Skip to main content

Advertisement

SpringerLink
Log in

Antidepressant-like effect of artemin in mice: a mechanism for acetyl-l-carnitine activity on depression

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Depression may be associated with altered plasticity of the nervous system. The importance of neurotrophic factor levels is strongly suggested, and the neuronal-related family is extensively studied with respect to glial-derived one.

Objectives

Aimed to contribute to the study of nervous plasticity modulation as therapeutical target in mood disorders, the role of the glial-derived factor artemin (ARTN) in depression and in the pharmacodynamics of the antidepressant and trophic compound acetyl-l-carnitine (ALCAR) was evaluated.

Methods

Male mice were treated with 100 mg kg−1 ALCAR daily for 7 days; 0.6 μg/mouse ARTN was acutely injected intracerebroventricularly. Gene knockdown of ARTN and GDNF family receptor alpha (GFRalpha3) was obtained by oligonucleotide antisense strategy. The forced swimming test was performed to evaluate antidepressant-like effects.

Results

Repeated ALCAR administration increased ARTN levels in spinal cord, hippocampus, and prefrontal cortex. No modulatory effect was detected on BDNF and glial cell line-derived neutrotrophic factor (GDNF). ARTN, 30 min after administration, showed a dose-dependent antidepressant-like effect. ALCAR needed a 7-day treatment to reach a comparable effect; nevertheless, both substances were able to induce a phosphorylation of the GDNF family receptor Ret. A decrease of the free ARTN level by a specific ARTN antibody impaired the antidepressant-like effect of acute ARTN and repeated ALCAR. Gene knockdown of ARTN or, alternatively, of its receptor GFRalpha3 fully prevented ALCAR effectiveness.

Conclusions

A mechanism for the antidepressant property of ALCAR is proposed, and the novelty of the possible role of ARTN in depression is suggested.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

  • Altar CA (1999) Neurotrophins and depression. Trends Pharmacol Sci 20:59–61

    Article  PubMed  CAS  Google Scholar 

  • Alves E, Binienda Z, Carvalho F, Alves CJ, Fernandes E, de Lourdes BM, Tavares MA, Summavielle T (2009) Acetyl-L-carnitine provides effective in vivo neuroprotection over 3,4-methylenedioximethamphetamine-induced mitochondrial neurotoxicity in the adolescent rat brain. Neuroscience 158:514–523

    Article  PubMed  CAS  Google Scholar 

  • Andres R, Forgie A, Wyatt S, Chen Q, de Sauvage FJ, Davies AM (2001) Multiple effects of artemin on sympathetic neurone generation, survival and growth. Development 128:3685–3695

    PubMed  CAS  Google Scholar 

  • Baloh RH, Tansey MG, Lampe PA, Fahrner TJ, Enomoto H, Simburger KS et al (1998) Artemin, a novel member of the GDNF ligand family, supports peripheral and central neurons and signals through the GFR[alpha]3-RET receptor complex. Neuron 21:1291–1302

    Article  PubMed  CAS  Google Scholar 

  • Bella R, Biondi R, Raffaele R, Pennisi G (1990) Effect of acetyl-L-carnitine on geriatric patients suffering from dysthymic disorders. Int J Clin Pharmacol Res 10:355–360

    PubMed  CAS  Google Scholar 

  • Bespalov MM, Saarma M (2007) GDNF family receptor complexes are emerging drug targets. Trends Pharmacol Sci 28:68–74

    Article  PubMed  CAS  Google Scholar 

  • Boldrini M, Underwood MD, Hen R, Rosoklija GB, Dwork AJ, John Mann J, Arango V (2009) Antidepressants increase neural progenitor cells in the human hippocampus. Neuropsychopharmacology 34:2376–2389

    Article  PubMed  CAS  Google Scholar 

  • Bremner JD, Krystal JH, Southwick SM, Charney DS (1995) Functional neuroanatomical correlates of the effects of stress on memory. J Trauma Stress 8:527–553

    Article  PubMed  CAS  Google Scholar 

  • Castren E (2004) Neurotrophic effects of antidepressant drugs. Curr Opin Pharmacol 4:58–64

