Skip to main content
SpringerLink
Log in

Protective Effects of Ascorbic Acid on Behavior and Oxidative Status of Restraint-Stressed Mice

Journal of Molecular Neuroscience Aims and scope Submit manuscript

Cite this article

Abstract

Studies have demonstrated an association between stressful conditions and the onset of clinical depression. Considering the antidepressant-like properties of ascorbic acid in both experimental and clinical approaches, we evaluated the beneficial effect of this vitamin on restraint stress-induced behavioral and neurochemical alterations. Acute restraint stress caused a depressive-like behavior in the forced swimming test, accompanied by increased lipid peroxidation (cerebral cortex and hippocampus); increased superoxide dismutase (cerebral cortex and hippocampus), glutathione reductase (cerebral cortex), and glutathione peroxidase (cerebral cortex and hippocampus) activities; and elevated expression of Bcl-2 (hippocampus). Oral administration of ascorbic acid (1 mg/kg) or fluoxetine (10 mg/kg) 1 h before restraint stress prevented the stress-induced increase on immobility time in the forced swimming test. Moreover, this vitamin reduced lipid peroxidation to control levels and restored the activity of superoxide dismutase, glutathione reductase, and glutathione peroxidase. Ascorbic acid had no effect on the increased level of Bcl-2 induced by stress. Glutathione levels, glycogen synthase kinase-3β phosphorylation, and Bax expression were not altered by stress or ascorbic acid administration. Besides reinforcing the antioxidant potential of ascorbic acid, our results support the notion that oxidative stress plays a role in the pathogenesis and treatment of stress-induced depression.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Adams JM, Cory S (2007) The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene 26:1324–1337

    Article  PubMed  CAS  Google Scholar 

  • Ahmad A, Rasheed N, Ashraf GM et al (2012) Brain region specific monoamine and oxidative changes during restraint stress. Can J Neurol Sci 39:311–318

    PubMed  Google Scholar 

  • Andreazza AC, Kauer-Sant’Anna M, Frey BN et al (2008) Oxidative stress markers in bipolar disorder: a meta-analysis. J Affect Disord 111:135–144

    Article  PubMed  CAS  Google Scholar 

  • Atif F, Yousuf S, Agrawal SK (2008) Restraint stress-induced oxidative damage and its amelioration with selenium. Eur J Pharmacol 600:59–63

    Article  PubMed  CAS  Google Scholar 

  • Bai F, Li X, Clay M, Lindstrom T, Skolnick P (2001) Intra- and interstrain differences in models of “behavioral despair”. Pharmacol Biochem Behav 70:187–192

    Article  PubMed  CAS  Google Scholar 

  • Balk RDS, Bridi JC, Portella Rde L et al (2010) Clomipramine treatment and repeated restraint stress alter parameters of oxidative stress in brain regions of male rats. Neurochem Res 35:1761–1770

    Article  Google Scholar 

  • Beaulieu JM, Gainetdinov RR, Caron MG (2009) Akt/GSK3 signaling in the action of psychotropic drugs. Annu Rev Pharmacol Toxicol 49:327–347

    Article  PubMed  CAS  Google Scholar 

  • Beaulieu JM, Zhang X, Rodriguiz RM et al (2008) Role of GSK3beta in behavioral abnormalities induced by serotonin deficiency. Proc Natl Acad Sci USA 105:1333–1338

    Article  PubMed  CAS  Google Scholar 

  • Benkovic SA, Connor JR (1993) Ferritin, transferrin, and iron in selected regions of the adult and aged rat brain. Neurology 338:97–113

    CAS  Google Scholar 

  • Bilici M, Efe H, Koroglu MA, Uydu HA, Bekaroglu M, Deger O (2001) Antioxidative enzyme activities and lipid peroxidation in major depression: alterations by antidepressant treatments. J Affect Disord 64:43–51

