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Metformin Inhibits the Development of l-DOPA-Induced Dyskinesia in a Murine Model of Parkinson’s Disease

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Abstract

Metformin is a medication that is widely prescribed for the management of type 2 diabetes. In addition to its anti-diabetic uses, metformin has been proposed as a therapeutically effective drug candidate in various central nervous system disorders, including Parkinson’s disease (PD). PD is characterized by severe movement defects and is commonly treated with the dopamine (DA) precursor 3,4-dihydroxyphenyl-l-alanine (l-DOPA). However, prolonged use of l-DOPA can lead to the development of l-DOPA-induced dyskinesia (LID). Here, we hypothesized that metformin co-treatment would improve LID in the 6-hydroxydopamine (6-OHDA)-lesioned mouse model of PD. Metformin did not interfere the pharmacotherapeutic effects of l-DOPA in the cylinder test. Furthermore, metformin co-treatment with l-DOPA attenuated the development of LID in unilaterally 6-OHDA-lesioned mice. Metformin showed a long-lasting effect on axial, limb, and orofacial abnormal involuntary movement scores for up to 20 days after treatment initiation. Interestingly, persistent enhancement of the mammalian target of rapamycin, dopamine D1 receptor, and extracellular signaling-regulated kinase 1/2 signaling was maintained in the DA-denervated striatum during metformin treatment. Metformin globally normalized the increased glycogen synthase kinase 3β activity induced by chronic treatment of l-DOPA in a manner associated with Akt activation in unilaterally 6-OHDA-lesioned mice. These findings suggest that metformin may have therapeutic potential for the suppression or management of l-DOPA-induced motor complications in patients with PD.

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References

  1. Van Den Eeden SK, Tanner CM, Bernstein AL et al (2003) Incidence of Parkinson’s disease: variation by age, gender, and race/ethnicity. Am J Epidemiol 157(11):1015–1022. https://doi.org/10.1093/aje/kwg068

    Article  Google Scholar 

  2. Cotzias GC (1968) L-Dopa for parkinsonism. N Engl J Med 278(11):630. https://doi.org/10.1056/NEJM196803142781127

    Article  PubMed  CAS  Google Scholar 

  3. Ahlskog JE, Muenter MD (2001) Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature. Mov Disord 16(3):448–458. https://doi.org/10.1002/mds.1090

    Article  PubMed  CAS  Google Scholar 

  4. Cenci MA, Konradi C (2010) Maladaptive striatal plasticity in L-DOPA-induced dyskinesia. Prog Brain Res 183:209–233. https://doi.org/10.1016/S0079-6123(10)83011-0

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  5. Pavon N, Martin AB, Mendialdua A, Moratalla R (2006) ERK phosphorylation and fosb expression are associated with L-DOPA-induced dyskinesia in hemiparkinsonian mice. Biol Psychiatry 59(1):64–74. https://doi.org/10.1016/j.biopsych.2005.05.044

    Article  PubMed  CAS  Google Scholar 

  6. Jenner P (2008) Molecular mechanisms of L-DOPA-induced dyskinesia. Nat Rev Neurosci 9(9):665–677. https://doi.org/10.1038/nrn2471

    Article  PubMed  CAS  Google Scholar 

  7. Fieblinger T, Graves SM, Sebel LE et al (2014) Cell type-specific plasticity of striatal projection neurons in parkinsonism and L-DOPA-induced dyskinesia. Nat Commun 5:5316. https://doi.org/10.1038/ncomms6316

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  8. Shen W, Plotkin JL, Francardo V et al (2015) M4 muscarinic receptor signaling ameliorates striatal plasticity deficits in models of L-DOPA-induced dyskinesia. Neuron 88(4):762–773. https://doi.org/10.1016/j.neuron.2015.10.039

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  9. Santini E, Heiman M, Greengard P, Valjent E, Fisone G (2009) Inhibition of mTOR signaling in Parkinson’s disease prevents L-DOPA-induced dyskinesia. Sci Signal 2(80):ra36. https://doi.org/10.1126/scisignal.2000308

    Article  PubMed  Google Scholar 

  10. Park HY, Kang YM, Kang Y et al (2014) Inhibition of adenylyl cyclase type 5 prevents L-DOPA-induced dyskinesia in an animal model of Parkinson’s disease. J Neurosci 34(35):11744–11753. https://doi.org/10.1523/JNEUROSCI.0864-14.2014

