion to pathological anxiety. Behav Brain Res 223:403–410. https://doi.org/10.1016/j.bbr.2011.04.025
doi: 10.1016/j.bbr.2011.04.025
pubmed: 21536077
pmcid: 3119771
Kinoshita PF, Leite JA, Orellana AMM et al (2016) The influence of Na+, K+-ATPase on glutamate signaling in neurodegenerative diseases and senescence. Front Physiol 7:1–19. https://doi.org/10.3389/fphys.2016.00195
doi: 10.3389/fphys.2016.00195
Kumagai A, Sasaki T, Matsuoka K et al (2019) Monitoring of glutamate-induced excitotoxicity by mitochondrial oxygen consumption. Synapse 73:e22067. https://doi.org/10.1002/syn.22067
doi: 10.1002/syn.22067
pubmed: 30120794
Kumar A, Palfrey HA, Pathak R et al (2017) The metabolism and significance of homocysteine in nutrition and health. Nutr Metab 14:1–12. https://doi.org/10.1186/s12986-017-0233-z
doi: 10.1186/s12986-017-0233-z
Lavinsky D, Arteni NS, Netto CA (2003) Agmatine induces anxiolysis in the elevated plus maze task in adult rats. Behav Brain Res 141:19–24. https://doi.org/10.1016/s0166-4328(02)00326-1
doi: 10.1016/s0166-4328(02)00326-1
pubmed: 12672555
Lebel CP, Ischiropoulos H (1992) Bondys SC (1992) Evaluation of the probe 2‘,7‘-dichiorofluorescin as an indicator of reactive oxygen species formation and oxidative stress. Chem Res Toxicol 5:227–231
doi: 10.1021/tx00026a012
Lewerenz J, Maher P, Maher P (2015) Chronic glutamate toxicity in neurodegenerative diseases — what is the evidence? Front Neurosci 9:1–20. https://doi.org/10.3389/fnins.2015.00469
doi: 10.3389/fnins.2015.00469
Li PA, Hou X, Hao S (2017) Mitochondrial biogenesis in neurodegeneration. J Neurosci Res 95:2025–2029. https://doi.org/10.1002/jnr.24042
doi: 10.1002/jnr.24042
pubmed: 28301064
Liu YY, Zhou XY, Yang LN et al (2017) Social defeat stress causes depression-like behavior with metabolite changes in the prefrontal cortex of rats. PLoS ONE 12:1–16. https://doi.org/10.1371/journal.pone.0176725
doi: 10.1371/journal.pone.0176725
Longoni A, Bellaver B, Bobermin LD et al (2017) Homocysteine induces glial reactivity in adult rat astrocyte cultures. Mol Neurobiol 55:1966–1976. https://doi.org/10.1007/s12035-017-0463-0
doi: 10.1007/s12035-017-0463-0
pubmed: 28255907
Lowry O, Rosebrough N, Farr A, Randall R (1951) Protein measurement with the Folin phenol reagent. Readings 193:265–275. https://doi.org/10.1016/0304-3894(92)87011-4
doi: 10.1016/0304-3894(92)87011-4
Maguire ME (1988) Magnesium and Cell Proliferation. Ann New York Acad Sci 551:201–217
doi: 10.1111/j.1749-6632.1988.tb22338.x
Mandaviya PR, Stolk L, Heil SG (2014) Homocysteine and DNA methylation : A review of animal and human literature. Mol Genet Metab 113:243–252. https://doi.org/10.1016/j.ymgme.2014.10.006
doi: 10.1016/j.ymgme.2014.10.006
pubmed: 25456744
Marek R, Strobel C, Bredy TW, Sah P (2013) The amygdala and medial prefrontal cortex: Partners in the fear circuit. J Physiol 591:2381–2391. https://doi.org/10.1113/jphysiol.2012.248575
doi: 10.1113/jphysiol.2012.248575
pubmed: 23420655
pmcid: 3678031
Marklund S (1985) Pyrogallol autoxidation. In: Greenwald RA (ed) Handbook of methods for oxygen radical research, 4th edn. CRC Press, Boca Raton
Marsden WN (2011) Stressor-induced NMDAR dysfunction as a unifying hypothesis for the aetiology, pathogenesis and comorbidity of clinical depression. Med Hypotheses 77:508–528. https://doi.org/10.1016/j.mehy.2011.06.021
doi: 10.1016/j.mehy.2011.06.021
pubmed: 21741771
Matté C, Mussulini BHMBHM, dos Santos TMTM et al (2010) Hyperhomocysteinemia reduces glutamate uptake in parietal cortex of rats. Int J Dev Neurosci 28:183–187. https://doi.org/10.1016/j.ijdevneu.2009.11.004
doi: 10.1016/j.ijdevneu.2009.11.004
pubmed: 19913086
McCully KS (2015) Homocysteine metabolism, atherosclerosis, and diseases of aging. Compr Physiol 6:471–505. https://doi.org/10.1002/cphy.c150021
doi: 10.1002/cphy.c150021
pubmed: 26756640
McEwen BS, Eiland L, Hunter RG, Miller MM (2012) Stress and anxiety: Structural plasticity and epigenetic regulation as a consequence of stress. Neuropharmacology 62:3–12. https://doi.org/10.1016/j.neuropharm.2011.07.014