    Article  PubMed  CAS  Google Scholar 

  • Binfaré RW, Rosa AO, Lobato KR, Santos ARS, Rodrigues ALS (2009) Ascorbic acid administration produces an antidepressant-like effect: evidence for the involvement of monoaminergic neurotransmission. Prog Neuropsychopharmacol Biol Psychiatry 33:530–540

    Article  PubMed  Google Scholar 

  • Brocardo PS, Assini F, Franco JL et al (2007) Zinc attenuates malathion-induced depressant-like behavior and confers neuroprotection in the rat brain. Toxicol Sci 97:140–148

    Article  PubMed  CAS  Google Scholar 

  • Brody S (2002) High-dose ascorbic acid increases intercourse frequency and improves mood: a randomized controlled clinical trial. Biol Psychiatry 52:371–374

    Article  PubMed  CAS  Google Scholar 

  • Budni J, Gadotti VM, Kaster MP, Santos AR, Rodrigues ALS (2007) Role of different types of potassium channels in the antidepressant-like effect of agmatine in the mouse forced swimming test. Eur J Pharmacol 575:87–93

    Article  PubMed  CAS  Google Scholar 

  • Buynitsky T, Mostofsky DI (2009) Restraint stress in biobehavioral research: recent developments. Neurosci Biobehav Rev 33:1089–1098

    Article  PubMed  Google Scholar 

  • Capra JC, Cunha MP, Machado DG et al (2010) Antidepressant-like effect of scopoletin, a coumarin isolated from Polygala sabulosa (Polygalaceae) in mice: evidence for the involvement of monoaminergic systems. Eur J Pharmacol 643:232–238

    Article  PubMed  CAS  Google Scholar 

  • Carlberg I, Mannervik B (1985) Glutathione reductase. Methods Enzymol 113:484–490

    Article  PubMed  CAS  Google Scholar 

  • Checkley S (1996) The neuroendocrinology of depression and chronic stress. Br Med Bull 52:597–617

    Article  PubMed  CAS  Google Scholar 

  • Cocchi P, Silenzi M, Calabri G, Salvi G (1980) Antidepressant effect of vitamin C. Pediatrics 65:862–863

    PubMed  CAS  Google Scholar 

  • Cordova FM, Rodrigues ALS, Giacomelli MB et al (2004) Lead stimulates ERK1/2 and p38MAPK phosphorylation in the hippocampus of immature rats. Brain Res 998:65–72

    Article  PubMed  CAS  Google Scholar 

  • Doble BW, Woodgett JR (2003) GSK-3: tricks of the trade for a multi-tasking kinase. J Cell Sci 116(Part 7):1175–1186

    Article  PubMed  CAS  Google Scholar 

  • de Vasconcellos AP, Nieto FB, Crema LM et al (2006) Chronic lithium treatment has antioxidant properties but does not prevent oxidative damage induced by chronic variate stress. Neurochem Res 31:1141–1151

    Article  PubMed  CAS  Google Scholar 

  • Dringen R, Pawlowski PG, Hirrlinger J (2005) Peroxide detoxification by brain cells. J Neurosci Res 79:157–165

    Article  PubMed  CAS  Google Scholar 

  • Elhwuegi AS (2004) Central monoamines and their role in major depression. Prog Neuropsychopharmacol Biol Psychiatry 28:435–451

    Article  PubMed  CAS  Google Scholar 

  • Ellman GL (1959) Tissue sulfhydryl groups. Arch Biochem Biophys 82:70–77

    Article  PubMed  CAS  Google Scholar 

  • Fontella FU, Siqueira IR, Vasconcellos APS, Tabajara AS, Netto CA, Dalmaz C (2005) Repeated restraint stress induces oxidative damage in rat hippocampus. Neurochem Res 30:105–111

    Article  PubMed  CAS  Google Scholar 

  • Frame S, Cohen P (2001) GSK3 takes centre stage more than 20 years after its discovery. Biochem J 359(Part 1):1–16

    Article  PubMed  CAS  Google Scholar 

  • Galecki P, Szemraj J, Bienkiewicz M, Florkowski A, Galecka E (2009a) Lipid peroxidation and antioxidant protection in patients during acute depressive episodes and in remission after fluoxetine treatment. Pharmacol Rep 61:436–447