    Article  PubMed  CAS  Google Scholar 

  11. Santini E, Alcacer C, Cacciatore S et al (2009) L-DOPA activates ERK signaling and phosphorylates histone H3 in the striatonigral medium spiny neurons of hemiparkinsonian mice. J Neurochem 108(3):621–633. https://doi.org/10.1111/j.1471-4159.2008.05831.x

    Article  PubMed  CAS  Google Scholar 

  12. Xie CL, Lin JY, Wang MH et al (2016) Inhibition of glycogen synthase kinase-3beta (GSK-3beta) as potent therapeutic strategy to ameliorates L-dopa-induced dyskinesia in 6-OHDA parkinsonian rats. Sci Rep 6:23527. https://doi.org/10.1038/srep23527

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  13. Kanda T, Uchida S (2014) Clinical/pharmacological aspect of adenosine A2A receptor antagonist for dyskinesia. Int Rev Neurobiol 119:127–150. https://doi.org/10.1016/B978-0-12-801022-8.00006-4

    Article  PubMed  Google Scholar 

  14. Duty S (2012) Targeting glutamate receptors to tackle the pathogenesis, clinical symptoms and levodopa-induced dyskinesia associated with Parkinson’s disease. CNS Drugs 26(12):1017–1032. https://doi.org/10.1007/s40263-012-0016-z

    Article  PubMed  CAS  Google Scholar 

  15. Rascol O, Fox S, Gasparini F et al (2014) Use of metabotropic glutamate 5-receptor antagonists for treatment of levodopa-induced dyskinesias. Parkinsonism Relat Disord 20(9):947–956. https://doi.org/10.1016/j.parkreldis.2014.05.003

    Article  PubMed  Google Scholar 

  16. Carta M, Tronci E (2014) Serotonin system implication in l-DOPA-induced dyskinesia: from animal models to clinical investigations. Front Neurol 5:78. https://doi.org/10.3389/fneur.2014.00078

    Article  PubMed  PubMed Central  Google Scholar 

  17. Martin-Montalvo A, Mercken EM, Mitchell SJ et al (2013) Metformin improves healthspan and lifespan in mice. Nat Commun 4:2192. https://doi.org/10.1038/ncomms3192

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  18. Pintana H, Apaijai N, Pratchayasakul W, Chattipakorn N, Chattipakorn SC (2012) Effects of metformin on learning and memory behaviors and brain mitochondrial functions in high fat diet induced insulin resistant rats. Life Sci 91(11–12):409–414. https://doi.org/10.1016/j.lfs.2012.08.017

    Article  PubMed  CAS  Google Scholar 

  19. Labuzek K et al (2010) Quantification of metformin by the HPLC method in brain regions, cerebrospinal fluid and plasma of rats treated with lipopolysaccharide. Pharmacol Rep 62(5):956–965. https://doi.org/10.1016/S1734-1140(10)70357-1

    Article  PubMed  CAS  Google Scholar 

  20. Dulovic M, Jovanovic M, Xilouri M et al (2014) The protective role of AMP-activated protein kinase in alpha-synuclein neurotoxicity in vitro. Neurobiol Dis 63:1–11. https://doi.org/10.1016/j.nbd.2013.11.002

    Article  PubMed  CAS  Google Scholar 

  21. Ng CH, Guan MS, Koh C et al (2012) AMP kinase activation mitigates dopaminergic dysfunction and mitochondrial abnormalities in drosophila models of Parkinson’s disease. J Neurosci 32(41):14311–14317. https://doi.org/10.1523/JNEUROSCI.0499-12.2012

    Article  PubMed  CAS  Google Scholar 

  22. Patil SP, Jain PD, Ghumatkar PJ, Tambe R, Sathaye S (2014) Neuroprotective effect of metformin in MPTP-induced Parkinson’s disease in mice. Neuroscience 277:747–754. https://doi.org/10.1016/j.neuroscience.2014.07.046

    Article  PubMed  CAS  Google Scholar 

  23. Wahlqvist ML, Lee MS, Hsu CC et al (2012) Metformin-inclusive sulfonylurea therapy reduces the risk of Parkinson’s disease occurring with type 2 diabetes in a Taiwanese population cohort. Parkinsonism Relat Disord 18(6):753–758. https://doi.org/10.1016/j.parkreldis.2012.03.010

    Article  PubMed  Google Scholar 

  24. Zhou G, Myers R, Li Y et al (2001) Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 108(8):1167–1174. https://doi.org/10.1172/JCI13505

