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Therapeutic Potential of N-Acetyl-Glucagon-Like Peptide-1 in Primary Motor Neuron Cultures Derived From Non-Transgenic and SOD1-G93A ALS Mice

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Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the death of motor neurons (MN) in the motor cortex, brain stem, and spinal cord. In the present study, we established an ALS in vitro model of purified embryonic MNs, derived from non-transgenic and mutant SOD1-G93A transgenic mice, the most commonly used ALS animal model. MNs were cultured together with either non-transgenic or mutant SOD1-G93A astrocyte feeder layers. Cell viability following exposure to kainate as excitotoxic stimulus was assessed by immunocytochemistry and calcium imaging. We then examined the neuroprotective effects of N-acetyl-GLP-1(7-34) amide (N-ac-GLP-1), a long-acting, N-terminally acetylated, C-terminally truncated analog of glucagon-like peptide-1 (GLP-1). GLP-1 has initially been studied as a treatment for type II diabetes based on its function as insulin secretagogue. We detected neuroprotective effects of N-ac-GLP-1 in our in vitro system, which could be attributed to an attenuation of intracellular calcium transients, not only due to these antiexcitotoxic capacities but also with respect to the increasing knowledge about metabolic deficits in ALS which could be positively influenced by N-ac-GLP-1, this compound represents an interesting novel candidate for further in vivo evaluation in ALS.

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Abbreviations

KA:

Kainate

N-ac-GLP-1:

N-Acetyl-glucagon-like peptide-1

ALS:

Amyotrophic lateral sclerosis

MN:

Motor neuron

A:

Astrocyte

SMI 32:

Monoclonal antibody to neurofilaments, phosphorylated epitope

MAPK:

Mitogen-activated protein kinase

PKA:

Protein kinase A

PI3K:

Phosphoinositide 3-kinase

CREB:

cAMP response element-binding

References

  • Baba NH, Sawaya S, Torbay N, Habbal Z, Azar S, Hashim SA (1999) High protein vs high carbohydrate hypoenergetic diet for the treatment of obese hyperinsulinemic subjects. Int J Obes Relat Metab Disord 23(11):1202–1206

    Article  PubMed  CAS  Google Scholar 

  • Barbin G, Katz DM, Chamak B, Glowinski J, Prochiantz A (1988) Brain astrocytes express region-specific surface glycoproteins in culture. Glia 1(1):96–103. doi:10.1002/glia.440010111

    Article  PubMed  CAS  Google Scholar 

  • Bensimon G, Lacomblez L, Meininger V (1994) A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group. N Engl J Med 330(9):585–591. doi:10.1056/NEJM199403033300901

    Article  PubMed  CAS  Google Scholar 

  • Bertilsson G, Patrone C, Zachrisson O, Andersson A, Dannaeus K, Heidrich J, Kortesmaa J, Mercer A, Nielsen E, Ronnholm H, Wikstrom L (2008) Peptide hormone exendin-4 stimulates subventricular zone neurogenesis in the adult rodent brain and induces recovery in an animal model of Parkinson’s disease. J Neurosci Res 86(2):326–338. doi:10.1002/jnr.21483

    Article  PubMed  CAS  Google Scholar 

  • Bogaert E, d’Ydewalle C, Van Den Bosch L (2010) Amyotrophic lateral sclerosis and excitotoxicity: from pathological mechanism to therapeutic target. CNS Neurol Disord 9(3):297–304

    Article  CAS  Google Scholar 

  • Brandoli C, Sanna A, De Bernardi MA, Follesa P, Brooker G, Mocchetti I (1998) Brain-derived neurotrophic factor and basic fibroblast growth factor downregulate NMDA receptor function in cerebellar granule cells. J Neurosci 18(19):7953–7961

    PubMed  CAS  Google Scholar 

  • Browne SE, Yang L, DiMauro JP, Fuller SW, Licata SC, Beal MF (2006) Bioenergetic abnormalities in discrete cerebral motor pathways presage spinal cord pathology in the G93A SOD1 mouse model of ALS. Neurobiol Dis 22(3):599–610. doi:10.1016/j.nbd.2006.01.001

    Article  PubMed  CAS  Google Scholar 

  • Campos RV, Lee YC, Drucker DJ (1994) Divergent tissue-specific and developmental expression of receptors for glucagon and glucagon-like peptide-1 in the mouse. Endocrinology 134(5):2156–2164