    PubMed  CAS  Google Scholar 

  • Galecki P, Szemraj J, Bienkiewicz M, Zboralski K, Galecka E (2009b) Oxidative stress parameters after combined fluoxetine and acetylsalicylic acid therapy in depressive patients. Hum Psychopharmacol 24:277–286

    Article  PubMed  CAS  Google Scholar 

  • Gamaro GD, Manoli LP, Torres IL, Silveira R, Dalmaz C (2003) Effects of chronic variate stress on feeding behavior and on monoamine levels in different rat brain structures. Neurochem Int 42:107–114

    Article  PubMed  CAS  Google Scholar 

  • García-Fernández M, Castilla-Ortega E, Pedraza C et al (2012) Chronic immobilization in the malpar1 knockout mice increases oxidative stress in the hippocampus. Int J Neurosci 122:583–589

    Article  PubMed  Google Scholar 

  • Gould TD, Manji HK (2005) Glycogen synthase kinase-3: a putative molecular target for lithium mimetic drugs. Neuropsychopharmacology 30:1223–1237

    PubMed  CAS  Google Scholar 

  • Gould TD, Einat H, Bhat R, Manji HK (2004) AR-A014418, a selective GSK-3 inhibitor, produces antidepressant-like effects in the forced swim test. Int J Neuropsychopharmacol 7:387–390

    Article  PubMed  CAS  Google Scholar 

  • Graumann R, Paris I, Martinez-Alvarado P et al (2002) Oxidation of dopamine to aminochrome as a mechanism for neurodegeneration of dopaminergic systems in Parkinson’s disease. Possible neuroprotective role of DT-diaphorase. Pol J Pharmacol 54:573–579

    PubMed  CAS  Google Scholar 

  • Harkin AJ, Bruce KH, Craft B, Paul IA (1999) Nitric oxide synthase inhibitors have antidepressant-like properties in mice. 1. Acute treatments are active in the forced swim test. Eur J Pharmacol 372:207–213

    Article  PubMed  CAS  Google Scholar 

  • He B, Meng YH, Mivechi NF (1998) Glycogen synthase kinase 3β and extracellular signal-regulated kinase inactivate heat shock transcription factor 1 by facilitating the disappearance of transcriptionally active granules after heat shock. Mol Cell Biol 18:6624–6633

    PubMed  CAS  Google Scholar 

  • Hernández-Martínez JM, Domínguez G, Blancas S, Morán J (2011) Oxidation of biomolecules in the apoptotic death of cerebellar granule neurons induced by potassium deprivation. Neurochem Res 36:677–685

    Article  PubMed  Google Scholar 

  • Holmes PV (2003) Rodent models of depression: reexamining validity without anthropomorphic inference. Crit Rev Neurobiol 15:143–174

    Article  PubMed  Google Scholar 

  • Jope RS, Johnson GVW (2004) The glamour and gloom of glycogen synthase kinase-3. Trends Biochem Sci 29:95–102

    Article  PubMed  CAS  Google Scholar 

  • Khanzode SD, Dakhale GN, Khanzode SS, Saoji A, Palasodkar R (2003) Oxidative damage and major depression: the potential antioxidant action of selective serotonin re-uptake inhibitors. Redox Rep 8:365–370

    Article  PubMed  CAS  Google Scholar 

  • Kioukia-Fougia N, Antoniou K, Bekris S, Liapi C, Christofidis I, Papadopoulou-Daifoti Z (2002) The effects of stress exposure on the hypothalamic–pituitary–adrenal axis, thymus, thyroid hormones and glucose levels. Prog Neuropsychopharmacol Biol Psychiatry 26:823–830

    Article  PubMed  CAS  Google Scholar 

  • Kovacheva-Ivanova S, Bakalova R, Ribavov SR (1994) Immobilization stress enhances lipid peroxidation in the rat lungs. Materials and methods. Gen Physiol Biophys 13:469–482