    Article  PubMed  CAS  Google Scholar 

  • Castrèn E, Voikar V, Rantamaki T (2007) Role of neurotrophic factors in depression. Curr Opin Pharmacol 7:18–21

    Article  PubMed  Google Scholar 

  • Chen B, Dowlatshahi D, MacQueen GM, Wang JF, Young LT (2001) Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication. Biol Psychiatry 50:260–265

    Article  PubMed  CAS  Google Scholar 

  • Cotter D, Mackay D, Chana G, Beasley C, Landau S, Everall IP (2002) Reduced neuronal size and glial cell density in area 9 of the dorsolateral prefrontal cortex in subjects with major depressive disorder. Cereb Cortex 12:386–394

    Article  PubMed  Google Scholar 

  • De Simone C, Catania S, Trinchieri V, Tzantzoglou S, Calvani M, Bagiella E (1988) Amelioration of the depression of HIV-infected subjects with l-acetyl-carnitine therapy. J Drug Dev 1:163–166

    Google Scholar 

  • Detke MJ, Johnson J, Lucki I (1997) Acute and chronic antidepressant drug treatment in the rat forced swimming test model of depression. Exp Clin Psychopharmacol 5:107–112

    Article  PubMed  CAS  Google Scholar 

  • Duman RS, Monteggia LM (2006) A neurotrophic model for stress-related mood disorders. Biol Psychiatry 59:1116–1127

    Article  PubMed  CAS  Google Scholar 

  • Eisch AJ, Bolanos CA, De Wit J, Simonak RD, Pudiak CM, Barrot M, Verhaagen J, Nestler EJ (2003) Brain-derived neurotrophic factor in the ventral midbrain–nucleus accumbens pathway: a role in depression. Biol Psychiatry 54:994–1005

    Article  PubMed  CAS  Google Scholar 

  • Fariello RG, Ferraro TN, Golden GT, Demattei M (1988) Systemic acetyl-carnitine elevates nigral levels of glutathione and GABA. Life Sci 43:289–292

    Article  PubMed  CAS  Google Scholar 

  • Foreman PJ, Perez-Polo JR, Angelucci L, Ramacci MT, Taglialatela G (1995) Effects of acetyl-L-carnitine treatment and stress exposure on the nerve growth factor receptor (p75NGFR) mRNA level in the central nervous system of aged rats. Prog Neuropsychopharmacol Biol Psychiatry 19:117–133

    Article  PubMed  CAS  Google Scholar 

  • Fuchs E, Czeh B, Kole MHP, Michaelis T, Lucassen PJ (2004) Alterations of neuroplasticity in depression: the hippocampus and beyond. Eur Neuropsychopharmacol 14:S481–S490

    Article  PubMed  CAS  Google Scholar 

  • Galeotti N, Bartolini A, Ghelardini C (2003) The phospholipase C-IP3 pathway is involved in muscarinic antinociception. Neuropsychopharmacology 28:888–897

    Article  PubMed  CAS  Google Scholar 

  • Garzya G, Corallo D, Fiore A, Lecciso G, Petrelli G, Zotti C (1990) Evaluation of the effects of L-acetylcarnitine on senile patients suffering from depression. Drugs Exp Clin Res 16:101–106

    PubMed  CAS  Google Scholar 

  • Gecele M, Francesetti G, Meluzzi A (1991) Acetyl-L-carnitine in aged subjects with major depression: clinical efficacy and effects on the circadian rhythm of cortisol. Dementia 2:333–337

    Google Scholar 

  • Guerrini G, Costanzo A, Ciciani G, Bruni F, Selleri S, Costagli C, Besnard F, Costa B, Martini C, De Siena G, Malmberg-Aiello P (2006) Benzodiazepine receptor ligands. 8: synthesis and pharmacological evaluation of new pyrazolo[5,1-c] [1,2,4]benzotriazine 5-oxide 3- and 8-disubstituted: high affinity ligands endowed with inverse-agonist pharmacological efficacy. Bioorg Med Chem 14:758–775

