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Trehalose induced antidepressant-like effects and autophagy enhancement in mice

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Abstract

Rationale

The disaccharide trehalose protects cells from hypoxic and anoxic injury and suppresses protein aggregation. In vivo studies with trehalose show cellular and behavioral beneficial effects in animal models of neurodegenerative diseases. Moreover, trehalose was shown to enhance autophagy, a process that had been recently suggested to be involved in the therapeutic action of antidepressant and mood-stabilizing drugs.

Objective

The present study was therefore designed to explore antidepressant and mood-stabilizing activity of trehalose in animal models for depression and mania.

Methods

Trehalose 1 or 2 % was administered for 3 weeks as a drinking solution to Black Swiss mice (a model of manic-like behaviors) or 2 % to ICR mice and their behavior evaluated in a number of tests related to depression or mania. The effects of trehalose were compared with similar chronic administration of the disaccharide maltose as well as with a vehicle (water) control.

Results

Chronic administration of trehalose resulted in a reduction of frontal cortex p62/beclin-1 ratio suggesting enhancement of autophagy. Trehalose had no mood-stabilizing effects on manic-like behavior in Black Swiss mice but instead augmented amphetamine-induced hyperactivity, an effect similar to antidepressant drugs. In ICR mice, trehalose did not alter spontaneous activity or amphetamine-induced hyperactivity but in two separate experiments had a significant effect to reduce immobility in the forced swim test, a standard screening test for antidepressant-like effects.

Conclusions

The results suggest that trehalose may have antidepressant-like properties. It is hypothesized that these behavioral changes could be related to trehalose effects to enhance autophagy.

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References

  • Aguib Y, Heiseke A, Gilch S, Riemer C, Baier M et al (2009) Autophagy induction by trehalose counteracts cellular prion infection. Autophagy 5(3):361–369

    Article  PubMed  CAS  Google Scholar 

  • Arora A, Ha C, Park CB (2004) Inhibition of insulin amyloid formation by small stress molecules. FEBS Lett 564(1–2):121–125

    Article  PubMed  CAS  Google Scholar 

  • Autry AE, Adachi M, Nosyreva E, Na ES, Los MF et al (2011) NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 475(7354):91–95

    Article  PubMed  CAS  Google Scholar 

  • Bachmann RF, Schloesser RJ, Gould TD, Manji HK (2005) Mood stabilizers target cellular plasticity and resilience cascades: implications for the development of novel therapeutics. Mol Neurobiol 32(2):173–202

    Article  PubMed  CAS  Google Scholar 

  • Beasley CL, Pennington K, Behan A, Wait R, Dunn MJ et al (2006) Proteomic analysis of the anterior cingulate cortex in the major psychiatric disorders: evidence for disease-associated changes. Proteomics 6(11):3414–3425

    Article  PubMed  CAS  Google Scholar 

  • Behan AT, Byrne C, Dunn MJ, Cagney G, Cotter DR (2009) Proteomic analysis of membrane microdomain-associated proteins in the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder reveals alterations in lamp, stxbp1 and basp1 protein expression. Mol Psychiatry 14(6):601–613

    Article  PubMed  CAS  Google Scholar 

  • Bennett GS, Hollander BA, Laskowska D, DiLullo C (1991) Rapid degradation of newly synthesized tubulin in lithium-treated sensory neurons. J Neurochem 57(1):130–139

    Article  PubMed  CAS  Google Scholar 

  • Calabrese F, Molteni R, Racagni G, Riva MA (2009) Neuronal plasticity: a link between stress and mood disorders. Psychoneuroendocrinology 34(Suppl 1):S208–216, Epub

    Article  PubMed  CAS  Google Scholar 

  • Cambiaghi M, Cursi M, Magri L, Castoldi V, Comi G et al (2012) Behavioural and eeg effects of chronic rapamycin treatment in a mouse model of tuberous sclerosis complex. Neuropharmacology 67C:1–7. doi:10.1016/j.neuropharm.2012.1011.1003

    Google Scholar 

  • Cannell GR, Bailey MJ, Dickinson RG (2002) Inhibition of tubulin assembly and covalent binding to microtubular protein by valproic acid glucuronide in vitro. Life Sci 71(22):2633–2643

    Article  PubMed  CAS  Google Scholar 

  • Chen Q, Haddad GG (2004) Role of trehalose phosphate synthase and trehalose during hypoxia: from flies to mammals. J Exp Biol 207(Pt 18):3125–3129