    Google Scholar 

  • Kovachich GB, Mishra OP (1983) The effect of ascorbic acid on malonaldehyde formation, K+, Na+ and water content of brain slices. Exp Brain Res 50:62–68

    Article  PubMed  CAS  Google Scholar 

  • Kowaltowski AJ, Fiskum G (2005) Redox mechanisms of cytoprotection by Bcl-2. Antioxid Redox Signal 7:508–514

    Article  PubMed  CAS  Google Scholar 

  • Kowaltowski AJ, Fenton RG, Fiskum G (2004) Bcl-2 family proteins regulate mitochondrial reactive oxygen production and protect against oxidative stress. Free Radic Biol Med 37:1845–1853

    Article  PubMed  CAS  Google Scholar 

  • Kozlovsky N, Belmaker RH, Agam G (2002) Lack of effect of acute, subchronic, or chronic stress on glycogen synthase kinase-3beta protein levels in rat frontal cortex. Prog Neuropsychopharmacol Biol Psychiatry 26:1309–1312

    Article  PubMed  CAS  Google Scholar 

  • Kumar A, Goyal R (2008) Quercetin protects against acute immobilization stress-induced behaviors and biochemical alterations in mice. J Med Food 11:469–473

    Article  PubMed  CAS  Google Scholar 

  • Kumari B, Kumar A, Dhir A (2007) Protective effect of non-selective and selective COX-2-inhibitors in acute immobilization stress-induced behavioral and biochemical alterations. Pharmacol Rep 59:699–707

    Google Scholar 

  • Li X, Jope RS (2010) Is glycogen synthase kinase-3 a central modulator in mood regulation? Neuropsychopharmacology 35:2143–2154

    Article  PubMed  CAS  Google Scholar 

  • Li X, Zhu W, Roh MS, Friedman AB, Rosborough K, Jope RS (2004) In vivo regulation of glycogen synthase kinase-3beta (GSK3beta) by serotonergic activity in mouse brain. Neuropsychopharmacology 29:1426–1431

    Article  PubMed  CAS  Google Scholar 

  • Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275

    PubMed  CAS  Google Scholar 

  • Maes M, Fišar Z, Medina M, Scapagnini G, Nowak G, Berk M (2012) New drug targets in depression: inflammatory, cell-mediated immune, oxidative and nitrosative stress, mitochondrial, antioxidant, and neuroprogressive pathways. And new drug candidates—Nrf2 activators and GSK-3 inhibitors. Inflammopharmacology 20:127–150

    Article  PubMed  CAS  Google Scholar 

  • Manoli LP, Gamaro GD, Silveira PP, Dalmaz C (2000) Effect of chronic variate stress on thiobarbituric-acid reactive species and on total radical-trapping potential in distinct regions of rat brain. Neurochem Res 25:915–921

    Article  PubMed  CAS  Google Scholar 

  • McCord JM, Edeas MA (2005) SOD, oxidative stress and human pathologies: a brief history and a future vision. Biomed Pharmacother 59:139–142

    Article  PubMed  CAS  Google Scholar 

  • Michel TM, Frangou S, Thiemeyer D et al (2007) Evidence for oxidative stress in the frontal cortex in patients with recurrent depressive disorder—a postmortem study. Psychiatry Res 151:145–150

    Article  PubMed  CAS  Google Scholar 

  • Mills GC (1957) Hemoglobin catabolism. I. Glutathione peroxidase, an erythrocyte enzyme which protects hemoglobin from oxidative breakdown. J Biol Chem 229:189–197

    PubMed  CAS  Google Scholar 

  • Misra HP, Fridovich I (1972) The purification and properties of superoxide dismutase from Neurospora crassa. J Biol Chem 247:3410–3414

    PubMed  CAS  Google Scholar 

  • Moretti M, Budni J, Ribeiro CM, Rodrigues ALS (2012a) Involvement of different types of potassium channels in the antidepressant-like effect of ascorbic acid in the mouse tail suspension test. Eur J Pharmacol 687:21–27