    Article  PubMed  CAS  Google Scholar 

  • Imperato A, Ramacci MT, Angelucci L (1989) Acetyl-L-carnitine enhances acetylcholine release in the striatum and hippocampus of awake freely moving rats. Neurosci Lett 107:251–255

    Article  PubMed  CAS  Google Scholar 

  • Inano A, Sai Y, Nikaido H, Hasimoto N, Asano M, Tsuji A, Tamai I (2003) Acetyl-L-carnitine permeability across the blood–brain barrier and involvement of carnitine transporter OCTN2. Biopharm Drug Dispos 24:357–365

    Article  PubMed  CAS  Google Scholar 

  • Jeong DG, Park WK, Park S (2008) Artemin activates axonal growth via SFK and ERK-dependent signalling pathways in mature dorsal root ganglia neurons. Cell Biochem Funct 26:210–220

    Article  PubMed  CAS  Google Scholar 

  • Kidd PM (2008) Alzheimer’s disease, amnestic mild cognitive impairment, and age-associated memory impairment: current understanding and progress toward integrative prevention. Altern Med Rev 13:85–115

    PubMed  Google Scholar 

  • Kornack DR, Rakic P (1999) Continuation of neurogenesis in the hippocampus of the adult macaque monkey. Proc Natl Acad Sci USA 96:5768–5773

    Article  PubMed  CAS  Google Scholar 

  • Le Hir H, Colucci-DAmato LG, Charlet-Berguerand N, Plouin PF, Bertagna X, de Franciscis V, Thermes C (2000) High levels of tyrosine phosphorylated proto-ret in sporadic pheochromocytomas. Cancer Res 60:1365–1370

    PubMed  Google Scholar 

  • Lopez-Rodriguez F, Kim J, Poland RE (2004) Total sleep deprivation decreases immobility in the forced-swim test. Neuropsychopharmacology 29:1105–1111

    Article  PubMed  CAS  Google Scholar 

  • Manfridi A, Forloni GL, Arrigoni-Martelli E, Mancia M (1992) Culture of dorsal root ganglion neurons from aged rats: effects of acetyl-L-carnitine and NGF. Int J Dev Neurosci 10:321–329

    Article  PubMed  CAS  Google Scholar 

  • Mansour HH (2006) Protective role of carnitine ester against radiation-induced oxidative stress in rats. Pharmacol Res 54:165–171

    Article  PubMed  CAS  Google Scholar 

  • Michel TM, Frangou S, Camara S, Thiemeyer D, Jecel J, Tatschner T, Zoechling R, Grunblatt E (2008) Altered glial cell line-derived neurotrophic factor (GDNF) concentrations in the brain of patients with depressive disorder: a comparative post-mortem study. Eur Psychiatry 23:413–420

    Article  PubMed  Google Scholar 

  • Nishino J, Mochida K, Ohfuji Y, Shimazaki T, Meno C, Ohishi S et al (1999) GFR[alpha]3, a component of the artemin receptor is required for migration and survival of the superior cervical ganglion. Neuron 23:725–736

    Article  PubMed  CAS  Google Scholar 

  • Otsuki K, Uchida S, Watanuki T, Wakabayashi Y, Fujimoto M, Matsubara T, Funato H, Watanabe Y (2008) Altered expression of neurotrophic factors in patients with major depression. J Psychiatr Res 42:1145–1153

    Article  PubMed  Google Scholar 

  • Pettegrew JW, Levine J, McClure RJ (2000) Acetyl-L-carnitine physical-chemical, metabolic, and therapeutic properties: relevance for its mode of action in Alzheimer’s disease and geriatric depression. Mol Psychiatry 5:616–632

    Article  PubMed  CAS  Google Scholar 

  • Pettegrew JW, Levine J, Gershon S, Stanley JA, Servan-Schreiber D, Panchalingam K, McClure RJ (2002) 31P-MRS study of acetyl-L-carnitine treatment in geriatric depression: preliminary results. Bipolar Disord 4:61–66