    Article  PubMed  CAS  Google Scholar 

  • Carbone M, Duty S, Rattray M (2012) Riluzole neuroprotection in a Parkinson’s disease model involves suppression of reactive astrocytosis but not GLT-1 regulation. BMC Neurosci 13:38. doi:10.1186/1471-2202-13-38

    Article  PubMed  CAS  Google Scholar 

  • Carriedo SG, Yin HZ, Weiss JH (1996) Motor neurons are selectively vulnerable to AMPA/kainate receptor-mediated injury in vitro. J Neurosci 16(13):4069–4079

    PubMed  CAS  Google Scholar 

  • Carriedo SG, Sensi SL, Yin HZ, Weiss JH (2000) AMPA exposures induce mitochondrial Ca(2+) overload and ROS generation in spinal motor neurons in vitro. J Neurosci 20(1):240–250

    PubMed  CAS  Google Scholar 

  • Chamak B, Fellous A, Glowinski J, Prochiantz A (1987) MAP2 expression and neuritic outgrowth and branching are coregulated through region-specific neuro-astroglial interactions. J Neurosci 7(10):3163–3170

    PubMed  CAS  Google Scholar 

  • Clement AM, Nguyen MD, Roberts EA, Garcia ML, Boillee S, Rule M, McMahon AP, Doucette W, Siwek D, Ferrante RJ, Brown RH Jr, Julien JP, Goldstein LS, Cleveland DW (2003) Wild-type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice. Science 302(5642):113–117. doi:10.1126/science.1086071302/5642/113

    Article  PubMed  CAS  Google Scholar 

  • Cleveland DW, Rothstein JD (2001) From Charcot to Lou Gehrig: deciphering selective motor neuron death in ALS. Nat Rev Neurosci 2(11):806–819. doi:10.1038/3509756535097565

    Article  PubMed  CAS  Google Scholar 

  • Di Giorgio FP, Carrasco MA, Siao MC, Maniatis T, Eggan K (2007) Non-cell autonomous effect of glia on motor neurons in an embryonic stem cell-based ALS model. Nat Neurosci 10(5):608–614

    Article  PubMed  Google Scholar 

  • Dorst J, Kuhnlein P, Hendrich C, Kassubek J, Sperfeld AD, Ludolph AC (2011) Patients with elevated triglyceride and cholesterol serum levels have a prolonged survival in amyotrophic lateral sclerosis. J Neurol 258(4):613–617. doi:10.1007/S00415-010-5805-Z

    Article  PubMed  CAS  Google Scholar 

  • Dupuis L, Oudart H, Rene F, Gonzalez de Aguilar JL, Loeffler JP (2004) Evidence for defective energy homeostasis in amyotrophic lateral sclerosis: benefit of a high-energy diet in a transgenic mouse model. Proc Natl Acad Sci USA 101(30):11159–11164. doi:10.1073/pnas.04020261010402026101

    Article  PubMed  CAS  Google Scholar 

  • Dupuis L, Corcia P, Fergani A, Gonzalez De Aguilar JL, Bonnefont-Rousselot D, Bittar R, Seilhean D, Hauw JJ, Lacomblez L, Loeffler JP, Meininger V (2008) Dyslipidemia is a protective factor in amyotrophic lateral sclerosis. Neurology 70(13):1004–1009. doi:10.1212/01.wnl.0000285080.70324.27

    Article  PubMed  CAS  Google Scholar 

  • Dupuis L, Pradat PF, Ludolph AC, Loeffler JP (2011) Energy metabolism in amyotrophic lateral sclerosis. Lancet Neurol 10(1):75–82. doi:10.1016/S1474-4422(10)70224-6

    Article  PubMed  CAS  Google Scholar 

  • During MJ, Cao L, Zuzga DS, Francis JS, Fitzsimons HL, Jiao X, Bland RJ, Klugmann M, Banks WA, Drucker DJ, Haile CN (2003) Glucagon-like peptide-1 receptor is involved in learning and neuroprotection. Nat Med 9(9):1173–1179. doi:10.1038/nm919nm919

    Article  PubMed  CAS  Google Scholar 

  • Fortin JP, Schroeder JC, Zhu YTE, Beinborn M, Kopin AS (2010) Pharmacological characterization of human incretin receptor missense variants. J Pharmacol Exp Ther 332(1):274–280. doi:10.1124/jpet.109.160531