    Article  PubMed  CAS  Google Scholar 

  • Moretti M, Colla A, de Oliveira Balen G et al (2012b) Ascorbic acid treatment, similarly to fluoxetine, reverses depressive-like behavior and brain oxidative damage induced by chronic unpredictable stress. J Psychiatr Res 46:331–340

    Article  PubMed  Google Scholar 

  • Moretti M, Freitas AE, Budni J, Fernandes SC, Balen GD, Rodrigues ALS (2011) Involvement of nitric oxide–cGMP pathway in the antidepressant-like effect of ascorbic acid in the tail suspension test. Behav Brain Res 225:328–333

    Article  PubMed  CAS  Google Scholar 

  • Naert G, Ixart G, Maurice T, Tapia-Arancibia L, Givalois L (2011) Brain-derived neurotrophic factor and hypothalamic–pituitary–adrenal axis adaptation processes in a depressive-like state induced by chronic restraint stress. Mol Cell Neurosci 46:55–66

    Article  PubMed  CAS  Google Scholar 

  • Ng F, Berk M, Dean O, Bush AI (2008) Oxidative stress in psychiatric disorders: evidence base and therapeutic implications. Int J Neuropsychopharmacol 11:851–876

    Article  PubMed  CAS  Google Scholar 

  • Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358

    Article  PubMed  CAS  Google Scholar 

  • Oishi K, Yokoi M, Maekawa S et al (1999) Oxidative stress and haematological changes in immobilized rats. Acta Physiol Scand 165:65–69

    Google Scholar 

  • O'Mahony CM, Sweeney FF, Daly E, Dinan TG, Cryan JF (2010) Restraint stress-induced brain activation patterns in two strains of mice differing in their anxiety behaviour. Behav Brain Res 213:148–154

    Article  PubMed  Google Scholar 

  • Osburn WO, Kensler TW (2008) Nrf2 signaling: an adaptive response pathway for protection against environmental toxic insults. Mutat Res 659:31–39

    Article  PubMed  CAS  Google Scholar 

  • Pajović SB, Pejic S, Stojiljkovic V, Gavrilovic L, Dronjak S, Kanazir DT (2006) Alterations in hippocampal antioxidant enzyme activities and sympatho-adrenomedullary system of rats in response to different stress models. Physiol Res 55:453–460

    PubMed  Google Scholar 

  • Park SH, Sim YB, Han PL, Lee JK, Suh HW (2010) Antidepressant-like effect of kaempferol and quercitirin, isolated from Opuntia ficus-indica var. saboten. Exp Neurobiol 19:30–38

    Article  PubMed  Google Scholar 

  • Park SW, Phuong VT, Lee CH et al (2011) Effects of antipsychotic drugs on BDNF, GSK-3β, and β-catenin expression in rats subjected to immobilization stress. Neurosci Res 71:335–340

    Article  PubMed  CAS  Google Scholar 

  • Peterson GL (1977) A simplification of the protein assay method of Lowry et al. which is more generally applicable. Anal Biochem 83:346–356

    Article  PubMed  CAS  Google Scholar 

  • Poleszak E, Wlaz P, Kedzierska E et al (2006) Immobility stress induces depression-like behavior in the forced swim test in mice: effect of magnesium and imipramine. Pharmacol Rep 58:746–752

    PubMed  CAS  Google Scholar 

  • Porsolt RD, Bertin A, Jalfre M (1977) Behavioral despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn Ther 229:327–336

    Google Scholar 

  • Prediger ME, Gamaro GD, Crema LM, Fontella FU, Dalmaz C (2004) Estradiol protects against oxidative stress induced by chronic variate stress. Neurochem Res 29:1923–1930

    Article  PubMed  CAS  Google Scholar 

  • Radak Z, Sasvari M, Nyakas C et al (2001) Single bout of exercise eliminates the immobilization-induced oxidative stress in rat brain. Neurochem Int 39:33–38