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  25. Hawley SA, Gadalla AE, Olsen GS, Hardie DG (2002) The antidiabetic drug metformin activates the AMP-activated protein kinase cascade via an adenine nucleotide-independent mechanism. Diabetes 51(8):2420–2425. https://doi.org/10.2337/diabetes.51.8.2420

    Article  PubMed  CAS  Google Scholar 

  26. Pernicova I, Korbonits M (2014) Metformin—mode of action and clinical implications for diabetes and cancer. Nat Rev Endocrinol 10(3):143–156. https://doi.org/10.1038/nrendo.2013.256

    Article  PubMed  CAS  Google Scholar 

  27. Peng M, Huang Y, Tao T et al (2016) Metformin and gefitinib cooperate to inhibit bladder cancer growth via both AMPK and EGFR pathways joining at Akt and Erk. Sci Rep 6:28611. https://doi.org/10.1038/srep28611

    Article  PubMed  PubMed Central  Google Scholar 

  28. Park HY, Ryu YK, Kim YH et al (2016) Gadd45beta ameliorates L-DOPA-induced dyskinesia in a Parkinson’s disease mouse model. Neurobiol Dis 89:169–179. https://doi.org/10.1016/j.nbd.2016.02.013

    Article  PubMed  CAS  Google Scholar 

  29. Rascol O, Perez-Lloret S, Ferreira JJ (2015) New treatments for levodopa-induced motor complications. Mov Disord 30(11):1451–1460. https://doi.org/10.1002/mds.26362

    Article  PubMed  CAS  Google Scholar 

  30. Metman LV, Del Dotto P, LePoole K et al (1999) Amantadine for levodopa-induced dyskinesias: a 1-year follow-up study. Arch Neurol 56(11):1383–1386. https://doi.org/10.1001/archneur.56.11.1383

    Article  PubMed  CAS  Google Scholar 

  31. Bido S, Marti M, Morari M (2011) Amantadine attenuates levodopa-induced dyskinesia in mice and rats preventing the accompanying rise in nigral GABA levels. J Neurochem 118(6):1043–1055. https://doi.org/10.1111/j.1471-4159.2011.07376.x

    Article  PubMed  CAS  Google Scholar 

  32. Lundblad M, Picconi B, Lindgren H, Cenci MA (2004) A model of L-DOPA-induced dyskinesia in 6-hydroxydopamine lesioned mice: relation to motor and cellular parameters of nigrostriatal function. Neurobiol Dis 16(1):110–123. https://doi.org/10.1016/j.nbd.2004.01.007

    Article  PubMed  CAS  Google Scholar 

  33. Lundblad M et al (2005) Pharmacological validation of a mouse model of l-DOPA-induced dyskinesia. Exp Neurol 194(1):66–75. https://doi.org/10.1016/j.expneurol.2005.02.002

    Article  PubMed  CAS  Google Scholar 

  34. Santini E, Valjent E, Usiello A et al (2007) Critical involvement of cAMP/DARPP-32 and extracellular signal-regulated protein kinase signaling in L-DOPA-induced dyskinesia. J Neurosci 27(26):6995–7005. https://doi.org/10.1523/JNEUROSCI.0852-07.2007

    Article  PubMed  CAS  Google Scholar 

  35. Musi N, Hirshman MF, Nygren J et al (2002) Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. Diabetes 51(7):2074–2081. https://doi.org/10.2337/diabetes.51.7.2074

    Article  PubMed  CAS  Google Scholar 

  36. Biever A, Valjent E, Puighermanal E (2015) Ribosomal protein S6 phosphorylation in the nervous system: from regulation to function. Front Mol Neurosci 8:75. https://doi.org/10.3389/fnmol.2015.00075

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  37. Bonito-Oliva A, Pallottino S, Bertran-Gonzalez J et al (2013) Haloperidol promotes mtorc1-dependent phosphorylation of ribosomal protein S6 via dopamine- and camp-regulated phosphoprotein of 32 kda and inhibition of protein phosphatase-1. Neuropharmacology 72:197–203. https://doi.org/10.1016/j.neuropharm.2013.04.043

    Article  PubMed  CAS  Google Scholar 

  38. Sindreu CB, Scheiner ZS, Storm DR (2007) Ca2+-stimulated adenylyl cyclases regulate ERK-dependent activation of MSK1 during fear conditioning. Neuron 53(1):79–89. https://doi.org/10.1016/j.neuron.2006.11.024