    Article  PubMed  CAS  Google Scholar 

  • Gilman CP, Perry T, Furukawa K, Grieg NH, Egan JM, Mattson MP (2003) Glucagon-like peptide 1 modulates calcium responses to glutamate and membrane depolarization in hippocampal neurons. J Neurochem 87(5):1137–1144

    Article  PubMed  CAS  Google Scholar 

  • Grosskreutz J, Haastert K, Dewil M, Van Damme P, Callewaert G, Robberecht W, Dengler R, Van Den Bosch L (2007) Role of mitochondria in kainate-induced fast Ca2 + transients in cultured spinal motor neurons. Cell Calcium 42(1):59–69. doi:10.1016/j.ceca.2006.11.010

    Article  PubMed  CAS  Google Scholar 

  • Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY, Alexander DD, Caliendo J, Hentati A, Kwon YW, Deng HX et al (1994) Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science 264(5166):1772–1775

    Article  PubMed  CAS  Google Scholar 

  • Hamilton A, Holscher C (2009) Receptors for the incretin glucagon-like peptide-1 are expressed on neurons in the central nervous system. NeuroReport 20(13):1161–1166. doi:10.1097/Wnr.0b013e32832fbf14

    Article  PubMed  CAS  Google Scholar 

  • Hamilton A, Patterson S, Porter D, Gault VA, Holscher C (2011) Novel GLP-1 mimetics developed to treat type 2 diabetes promote progenitor cell proliferation in the brain. J Neurosci Res 89(4):481–489. doi:10.1002/jnr.22565

    Article  PubMed  CAS  Google Scholar 

  • Jahn K, Grosskreutz J, Haastert K, Ziegler E, Schlesinger F, Grothe C, Dengler R, Bufler J (2006) Temporospatial coupling of networked synaptic activation of AMPA-type glutamate receptor channels and calcium transients in cultured motoneurons. Neuroscience 142(4):1019–1029. doi:10.1016/j.neuroscience.2006.07.034

    Article  PubMed  CAS  Google Scholar 

  • John H, Maronde E, Forssmann WG, Meyer M, Adermann K (2008) N-terminal acetylation protects glucagon-like peptide GLP-1-(7–34)-amide from DPP-IV-mediated degradation retaining cAMP- and insulin-releasing capacity. Eur J Med Res 13(2):73–78

    PubMed  CAS  Google Scholar 

  • Kanazawa I (2001) How do neurons die in neurodegenerative diseases? Trends Mol Med 7(8):339–344

    Article  PubMed  CAS  Google Scholar 

  • Kim YK, Park JH, Park SH, Lim B, Baek WK, Suh SI, Lim JG, Ryu GR, Song DK (2010) Protective role of glucagon-like peptide-1 against glucosamine-induced cytotoxicity in pancreatic beta cells. Cell Physiol Biochem 25(2–3):211–220. doi:10.1159/000276555

    Article  PubMed  CAS  Google Scholar 

  • Klivenyi P, Ferrante RJ, Matthews RT, Bogdanov MB, Klein AM, Andreassen OA, Mueller G, Wermer M, Kaddurah-Daouk R, Beal MF (1999) Neuroprotective effects of creatine in a transgenic animal model of amyotrophic lateral sclerosis. Nat Med 5(3):347–350. doi:10.1038/6568

    Article  PubMed  CAS  Google Scholar 

  • Kotsiari A, Voss EV, Pul R, Skripuletz T, Ragancokova D, Trebst C, Stangel M (2010) Interferon-beta treatment normalises the inhibitory effect of serum from multiple sclerosis patients on oligodendrocyte progenitor proliferation. Neurosci Lett 485(2):107–111. doi:10.1016/j.neulet.2010.08.075

    Article  PubMed  CAS  Google Scholar 

  • Lau A, Tymianski M (2010) Glutamate receptors, neurotoxicity and neurodegeneration. Pflugers Arch 460(2):525–542. doi:10.1007/s00424-010-0809-1

    Article  PubMed  CAS  Google Scholar 

  • Lee SH, Kim WT, Cornell-Bell AH, Sontheimer H (1994) Astrocytes exhibit regional specificity in gap-junction coupling. Glia 11(4):315–325. doi:10.1002/glia.440110404