    Article  PubMed  CAS  Google Scholar 

  • Piovesan P, Pacifici L, Taglialatela G, Ramacci MT, Angelucci L (1994) Acetyl-L-carnitine treatment increases choline acetyltransferase activity and NGF levels in the CNS of adult rats following total fimbria-fornix transection. Brain Res 633:77–82

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Quartu M, Serra MP, Manca A, Mascia F, FollesA P, Del Fiacco M (2005) Neurturin, persephin, and artemin in the human pre- and full-term newborn and adult hippocampus and fascia dentate. Brain Res 1041:157–166

    Article  PubMed  CAS  Google Scholar 

  • Rajkowska G, Miguel-Hidalgo JJ (2007) Gliogenesis and glial pathology in depression. CNS Neurol Disord Drug Targets 6:219–233

    Article  PubMed  CAS  Google Scholar 

  • Rajkowska G, Miguel-Hidalgo JJ, Wei J, Dilley G, Pittman SD, Meltzer HY et al (1999) Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biol Psychiatry 45:1085–1098

    Article  PubMed  CAS  Google Scholar 

  • Rajkowska G, Halaris A, Selemon LD (2001) Reductions on neuronal and glial density and characterize the dorsolateral prefrontal cortex in bipolar disorder. Biol Psychiatry 49:741–752

    Article  PubMed  CAS  Google Scholar 

  • Saarelainen T, Hendolin P, Lucas G, Koponen E, Sairanen M, MacDonald E, Agerman K, Haapasalo A, Nawa H, Aloyz R et al (2003) Activation of the TrkB neurotrophin receptor is induced by antidepressant drugs and is required for antidepressant-induced behavioral effects. J Neurosci 23:349–357

    PubMed  CAS  Google Scholar 

  • Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O et al (2003) Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301:805–809

    Article  PubMed  CAS  Google Scholar 

  • Scafidi S, Fiskum G, Lindauer SL, Bamford P, Shi D, Hopkins I, McKenna MC (2010) Metabolism of acetyl-L-carnitine for energy and neurotransmitter synthesis in the immature rat brain. J Neurochem 114:820–831

    Article  PubMed  CAS  Google Scholar 

  • Sheline YI, Sanghavi M, Mintun MA, Gado MH (1999) Depression duration but not age predicts hippocampal volume loss in medically healthy women with recurrent major depression. J Neurosci 19:5034–5043

    PubMed  CAS  Google Scholar 

  • Sheline YI, Mittler BL, Mintun MA (2002) The hippocampus and depression. Eur Psychiatry 17:300–305

    Article  PubMed  Google Scholar 

  • Strelau J, Unsicker K (1999) GDNF family members and their receptors: expression and functions in two oligodendroglial cell lines representing distinct stages of oligodendroglial development. Glia 26:291–330

    Article  PubMed  CAS  Google Scholar 

  • Stromberg I, Bjorklund L, Johansson M, Tomac A, Collins F, Olson L et al (1993) Glial cell line-derived neurotrophic factor is expressed in the developing but not adult striatum and stimulates developing dopamine neurons in vivo. Exp Neurol 124:401–412

    Article  PubMed  CAS  Google Scholar 

  • Taglialatela G, Angelucci L, Ramacci MT, Werrbach-Perez K, Jackson GR, Perez-Polo JR (1991) Acetyl-L-carnitine enhances the response of PC12 cells to nerve growth factor. Brain Res Dev Brain Res 59:221–230

    Article  PubMed  CAS  Google Scholar 

  • Tempesta E, Janiri L, Pirrongelli C (1985) Stereospecific effects of acetylcarnitine on the spontaneous activity of brainstem neurones and their responses to acetylcholine and serotonin. Neuropharmacology 24:43–50

    Article  PubMed  CAS  Google Scholar 

  • Tempesta E, Casella L, Pirrongelli C, Janiri L, Calvani M, Ancona L (1987) L-acetylcarnitine in depressed elderly subjects. A cross-over study vs placebo. Drug Exp Clin Res 13:417–423

    CAS  Google Scholar 

  • Tolu P, Masi F, Leggio B, Scheggi S, Tagliamonte A, De Montis MG, Gambarana C (2002) Effects of long-term acetyl-L-carnitine administration in rats: I. increased dopamine output in mesocorticolimbic areas and protection toward acute stress exposure. Neuropsychopharmacol 27:410–420