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  39. Snyder GL, Allen PB, Fienberg AA et al (2000) Regulation of phosphorylation of the glur1 AMPA receptor in the neostriatum by dopamine and psychostimulants in vivo. J Neurosci 20(12):4480–4488

    Article  PubMed  CAS  Google Scholar 

  40. Urs NM, Snyder JC, Jacobsen JP, Peterson SM, Caron MG (2012) Deletion of GSK3beta in D2R-expressing neurons reveals distinct roles for beta-arrestin signaling in antipsychotic and lithium action. Proc Natl Acad Sci U S A 109(50):20732–20737. https://doi.org/10.1073/pnas.1215489109

    Article  PubMed  PubMed Central  Google Scholar 

  41. Beaulieu JM, Sotnikova TD, Marion S et al (2005) An Akt/beta-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior. Cell 122(2):261–273. https://doi.org/10.1016/j.cell.2005.05.012

    Article  PubMed  CAS  Google Scholar 

  42. Beaulieu JM, Sotnikova TD, Yao WD et al (2004) Lithium antagonizes dopamine-dependent behaviors mediated by an AKT/glycogen synthase kinase 3 signaling cascade. Proc Natl Acad Sci U S A 101(14):5099–5104. https://doi.org/10.1073/pnas.0307921101

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  43. Abdelsaid M, Prakash R, Li W et al (2015) Metformin treatment in the period after stroke prevents nitrative stress and restores angiogenic signaling in the brain in diabetes. Diabetes 64(5):1804–1817. https://doi.org/10.2337/db14-1423

    Article  PubMed  CAS  Google Scholar 

  44. Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA (1995) Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378(6559):785–789. https://doi.org/10.1038/378785a0

    Article  PubMed  CAS  Google Scholar 

  45. Ory-Magne F, Corvol JC, Azulay JP et al (2014) Withdrawing amantadine in dyskinetic patients with Parkinson disease: the AMANDYSK trial. Neurology 82(4):300–307. https://doi.org/10.1212/WNL.0000000000000050

    Article  PubMed  CAS  Google Scholar 

  46. Pahwa R, Tanner CM, Hauser RA et al (2015) Amantadine extended release for levodopa-induced dyskinesia in Parkinson’s disease (EASED Study). Mov Disord 30(6):788–795. https://doi.org/10.1002/mds.26159

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  47. Thomas A, Iacono D, Luciano AL et al (2004) Duration of amantadine benefit on dyskinesia of severe Parkinson’s disease. J Neurol Neurosurg Psychiatry 75(1):141–143

    Article  PubMed  CAS  Google Scholar 

  48. Heikkila RE, Cohen G (1972) Evaluation of amantadine as a releasing agent or uptake blocker for H3-dopamine in rat brain slices. Eur J Pharmacol 20(2):156–160. https://doi.org/10.1016/0014-2999(72)90144-6

    Article  PubMed  CAS  Google Scholar 

  49. Mizoguchi K, Yokoo H, Yoshida M, Tanaka T, Tanaka M (1994) Amantadine increases the extracellular dopamine levels in the striatum by re-uptake inhibition and by N-methyl-D-aspartate antagonism. Brain Res 662(1–2):255–258. https://doi.org/10.1016/0006-8993(94)90821-4

    Article  PubMed  CAS  Google Scholar 

  50. Beaulieu JM, Gainetdinov RR, Caron MG (2009) Akt/GSK3 signaling in the action of psychotropic drugs. Annu Rev Pharmacol Toxicol 49:327–347. https://doi.org/10.1146/annurev.pharmtox.011008.145634

    Article  PubMed  CAS  Google Scholar 

  51. Wider C, Vilariño-Güell C, Heckman MG et al (2011) SNCA, MAPT, and GSK3B in Parkinson disease: a gene-gene interaction study. Eur J Neurol 18(6):876–881. https://doi.org/10.1111/j.1468-1331.2010.03297.x

    Article  PubMed  CAS  Google Scholar 

  52. Petit-Paitel A, Brau F, Cazareth J, Chabry J (2009) Involvment of cytosolic and mitochondrial GSK-3beta in mitochondrial dysfunction and neuronal cell death of MPTP/MPP-treated neurons. PLoS One 4(5):e5491. https://doi.org/10.1371/journal.pone.0005491