    Article  PubMed  CAS  Google Scholar 

  • Cleary C, Linde JA, Hiscock KM, Hadas I, Belmaker RH et al (2008) Antidepressive-like effects of rapamycin in animal models: implications for mtor inhibition as a new target for treatment of affective disorders. Brain Res Bull 76(5):469–473

    Article  PubMed  CAS  Google Scholar 

  • Cloonan SM, Williams DC (2011) The antidepressants maprotiline and fluoxetine induce type ii autophagic cell death in drug-resistant burkitt's lymphoma. Int J Cancer 128(7):1712–1723

    Article  PubMed  CAS  Google Scholar 

  • Costain WJ, Haqqani AS, Rasquinha I, Giguere MS and Slinn J (2012) Cerebral ischemia induced proteomic alterations: consequences for the synapse and organelles. Advances in the Preclinical Study of Ischemic Stroke. M Balestrino

  • Cryan JF, O'Leary OF (2010) Neuroscience. A glutamate pathway to faster-acting antidepressants? Science 329(5994):913–914

    Article  PubMed  CAS  Google Scholar 

  • de Felipe MC, Jimenez I, Castro A, Fuentes JA (1989) Antidepressant action of imipramine and iprindole in mice is enhanced by inhibitors of enkephalin-degrading peptidases. Eur J Pharmacol 159(2):175–180

    Article  PubMed  Google Scholar 

  • Dengjel J, Hoyer-Hansen M, Nielsen MO, Eisenberg T, Harder LM et al (2012) Identification of autophagosome-associated proteins and regulators by quantitative proteomic analysis and genetic screens. Mol Cell Proteomics 11(3):M111–014035

    PubMed  Google Scholar 

  • Dwyer JM, Lepack AE, Duman RS (2011) Mtor activation is required for the antidepressant effects of mglur2/3 blockade. Int J Neuropsychopharmacol 24:1–6

    Google Scholar 

  • Dziedzicka-Wasylewska M, Faron-Gorecka A, Rogoz Z, Solich J (2004) The effect of combined treatment with imipramine and amantadine on the behavioral reactivity of central alpha1-adrenergic system in rats. Behav Pharmacol 15(2):159–165

    Article  PubMed  CAS  Google Scholar 

  • Einat H, Manji HK (2006) Cellular plasticity cascades: gene to behavior pathways in animal models of bipolar disorder. Biol Psychiatry 59(12):1960–1971

    Article  Google Scholar 

  • Flaisher-Grinberg S, Einat H (2009) A possible utilization of the mice forced swim test for modeling manic-like increase in vigor and goal-directed behavior. J Pharmacol Toxicol Methods 59(3):141–145

    Article  PubMed  CAS  Google Scholar 

  • Flaisher-Grinberg S, Einat H (2010) Strain specific battery of tests for separate behavioral domains of mania. Front Psychiatry 1(Article 10):1–10

    Google Scholar 

  • Flaisher-Grinberg S, Overgaard S, Einat H (2009) Attenuation of high sweet solution preference by mood stabilizers: a possible mouse model for the increased reward-seeking domain of mania. J Neurosci Methods 177(1):44–50

    Article  PubMed  CAS  Google Scholar 

  • Garcia LS, Comim CM, Valvassori SS, Reus GZ, Barbosa LM et al (2008) Acute administration of ketamine induces antidepressant-like effects in the forced swimming test and increases bdnf levels in the rat hippocampus. Prog Neuropsychopharmacol Biol Psychiatry 32(1):140–144, Epub 2007

    Article  PubMed  CAS  Google Scholar 

  • Gould TD, Einat H, O'Donnell KC, Picchini AM, Schloesser RJ et al (2007a) Beta-catenin overexpression in the mouse brain phenocopies lithium-sensitive behaviors. Neuropsychopharmacology 32(10):2173–2183

    Article  PubMed  CAS  Google Scholar 

  • Gould TD, O'Donnell KC, Picchini AM, Manji HK (2007b) Strain differences in lithium attenuation of d-amphetamine-induced hyperlocomotion: a mouse model for the genetics of clinical response to lithium. Neuropsychopharmacology 32(6):1321–1333

    Article  PubMed  CAS  Google Scholar 

  • Gould TD, Picchini AM, Einat H, Manji HK (2006) Targeting glycogen synthase kinase-3 in the cns: implications for the development of new treatments for mood disorders. Curr Drug Targets 7(11):1399–1409

    Article  PubMed  CAS  Google Scholar 

  • Hannah-Poquette C, Anderson GW, Flaisher-Grinberg S, Wang J, Meinerding TM et al (2011) Modeling mania: further validation for black swiss mice as model animals. Behav Brain Res 223(1):222–226