doi: 10.1016/j.neuropharm.2011.07.014
pubmed: 21807003
Minagawa H, Watanabe A, Akatsu H et al (2010) Homocysteine, another risk factor for alzheimer disease, impairs apolipoprotein E3 function. J Biol Chem 285:38382–38388. https://doi.org/10.1074/jbc.M110.146258
doi: 10.1074/jbc.M110.146258
pubmed: 20889503
pmcid: 2992271
Moseley AE, Williams MT, Schaefer TL et al (2007) Deficiency in Na+, K+-ATPase alpha isoform genes alters spatial learning, motor activity, and anxiety in mice. J Neurosci 27:616–626. https://doi.org/10.1523/JNEUROSCI.4464-06.2007
doi: 10.1523/JNEUROSCI.4464-06.2007
pubmed: 17234593
pmcid: 6672804
Mosmann T (1983) Rapid Colorimetric Assay for Cellular Growth and Survival : Application to Proliferation and Cytotoxicity Assays 65:55–63
Moustafa A, Hewedi D, Eissa A et al (2015) Homocysteine levels in neurologicaL disorders. In: Farooqui T, Farooqui AA (eds) Diet and exercise in cognitive function and neurological diseases. John Wiley & Sons Inc, First Edit, pp 73–81
Moustafa AA, Hewedi DH, Eissa AM et al (2014) Homocysteine levels in schizophrenia and affective disorders — focus on cognition. Front Behav Neurosci 8:1–10. https://doi.org/10.3389/fnbeh.2014.00343
doi: 10.3389/fnbeh.2014.00343
Nielsen CK, Arnt J, Sa C (2000) Intracranial Self-Stimulation and Sucrose Intake Differ as Hedonic Measures following Chronic Mild Stress : Interstrain and Interindividual Differences 107:21–33
Park K, Oh JH, Yoo H et al (2010) Neuroscience Letters ( − ) -Epigallocatechin-3- O -gallate ( EGCG ) reverses caffeine-induced anxiogenic-like effects. Neurosci Lett 481:131–134. https://doi.org/10.1016/j.neulet.2010.06.072
doi: 10.1016/j.neulet.2010.06.072
pubmed: 20599478
Patki G, Solanki N, Atrooz F et al (2014) Novel mechanistic insights into treadmill exercise based rescue of social defeat-induced anxiety-like behavior and memory impairment in rats. Physiol Behav 130:135–144. https://doi.org/10.1016/j.physbeh.2014.04.011
doi: 10.1016/j.physbeh.2014.04.011
pubmed: 24732411
pmcid: 4416646
Paxinos G, Watson C (2007) The Rat Brain in Stereotaxic Coordinates, 6th Editio. Academic Press, San Diego, CA
Pellow S, Chopin P, File SE, Briley M (1985) Validation of open: closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods 14:149–167. https://doi.org/10.1016/0165-0270(85)90031-7
doi: 10.1016/0165-0270(85)90031-7
pubmed: 2864480
Petrea RE, Seshadri S (2008) Homocysteine and neurological disorders. Glutathione Sulfur Amin Acids Hum Heal Dis. https://doi.org/10.1002/9780470475973.ch18
doi: 10.1002/9780470475973.ch18
Porsolt RD, Le PM, Jalfre M (1977) Depression : a new animal model sensitive to antidepressant treatments. Nature 266:730–732
doi: 10.1038/266730a0
Roigé-Castellví J, Murphy M, Fernández-Ballart J, Canals J (2019) Moderately elevated preconception fasting plasma total homocysteine is a risk factor for psychological problems in childhood. Public Health Nutr 22:1615–1623. https://doi.org/10.1017/S1368980018003610
doi: 10.1017/S1368980018003610
pubmed: 30636652
Rubin H (2005) Central Roles of Mg2+ and MgATP2- in the Regulation of Protein Synthesis and Cell Proliferation : Significance for Neoplastic Transformation. Adv Cancer Res 1–58. Doi: https://doi.org/10.1016/S0065-230X(05)93001-7
Sanui H, Rubin H (1982) Changes of intracellular and externally bound cations accompanying serum stimulation of mouse BALB/c 3T3 cells. Exp Cell Res 139:15–25
doi: 10.1016/0014-4827(82)90314-7
Scherer EBS, da Cunha AA, Kolling J et al (2011) Development of an animal model for chronic mild hyperhomocysteinemia and its response to oxidative damage. Int J Dev Neurosci 29:693–699. https://doi.org/10.1016/j.ijdevneu.2011.06.004
doi: 10.1016/j.ijdevneu.2011.06.004
pubmed: 21704148
Scherer EBS, Loureiro SO, Vuaden FC et al (2013) Mild hyperhomocysteinemia reduces the activity and immunocontent, but does not alter the gene expression, of catalytic α subunits of cerebral Na +, K+-ATPase. Mol Cell Biochem 378:91–97. https://doi.org/10.1007/s11010-013-1598-6