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  53. Nagao M, Hayashi H (2009) Glycogen synthase kinase-3beta is associated with Parkinson’s disease. Neurosci Lett 449(2):103–107. https://doi.org/10.1016/j.neulet.2008.10.104

    Article  PubMed  CAS  Google Scholar 

  54. Ge XH, Zhu GJ, Geng DQ et al (2017) Metformin protects the brain against ischemia/reperfusion injury through PI3K/Akt1/JNK3 signaling pathways in rats. Physiol Behav 170:115–123. https://doi.org/10.1016/j.physbeh.2016.12.021

    Article  PubMed  CAS  Google Scholar 

  55. Peineau S, Bradley C, Taghibiglou C et al (2008) The role of GSK-3 in synaptic plasticity. Br J Pharmacol 153(Suppl 1):S428–S437. https://doi.org/10.1038/bjp.2008.2

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  56. Lucas FR, Goold RG, Gordon-Weeks PR, Salinas PC (1998) Inhibition of GSK-3beta leading to the loss of phosphorylated MAP-1B is an early event in axonal remodelling induced by WNT-7a or lithium. J Cell Sci 111(Pt 10):1351–1361

    PubMed  CAS  Google Scholar 

  57. Rui Y, Myers KR, Yu K et al (2013) Activity-dependent regulation of dendritic growth and maintenance by glycogen synthase kinase 3beta. Nat Commun 4:2628. https://doi.org/10.1038/ncomms3628

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  58. Golpich M, Amini E, Hemmati F et al (2015) Glycogen synthase kinase-3 beta (GSK-3beta) signaling: implications for Parkinson’s disease. Pharmacol Res 97:16–26. https://doi.org/10.1016/j.phrs.2015.03.010

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by the KRIBB Research Initiative Program of the Republic of Korea and by the Development of Platform Technology for Innovative Medical Measurements funded by Korea Research Institute of Standards and Science (KRISS-2017-GP2017-0020).

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Authors and Affiliations

  1. Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Gwahak-ro 125, Yuseong-gu, Daejeon, 34141, Republic of Korea

    Young-Kyoung Ryu, Hye-Yeon Park, Jun Go, Dong-Hee Choi, Yong-Hoon Kim, Jung Hwan Hwang, Jung-Ran Noh, Chul-Ho Lee & Kyoung-Shim Kim

  2. Department of Functional Genomics, University of Science and Technology, Daejeon, 34113, Republic of Korea

    Yong-Hoon Kim, Jung Hwan Hwang, Chul-Ho Lee & Kyoung-Shim Kim

  3. Center for Nano-Bio Measurement, Korea Research Institute of Standards and Science, Daejeon, 34113, Republic of Korea

    Tae Geol Lee

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Electronic supplementary material

Supplementary Figure 1

Effects of 6-OHDA lesioning in vehicle- and metformin-treated mice. a Number of D-AMPH-induced ipsilateral rotations at 2 weeks after 6-OHDA lesioning. b TH immunoreactivity in the 6-OHDA-lesioned and 6-OHDA-unlesioned striata and SNc regions of the vehicle + l-DOPA (“Vehicle”), 100 mg/kg/day metformin + l-DOPA (“Met100”), and 200 mg/kg/day metformin + l-DOPA (“Met200”) groups. c Percentage losses of TH+ cells in the lesioned SNc regions of the “Vehicle” (n = 17–20), “Met100” (n = 7–10), and “Met200” (n = 16–23) groups. Data are presented as the mean ± SEM. Scale bar = 500 μm. (GIF 441 kb)

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Supplementary Figure 2

Simple linear regression analysis of TH depletion and total AIM scores. Simple linear regression analysis detected no significant correlations between TH depletion and total AIM scores in the vehicle + l-DOPA (“Vehicle”; n = 17) (a); 100 mg/kg metformin + l-DOPA (“Met100”; n = 7) (b); and 200 mg/kg metformin + l-DOPA (“Met200”; n = 16) (c) groups. “Vehicle”: r = 0.1170, p = 0.1789; “Met100”: r = 0.2480, p = 0.2553; and “Met200”: r = 0.0251, p = 0.5578. (GIF 62 kb)