    Article  PubMed  CAS  Google Scholar 

  • Li Y, Perry T, Kindy MS, Harvey BK, Tweedie D, Holloway HW, Powers K, Shen H, Egan JM, Sambamurti K, Brossi A, Lahiri DK, Mattson MP, Hoffer BJ, Wang Y, Greig NH (2009) GLP-1 receptor stimulation preserves primary cortical and dopaminergic neurons in cellular and rodent models of stroke and Parkinsonism. Proc Natl Acad Sci USA 106(4):1285–1290. doi:10.1073/pnas.0806720106

    Article  PubMed  CAS  Google Scholar 

  • Li Y, Tweedie D, Mattson MP, Holloway HW, Greig NH (2010) Enhancing the GLP-1 receptor signaling pathway leads to proliferation and neuroprotection in human neuroblastoma cells. J Neurochem 113(6):1621–1631. doi:10.1111/j.1471-4159.2010.06731.x

    PubMed  CAS  Google Scholar 

  • Li Y, Chigurupati S, Holloway HW, Mughal M, Tweedie D, Bruestle DA, Mattson MP, Wang Y, Harvey BK, Ray B, Lahiri DK, Greig NH (2012) Exendin-4 ameliorates motor neuron degeneration in cellular and animal models of amyotrophic lateral sclerosis. PLoS one 7(2):e32008. doi:10.1371/journal.pone.0032008PONE-D-11-18962

    Article  PubMed  CAS  Google Scholar 

  • Lovshin JA, Drucker DJ (2009) Incretin-based therapies for type 2 diabetes mellitus. Nat Rev Endocrinol 5(5):262–269. doi:10.1038/nrendo.2009.48

    Article  PubMed  CAS  Google Scholar 

  • MacDonald PE, El-Kholy W, Riedel MJ, Salapatek AM, Light PE, Wheeler MB (2002) The multiple actions of GLP-1 on the process of glucose-stimulated insulin secretion. Diabetes 51(Suppl 3):S434–S442

    Article  PubMed  CAS  Google Scholar 

  • Martin D, Thompson MA, Nadler JV (1993) The neuroprotective agent riluzole inhibits release of glutamate and aspartate from slices of hippocampal area Ca1. Eur J Pharmacol 250(3):473–476. doi:10.1016/0014-2999(93)90037-I

    Article  PubMed  CAS  Google Scholar 

  • Mattson MP (2003) Excitotoxic and excitoprotective mechanisms: abundant targets for the prevention and treatment of neurodegenerative disorders. Neuromol Med 3(2):65–94. doi:10.1385/NMM:3:2:65

    Article  CAS  Google Scholar 

  • Mattson MP, Lovell MA, Furukawa K, Markesbery WR (1995) Neurotrophic factors attenuate glutamate-induced accumulation of peroxides, elevation of intracellular Ca2 + concentration, and neurotoxicity and increase antioxidant enzyme activities in hippocampal neurons. J Neurochem 65(4):1740–1751

    Article  PubMed  CAS  Google Scholar 

  • McClean PL, Parthsarathy V, Faivre E, Holscher C (2011) The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer’s disease. J Neurosci 31(17):6587–6594. doi:10.1523/JNEUROSCI.0529-11.2011

    Article  PubMed  CAS  Google Scholar 

  • Nagai M, Re DB, Nagata T, Chalazonitis A, Jessell TM, Wichterle H, Przedborski S (2007) Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons. Nat Neurosci 10(5):615–622. doi:10.1038/nn1876

    Article  PubMed  CAS  Google Scholar 

  • Pasinelli P, Brown RH (2006) Molecular biology of amyotrophic lateral sclerosis: insights from genetics. Nat Rev Neurosci 7(9):710–723. doi:10.1038/nrn1971

    Article  PubMed  CAS  Google Scholar 

  • Perry T, Haughey NJ, Mattson MP, Egan JM, Greig NH (2002) Protection and reversal of excitotoxic neuronal damage by glucagon-like peptide-1 and exendin-4. J Pharmacol Exp Ther 302(3):881–888. doi:10.1124/jpet.102.037481

    Article  PubMed  CAS  Google Scholar 

  • Perry T, Lahiri DK, Sambamurti K, Chen D, Mattson MP, Egan JM, Greig NH (2003) Glucagon-like peptide-1 decreases endogenous amyloid-beta peptide (Abeta) levels and protects hippocampal neurons from death induced by Abeta and iron. J Neurosci Res 72(5):603–612. doi:10.1002/jnr.10611