doi: 10.1007/s11010-013-1598-6
pubmed: 23467881
Schulkin J (2006) Angst and the amygdala. Dialogues Clin Neurosci 8:407–416. https://doi.org/10.1038/145370a0
doi: 10.1038/145370a0
pubmed: 17290799
pmcid: 3181834
Sharma M, Tiwari M, Tiwari RK (2015) Hyperhomocysteinemia: Impact on neurodegenerative diseases. Basic Clin Pharmacol Toxicol 117:287–296. https://doi.org/10.1111/bcpt.12424
doi: 10.1111/bcpt.12424
pubmed: 26036286
Skovierová H, Vidomanová E, Mahmood S et al (2016) The molecular and cellular effect of homocysteine metabolism imbalance on human health. Int J Mol Sci 17:1–18. https://doi.org/10.3390/ijms17101733
doi: 10.3390/ijms17101733
Smith K (2014) Mental health: a world of depression. Nature 15:180–181
doi: 10.1038/515180a
Srejovic I, Jakovljevic V, Zivkovic V et al (2014) The effects of the modulation of NMDA receptors by homocysteine thiolactone and dizocilpine on cardiodynamics and oxidative stress in isolated rat heart. Mol Cell Biochem 401:97–105. https://doi.org/10.1007/s11010-014-2296-8
doi: 10.1007/s11010-014-2296-8
pubmed: 25467376
Stanger O, Fowler B, Pietrzik K et al (2009) Homocysteine, folate and vitamin B12 in neuropsychiatric diseases: Review and treatment recommendations. Expert Rev Neurother 9:1393–1412. https://doi.org/10.1586/ern.09.75
doi: 10.1586/ern.09.75
pubmed: 19769453
Stefanello N, Schmatz R, Belmonte L et al (2014) Effects of chlorogenic acid, caffeine, and coffee on behavioral and biochemical parameters of diabetic rats. Mol Cell Biochem 388:277–286. https://doi.org/10.1007/s11010-013-1919-9
doi: 10.1007/s11010-013-1919-9
pubmed: 24370728
Steimer T (2002) The biology of fear- and anxiety-related behaviors. Dialogues Clin Neurosci 4:231–249. https://doi.org/10.1097/ALN.0b013e318212ba87
doi: 10.1097/ALN.0b013e318212ba87
pubmed: 22033741
pmcid: 3181681
Suhail M (2010) Na, K-ATPase: Ubiquitous multifunctional transmembrane protein and its relevance to various pathophysiological conditions. J Clin Med Res 2:1–17. https://doi.org/10.4021/jocmr2010.02.263w
doi: 10.4021/jocmr2010.02.263w
pubmed: 22457695
pmcid: 3299169
Tagliari B, Dos Santos TM, Cunha AA et al (2010) Chronic variable stress induces oxidative stress and decreases butyrylcholinesterase activity in blood of rats. J Neural Transm. https://doi.org/10.1007/s00702-010-0445-0
doi: 10.1007/s00702-010-0445-0
pubmed: 20686907
Tagliari B, Tagliari AP, Schmitz F et al (2011) Chronic variable stress alters inflammatory and cholinergic parameters in hippocampus of rats. Neurochem Res a 36:487–493. https://doi.org/10.1007/s11064-010-0367-0
doi: 10.1007/s11064-010-0367-0
Walf AA, Frye CA (2007). The Use of the Elevated plus Maze as an Assay of Anxiety-Related Behavior in Rodents. https://doi.org/10.1038/nprot.2007.44
doi: 10.1038/nprot.2007.44
Wendel A (1981) Glutathione peroxidase. Methods Enzymol 77:325–333
doi: 10.1016/S0076-6879(81)77046-0
Williams KT, Schalinske KL (2010) Homocysteine metabolism and its relation to health and disease. BioFactors 36:19–24. https://doi.org/10.1002/biof.71
doi: 10.1002/biof.71
pubmed: 20091801
Wyse ATS, Bavaresco CS, Reis EA et al (2004) Training in inhibitory avoidance causes a reduction of Na+, K+-ATPase activity in rat hippocampus. Physiol Behav 80:475–479. https://doi.org/10.1016/j.physbeh.2003.10.002
doi: 10.1016/j.physbeh.2003.10.002
pubmed: 14741232
Wyse ATS, Sanches EF, Dos Santos TM et al (2020) Chronic mild hyperhomocysteinemia induces anxiety-like symptoms, aversive memory deficits and hippocampus atrophy in adult rats: New insights into physiopathological mechanisms. Brain Res 1728:146592. https://doi.org/10.1016/J.BRAINRES.2019.146592
doi: 10.1016/J.BRAINRES.2019.146592
pubmed: 31816318
Zhou Y, Danbolt NC (2014) Glutamate as a neurotransmitter in the healthy brain. J Neural Transm 121:799–817. https://doi.org/10.1007/s00702-014-1180-8
doi: 10.1007/s00702-014-1180-8
pubmed: 24578174