    Article  PubMed  Google Scholar 

  • He C, Klionsky DJ (2009) Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 43:67–93

    Article  PubMed  CAS  Google Scholar 

  • Higashiyama T (2002) Novel functions and applications of trehalose. Pure Appl Chem 74(7):1263–1269

    Article  CAS  Google Scholar 

  • Hiscock KM, Linde JA and Einat H (2007). Black swiss mice as a new animal model for mania: a preliminary study. J Med Biol Sci 1(2)

  • Kalinichev M, Dawson LA (2011) Evidence for antimanic efficacy of glycogen synthase kinase-3 (gsk-3) inhibitors in a strain specific model of acute mania. Int J Neuropsychopharmacol 6:1–17

    Google Scholar 

  • Kampov-Polevoy AB, Garbutt JC, Janowsky DS (1999) Association between preference for sweets and excessive alcohol intake: a review of animal and human studies. Alcohol Alcohol 34(3):386–395

    Article  PubMed  CAS  Google Scholar 

  • Klionsky DJ, Abeliovich H, Agostinis P, Agrawal DK, Aliev G et al (2008) Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy 4(2):151–175

    PubMed  CAS  Google Scholar 

  • Lang UE, Heger J, Willbring M, Domula M, Matschke K et al (2009) Immunosuppression using the mammalian target of rapamycin (mtor) inhibitor everolimus: pilot study shows significant cognitive and affective improvement. Transplant Proc 41(10):4285–4288

    Article  PubMed  CAS  Google Scholar 

  • Leliveld SR, Bader V, Hendriks P, Prikulis I, Sajnani G et al (2008) Insolubility of disrupted-in-schizophrenia 1 disrupts oligomer-dependent interactions with nuclear distribution element 1 and is associated with sporadic mental disease. J Neurosci 28(15):3839–3845

    Article  PubMed  CAS  Google Scholar 

  • Li N, Lee B, Liu RJ, Banasr M, Dwyer JM et al (2010) Mtor-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329(5994):959–964

    Article  PubMed  CAS  Google Scholar 

  • Maj J (1984) Central effects following repeated treatment with antidepressant drugs. Pol J Pharmacol Pharm 36(2–3):87–99

    PubMed  CAS  Google Scholar 

  • Maj J, Wedzony K (1985) Repeated treatment with imipramine or amitriptyline increases the locomotor response of rats to (+)-amphetamine given into the nucleus accumbens. J Pharm Pharmacol 37(5):362–364

    Article  PubMed  CAS  Google Scholar 

  • Piazza PV, Deminiere JM, le Moal M, Simon H (1990) Stress- and pharmacologically-induced behavioral sensitization increases vulnerability to acquisition of amphetamine self-administration. Brain Res 514(1):22–26

    Article  PubMed  CAS  Google Scholar 

  • Porsolt RD, Anton G, Blavet N, Jalfre M (1978a) Behavioural despair in rats: a new model sensitive to antidepressant treatments. Eur J Pharmacol 47(4):379–391

    Article  PubMed  CAS  Google Scholar 

  • Porsolt RD, Bertin A, Jalfre M (1978b) “Behavioural despair” in rats and mice: strain differences and the effects of imipramine. Eur J Pharmacol 51(3):291–294

    Article  PubMed  CAS  Google Scholar 

  • Racagni G, Popoli M (2008) Cellular and molecular mechanisms in the long-term action of antidepressants. Dialogues Clin Neurosci 10(4):385–400

    PubMed  Google Scholar 

  • Robinson TE, Becker JB (1986) Enduring changes in brain and behavior produced by chronic amphetamine administration: a review and evaluation of animal models of amphetamine psychosis. Brain Res 396(2):157–198

    Article  PubMed  CAS  Google Scholar 

  • Rodriguez-Navarro JA, Rodriguez L, Casarejos MJ, Solano RM, Gomez A et al (2010) Trehalose ameliorates dopaminergic and tau pathology in parkin deleted/tau overexpressing mice through autophagy activation. Neurobiol 39(3):423–438

    CAS  Google Scholar 

  • Sarkar S, Perlstein EO, Imarisio S, Pineau S, Cordenier A et al (2007) Small molecules enhance autophagy and reduce toxicity in huntington's disease models. Nat Chem Biol 3(6):331–338

    Article  PubMed  CAS  Google Scholar 

  • Sarkar S, Rubinsztein DC (2006) Inositol and ip3 levels regulate autophagy: biology and therapeutic speculations. Autophagy 2(2):132–134