    Article  PubMed  CAS  Google Scholar 

  • Pradat PF, Bruneteau G, Gordon PH, Dupuis L, Bonnefont-Rousselot D, Simon D, Salachas F, Corcia P, Frochot V, Lacorte JM, Jardel C, Coussieu C, Le Forestier N, Lacomblez L, Loeffler JP, Meininger V (2010) Impaired glucose tolerance in patients with amyotrophic lateral sclerosis. Amyotroph Lateral Scler 11(1–2):166–171. doi:10.3109/17482960902822960

    Article  PubMed  CAS  Google Scholar 

  • Ragancokova D, Jahn K, Kotsiari A, Schlesinger F, Haastert K, Stangel M, Petri S, Krampfl K (2009) Analysis of neuroprotective effects of valproic acid on primary motor neurons in monoculture or co-cultures with astrocytes or Schwann cells. Cell Mol Neurobiol 29(6–7):1037–1043. doi:10.1007/s10571-009-9393-3

    Article  PubMed  CAS  Google Scholar 

  • Rosen DR (2004) A shared chromosome-21 haplotype among amyotrophic lateral sclerosis families with the A4V SOD1 mutation. Clin Genet 66(3):247–250. doi:10.1111/j.1399-0004.2004.00298.xCGE298

    Article  PubMed  CAS  Google Scholar 

  • Thau N, Jungnickel J, Knippenberg S, Ratzka A, Dengler R, Petri S, Grothe C (2012) Prolonged survival and milder impairment of motor function in the SOD1 ALS mouse model devoid of fibroblast growth factor 2. Neurobiol Dis 47(2):248–257. doi:10.1016/j.nbd.2012.04.008

    Article  PubMed  CAS  Google Scholar 

  • Vandenberghe W, Van Den Bosch L, Robberecht W (1998) Glial cells potentiate kainate-induced neuronal death in a motoneuron-enriched spinal coculture system. Brain Res 807(1–2):1–10

    Article  PubMed  CAS  Google Scholar 

  • Westergaard N, Fosmark H, Schousboe A (1991) Metabolism and release of glutamate in cerebellar granule cells cocultured with astrocytes from cerebellum or cerebral cortex. J Neurochem 56(1):59–66

    Article  PubMed  CAS  Google Scholar 

  • Wiese S, Herrmann T, Drepper C, Jablonka S, Funk N, Klausmeyer A, Rogers ML, Rush R, Sendtner M (2010) Isolation and enrichment of embryonic mouse motoneurons from the lumbar spinal cord of individual mouse embryos. Nat Protoc 5(1):31–38. doi:10.1038/nprot.2009.193

    Article  PubMed  CAS  Google Scholar 

  • Wong PC, Pardo CA, Borchelt DR, Lee MK, Copeland NG, Jenkins NA, Sisodia SS, Cleveland DW, Price DL (1995) An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria. Neuron 14(6):1105–1116

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We are grateful to C. Kassebaum, C. Hotopp Herrgesell, and A. Niesel for expert technical assistance. Hui Sun was supported by China Scholarship Council.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Neurology, Hannover Medical School, OE 7210, Carl-Neuberg-Straße 1, 30625, Hannover, Germany

    Hui Sun, Sarah Knippenberg, Nadine Thau, Sonja Körner, Reinhard Dengler & Susanne Petri

  2. Center for Systems Neuroscience, Hannover, Germany

    Hui Sun, Sarah Knippenberg, Nadine Thau, Reinhard Dengler & Susanne Petri

  3. Department of Neuroscience, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany

    Daniela Ragancokova

  4. East Hospital, Tongji University, Shanghai, China

    Dongya Huang

  5. Curatis Pharma GmbH Hannover, Hannover, Germany

    Klaus Döhler

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  1. Hui Sun
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  2. Sarah Knippenberg
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  3. Nadine Thau
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  4. Daniela Ragancokova
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  9. Susanne Petri
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Correspondence to Susanne Petri.

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Sun, H., Knippenberg, S., Thau, N. et al. Therapeutic Potential of N-Acetyl-Glucagon-Like Peptide-1 in Primary Motor Neuron Cultures Derived From Non-Transgenic and SOD1-G93A ALS Mice. Cell Mol Neurobiol 33, 347–357 (2013). https://doi.org/10.1007/s10571-012-9900-9

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