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Supplementary Figure 3

Effect of 6-OHDA lesioning in vehicle-, amantadine-, and metformin-treated mice. a Experimental design for 6-OHDA lesioning, drug treatment, and behavioral testing (cylinder test and AIM test). b The number of D-AMPH-induced ipsilateral rotations at 2 weeks after 6-OHDA lesioning. c TH immunoreactivity in the 6-OHDA-lesioned and 6-OHDA-unlesioned SNc regions in the vehicle + l-DOPA (“Vehicle”; n = 7), 40 mg/kg amantadine + l-DOPA (“AM40”; n = 7), and 200 mg/kg metformin + l-DOPA (“Met200”; n = 8) groups. d Percentage losses of TH+ cells in the lesioned SNc regions in the “Vehicle,” “AM40,” and “Met200” groups. e Right forelimb use in the cylinder test before (“Pre-test”) and after 6-OHDA lesioning (“6-OHDA”), and 30 min after the first treatment of l-DOPA with vehicle, 40 mg/kg amantadine, or 200 mg/kg metformin (“6-OHDA/l-DOPA”). ** p < 0.01 vs. “Vehicle” and ## p < 0.01 vs. “6-OHDA” (one-way ANOVA followed by Tukey-Kramer post hoc test). Data are presented as the mean ± SEM. Scale bar = 500 μm. (GIF 547 kb)

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Supplementary Figure 4

Time course of total and subscale AIM scores in 6-OHDA mice treated with l-DOPA alone or in combination with amantadine or metformin. Time course of total AIM (a, d), LOC (b, e), and ALO (c, f) scores for 120 min after l-DOPA administration on day 10 (a–c) and day 20 (d–f). Two-way repeated measures ANOVA with Bonferroni post hoc tests. Amantadine on day 10: total AIMs, F (1, 12) = 11.38, p = 0.0055; LOC, F (1, 12) = 2.91, p = 0.1136; and ALO, F (1, 12) = 16.89, p = 0.0014. Amantadine on day 20: total AIMs, F (1, 12) = 5.07, p = 0.0438; LOC, F (1, 12) = 5.54, p = 0.0365; and ALO, F (1, 12) = 2.38, p = 0.1487. Metformin on day 10: total AIMs, F (1, 13) = 9.49, p = 0.0088; LOC, F (1, 13) = 3.49, p = 0.0844; and ALO, F (1, 13) = 9.85, p = 0.0079. Metformin on day 20: total AIMs, F (1, 13) = 12.07, p = 0.0041; LOC, F (1, 13) = 4.29, p = 0.0589; and ALO, F (1, 13) = 13.48, p = 0.0028. Data are presented as the mean ± SEM. (GIF 144 kb)

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Supplementary Figure 5

Representative photomicrographs of p-rpS6, p-ERK1/2, PKA substrates, p-AcH3, and ΔFosB immunoreactive cells in the 6-OHDA-lesioned and 6-OHDA-unlesioned striata of the “Vehicle,” “Met100,” and “Met200” groups. Thirty minutes after completion of the 11-day l-DOPA treatment schedule, we performed immunohistochemistry or immunofluorescence of the 6-OHDA-lesioned dorsal striata. Immunofluorescence of p-Ser235/236-rpS6 (a), p-Ser240/244-rpS6 (b), and p- Thr202/Tyr204-ERK1/2 (c) cells and immunoreactivity of PKA substrates (d), p-Ser10-AcH3 (e), and ΔFosB (f) in the vehicle + l-DOPA (“Vehicle”), 100 mg/kg metformin + l-DOPA (“Met100”), and 200 mg/kg metformin + l-DOPA (“Met200”) groups. Scale bar = 200 μm. (GIF 1741 kb)

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Supplementary Figure 6

Regulation of AMPK activity in unilaterally 6-OHDA-lesioned mice treated with single or repeated l-DOPA administration. a Thirty minutes after l-DOPA administration on day 1 (single) and day 11 (repeated), western blots were performed with the striata of unilaterally 6-OHDA-lesioned mice. b Metformin (200 mg/kg, “Met200”) was administered 30 min prior to l-DOPA. Quantification of striatal p-Thr172-AMPK levels normalized to β-actin. One asterisk and two asterisks denote the difference between indicated groups at p < 0.05 and p < 0.01, respectively (one-way ANOVA followed by Tukey-Kramer post hoc test). Data are presented as the mean ± SEM. (GIF 193 kb)

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Ryu, YK., Park, HY., Go, J. et al. Metformin Inhibits the Development of l-DOPA-Induced Dyskinesia in a Murine Model of Parkinson’s Disease. Mol Neurobiol 55, 5715–5726 (2018). https://doi.org/10.1007/s12035-017-0752-7

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  • DOI: https://doi.org/10.1007/s12035-017-0752-7

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