    PubMed  CAS  Google Scholar 

  • Shamir A, Elhadad N, Belmaker RH, Agam G (2005) Interaction of calbindin d28k and inositol monophosphatase in human postmortem cortex: possible implications for bipolar disorder. Bipolar Disord 7(1):42–48

    Article  PubMed  CAS  Google Scholar 

  • Singer MA, Lindquist S (1998) Multiple effects of trehalose on protein folding in vitro and in vivo. Mol Cell 1(5):639–648

    Article  PubMed  CAS  Google Scholar 

  • Tanaka M, Machida Y, Niu S, Ikeda T, Jana NR et al (2004) Trehalose alleviates polyglutamine-mediated pathology in a mouse model of huntington disease. Nat Med 10(2):148–154, Epub 2004

    Article  PubMed  CAS  Google Scholar 

  • Taylor JP, Hardy J, Fischbeck KH (2002) Toxic proteins in neurodegenerative disease. Science 296(5575):1991–1995

    Article  PubMed  CAS  Google Scholar 

  • Tottori K, Miwa T, Uwahodo Y, Yamada S, Nakai M et al (2001) Antidepressant-like responses to the combined sigma and 5-ht1a receptor agonist opc-14523. Neuropharmacology 41(8):976–988

    Article  PubMed  CAS  Google Scholar 

  • Vezina P, Giovino AA, Wise RA, Stewart J (1989) Environment-specific cross-sensitization between the locomotor activating effects of morphine and amphetamine. Pharmacol Biochem Behav 32(2):581–584

    Article  PubMed  CAS  Google Scholar 

  • Wang J, Flaisher-Grinberg S, Li S, Liu H, Sun L et al (2010) Antidepressant-like effects of the active acidic polysaccharide portion of ginseng in mice. J Ethnopharmacol 132(1):65–69

    Article  PubMed  CAS  Google Scholar 

  • Willner P, Towell A, Sampson D, Sophokleous S, Muscat R (1987) Reduction of sucrose preference by chronic unpredictable mild stress, and its restoration by a tricyclic antidepressant. Psychopharmacology (Berl) 93(3):358–364

    Article  CAS  Google Scholar 

  • Yang CR, Yu RK (2009) Intracerebral transplantation of neural stem cells combined with trehalose ingestion alleviates pathology in a mouse model of huntington's disease. J Neurosci Res 87(1):26–33

    Article  PubMed  CAS  Google Scholar 

  • Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R et al (2006) A randomized trial of an n-methyl-d-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 63(8):856–864

    Article  PubMed  CAS  Google Scholar 

  • Zschocke J, Zimmermann N, Berning B, Ganal V, Holsboer F, et al (2011) Antidepressant drugs diversely affect autophagy pathways in astrocytes and neurons-dissociation from cholesterol homeostasis. Neuropsychopharmacology 2011: 20

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Acknowledgments

The study was partially supported by a grant from the United States–Israel Binational Science Foundation to Haim Einat and Grant W Anderson (grant # 2011313). The authors would like to thank the Endowment for Medical Research (Huston, TX) for their generous donation of trehalose. We would also like to thank Dr. Shlomit Flaisher-Grinberg, Ms. Sara Schuster, Ms. Keren Raphael, and Mr. Jesse Juetten for their technical assistance.

Conflict of interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beersheba, Israel

    N. Z. Kara, L. Toker, G. Agam & H. Einat

  2. School of Behavioral Sciences, Tel Aviv-Yaffo Academic College, 2 Rabenu Yeruham St, Tel Aviv, Israel

    N. Z. Kara & H. Einat

  3. Psychiatry Research Unit, Faculty of Health Sciences, Ben-Gurion University of the Negev, and Mental Health Center, Beersheba, Israel

    L. Toker, G. Agam & R. H. Belmaker

  4. College of Pharmacy, University of Minnesota, Duluth, MN, USA

    G. W. Anderson & H. Einat

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  1. N. Z. Kara
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  2. L. Toker
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  3. G. Agam
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  4. G. W. Anderson
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  5. R. H. Belmaker
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  6. H. Einat
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Correspondence to H. Einat.

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Kara, N.Z., Toker, L., Agam, G. et al. Trehalose induced antidepressant-like effects and autophagy enhancement in mice. Psychopharmacology 229, 367–375 (2013). https://doi.org/10.1007/s00213-013-3119-4

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  • DOI: https://doi.org/10.1007/s00213-013-3119-4

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