    Google Scholar 

  • Rice ME (2000) Ascorbate regulation and its neuroprotective role in the brain. Trends Neurosci 23:209–216

    Article  PubMed  CAS  Google Scholar 

  • Rudin CM, Yang Z, Schumaker LM et al (2003) Inhibition of glutathione synthesis reverses Bcl-2-mediated cisplatin resistance. Cancer Res 63:312–318

    PubMed  CAS  Google Scholar 

  • Sahin E, Gumuslu S (2007) Immobilization stress in rat tissues: alterations in protein oxidation, lipid peroxidation and antioxidant defense system. Comp Biochem Physiol C Toxicol Pharmacol 144:342–347

    Article  PubMed  Google Scholar 

  • Santos IM, Tomé AR, Saldanha GB, Ferreira PM, Militão GC, Freitas RM (2009) Oxidative stress in the hippocampus during experimental seizures can be ameliorated with the antioxidant ascorbic acid. Oxid Med Cell Longev 2:214–221

    Article  PubMed  Google Scholar 

  • Selek S, Savas HA, Gergerlioglu HS, Bulbul F, Uz E, Yumru M (2008) The course of nitric oxide and superoxide dismutase during treatment of bipolar depressive episode. J Affect Disord 107:89–94

    Article  PubMed  CAS  Google Scholar 

  • Seregi A, Schaefer A, Komlós M (1978) Protective role of brain ascorbic acid content against lipid peroxidation. Experientia 34:1056–1057

    Article  PubMed  CAS  Google Scholar 

  • Shoji H, Mizoguchi K (2010) Acute and repeated stress differentially regulates behavioral, endocrine, neural parameters relevant to emotional and stress response in young and aged rats. Behav Brain Res 211:169–177

    Article  PubMed  CAS  Google Scholar 

  • Steckert AV, Valvassori SS, Moretti M, Dal-Pizzol F, Quevedo J (2010) Role of oxidative stress in the pathophysiology of bipolar disorder. Neurochem Res 35:1295–1301

    Article  PubMed  CAS  Google Scholar 

  • Trevisan R, Uliano-Silva M, Pandolfo P et al (2008) Antioxidant and acetylcholinesterase response to repeated malathion exposure in rat cerebral cortex and hippocampus. Basic Clin Pharmacol Toxicol 102:365–369

    Article  PubMed  CAS  Google Scholar 

  • Trivedi MH, Rush AJ, Wisniewski SR et al (2006) Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry 163:28–40

    Article  PubMed  Google Scholar 

  • Wendel A (1981) Glutathione peroxidase. Methods Enzymol 77:325–333

    Article  PubMed  CAS  Google Scholar 

  • Wilkinson MB, Dias C, Magida J et al (2011) A novel role of the WNT-disheveled–GSK3β signaling cascade in the mouse nucleus accumbens in a social defeat model of depression. J Neurosci 31:9084–9092

    Article  PubMed  CAS  Google Scholar 

  • Zafir A, Ara A, Banu N (2009) In vivo antioxidant status: a putative target of antidepressant action. Prog Neuropsychopharmacol Biol Psychiatry 33:220–228

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, 88040-900, SC, Brazil

    Morgana Moretti, Josiane Budni, Danubia Bonfanti dos Santos, Alessandra Antunes, Juliana Felipe Daufenbach, Luana Meller Manosso, Marcelo Farina & Ana Lúcia S. Rodrigues

Authors
  1. Morgana Moretti
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Josiane Budni
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Danubia Bonfanti dos Santos
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alessandra Antunes
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Juliana Felipe Daufenbach
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Luana Meller Manosso
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Marcelo Farina
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ana Lúcia S. Rodrigues
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ana Lúcia S. Rodrigues.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Moretti, M., Budni, J., dos Santos, D.B. et al. Protective Effects of Ascorbic Acid on Behavior and Oxidative Status of Restraint-Stressed Mice. J Mol Neurosci 49, 68–79 (2013). https://doi.org/10.1007/s12031-012-9892-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-012-9892-4

Keywords

search

Navigation