    Article  CAS  Google Scholar 

  • Villardita C, Smini P, Vecchio I (1984) L-Acetylcarnitine in depressed and elderly patients. Eur Rev Med Pharmacol 62:341–344

    Google Scholar 

  • Virmani MA, Biselli R, Spadoni A, Rossi S, Corsico N, Calvani M, Fattorossi A, De Simone C, Arrigoni-Martelli E (1995) Protective actions of L-carnitine and acetyl-L-carnitine on the neurotoxicity evoked by mitochondrial uncoupling or inhibitors. Pharmacol Res 32:383–389

    Article  PubMed  CAS  Google Scholar 

  • Vivoli E, Di Cesare ML, Salvicchi A, Bartolini A, Koverech A, Nicolai R, Benatti P, Ghelardini C (2010) Acetyl-l-carnitine increases artemin level and prevents neurotrophic factor alterations during neuropathy. Neuroscience 167:1168–1174

    Article  PubMed  CAS  Google Scholar 

  • Warnecke A, Scheper V, Buhr I, Wenzel GI, Wissel K, Paasche G, Berkingali N, Jørgensen JR, Lenarz T, Stöver T (2010) Artemin improves survival of spiral ganglion neurons in vivo and in vitro. Neuroreport 21:517–521

    Article  PubMed  CAS  Google Scholar 

  • Willner P (1984) The validity of animal models of depression. Psychopharmacology 83:1–16

    Article  PubMed  CAS  Google Scholar 

  • Zanardi R, Smeraldi E (2006) A double-blind, randomised, controlled clinical trial of acetyl-L-carnitine vs. amisulpride in the treatment of dysthymia. Eur Neuropsychopharmacol 16:281–287

    Article  PubMed  CAS  Google Scholar 

  • Zhang X, Zhang Z, Xie C, Xi G, Zhou H, Zhang Y et al (2008) Effect of treatment on serum glial cell line-derived neurotrophic factor in depressed patients. Prog Neuropsychopharmacol Biol Psychiatry 32:886–890

    Article  PubMed  CAS  Google Scholar 

  • Zihlmann KB, Ducray AD, Schaller B, Huber AW, Krebs SH, Andres RH et al (2005) The GDNF family members neurturin, artemin and persephin promote the morphological differentiation of cultured ventral mesencephalic dopaminergic neurons. Brain Res Bull 68:42–53

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors declare that this work was funded by the Italian Ministry of Instruction, University and Research and by Sigma-Tau Industrie Farmaceutiche Riunite.

Author information

Authors and Affiliations

  1. Department of Preclinical and Clinical Pharmacology, University of Florence, Viale Pieraccini 6, 50139, Florence, Italy

    Lorenzo Di Cesare Mannelli, Elisa Vivoli, Alberto Salvicchi, Alessandro Bartolini & Carla Ghelardini

  2. Department of Experimental Pathology and Oncology, University of Florence, Viale Morgagni 85, 50134, Florence, Italy

    Nicola Schiavone

  3. Sigma-Tau Industrie Farmaceutiche Riunite S.p.A, Via Pontina km 30,400, 00040, Pomezia, Rome, Italy

    Aleardo Koverech, Masa Messano, Raffaella Nicolai & Paola Benatti

Authors
  1. Lorenzo Di Cesare Mannelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elisa Vivoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alberto Salvicchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nicola Schiavone
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Aleardo Koverech
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Masa Messano
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Raffaella Nicolai
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Paola Benatti
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Alessandro Bartolini
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Carla Ghelardini
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lorenzo Di Cesare Mannelli.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Di Cesare Mannelli, L., Vivoli, E., Salvicchi, A. et al. Antidepressant-like effect of artemin in mice: a mechanism for acetyl-l-carnitine activity on depression. Psychopharmacology 218, 347–356 (2011). https://doi.org/10.1007/s00213-011-2326-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-011-2326-0

Keywords

Search

Navigation