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Effect of nicotine on l-dopa-induced dyskinesia in animal models of Parkinson’s disease: a systematic review and meta-analysis

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Abstract

l-dopa-induced dyskinesias (LIDs) are abnormal involuntary movements (AIM) that develop with long-term l-dopa therapy for Parkinson’s disease (PD). In this study, we used these tools to describe the efficacy of nicotine reduced LID in animal models of PD. Studies were identified by electronic searching of six online databases up to September of 2013 to identify preclinical trials involving nicotine for LID in animal model. Data were extracted for AIM compared with LID animals. Pre-specified subgroup analysis was carried out according to method of model, gender, anesthetic used, and species. Combined standardized mean difference (SMD) estimates and 95 % confidence intervals (CIs) were calculated using a random-effects model. Eleven studies involving 181 animals which described the effect of nicotine on LID were included in the meta-analysis. Nicotine was efficacious in reducing total AIM compared with control group (SMD −3.77, 95 % CI −5.30 to −2.23, P < 0.00001). Meanwhile, four studies showed certain effects of nicotine for improving the axial AIM (SMD −2.21, 95 % CI −4.17 to −0.24, P = 0.03); oral AIM and forelimb AIM were obvious improved in six studies in the nicotine group (SMD −3.00, 95 % CI −4.55 to −1.44, P = 0.0002; SMD −2.52, 95 % CI −3.52 to −1.53, P < 0.00001, respectively). We conclude that nicotine appears to have efficacy in animal models of LID. Large randomized clinical trials testing the effect of nicotine in PD patients with LID are warranted.

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References

  1. Toulouse A, Sullivan AM (2008) Progress in Parkinson’s disease-where do we stand? Prog Neurobiol 85:376–392

    Article  PubMed  Google Scholar 

  2. Rascol O, Fitzer-Attas CJ, Hauser R, Jankovic J, Lang A, Langston JW, Melamed E, Poewe W, Stocchi F, Tolosa E, Eyal E, Weiss YM, Olanow CW (2011) A double-blind, delayed-start trial of rasagiline in Parkinson’s disease (the ADAGIO study): prespecified and post hoc analyses of the need for additional therapies, changes in UPDRS scores, and non-motor outcomes. Lancet Neurol 10:415–423

    Article  CAS  PubMed  Google Scholar 

  3. Schapira AH, Jenner P (2011) Etiology and pathogenesis of Parkinson’s disease. Mov Disord 26:1049–1055

    Article  PubMed  Google Scholar 

  4. Brotchie J, Jenner P (2011) New approaches to therapy. Int Rev Neurobiol 98:123–150

    Article  CAS  PubMed  Google Scholar 

  5. Fisone G, Bezard E (2011) Molecular mechanisms of l-DOPA-induced dyskinesia. Int Rev Neurobiol 98:95–122

    Article  CAS  PubMed  Google Scholar 

  6. Johnston TH, Huot P, Fox SH, Koprich JB, Szeliga KT, James JW, Graef JD, Letchworth SR, Jordan KG, Hill MP, Brotchie JM (2013) TC-8831, a nicotinic acetylcholine receptor agonist, reduces l-DOPA-induced dyskinesia in the MPTP macaque. Neuropharmacology 73:337–347

    Article  CAS  PubMed  Google Scholar 

  7. Quik M, Campos C, Bordia T, Strachan JP, Zhang J, McIntosh JM (2013) Alpha4beta2 nicotinic receptors play a role in the nAChR-mediated decline in l-dopa-induced dyskinesia in parkinsonian rats. Neuropharmacology 71:191–203

    Article  CAS  PubMed  Google Scholar 

  8. Huang LZ, Grady SR, Quik M (2011) Nicotine reduces L-DOPA-induced dyskinesia by acting at beta2* nicotinic receptors. J Pharmacol Exp Ther 338:932–941

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Albuquerque EX, Pereira EF, Alkondon M, Rogers SW (2009) Mammalian nicotinic acetylcholine receptors: from structure to function. Physiol Rev 89:73e120

    Article  Google Scholar 

  10. Quik M, Mallela A, Chin M, McIntosh JM, Perez XA, Bordia T (2013) Nicotine-mediated improvement in l-dopa-induced dyskinesia in MPTP-lesioned monkeys is dependent on dopamine nerve terminal function. Neurobiol Dis 50:30–41

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Bordia T, McIntosh JM, Quik M (2013) The nicotine-mediated decline in l-dopa-induced dyskinesia is associated with a decrease in striatal dopamine release. J Neurochem. doi:10.1111/jnc.12179

    PubMed  Google Scholar 

  12. Macleod MR, O’Collins T, Howells DW, Donnan GA (2004) Pooling of animal experimental data reveals influence of study design and publication bias. Stroke 35:1203–1208

    Article  PubMed  Google Scholar 

  13. Quik M, Cox H, Parameswaran N, O’Leary K, Langston JW, Di Monte D (2007) Nicotine reduces levodopa-induced dyskinesia in lesioned monkeys. Ann Neurol 62:588–596

    Article  CAS  PubMed  Google Scholar 

  14. Bordia T, Campos C, Huang L, Quik M (2008) Continuous and intermittent nicotine treatment reduces l-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesia in a rat model of Parkinson’s disease. J Pharmacol Exp Ther 327:239–247

    Article  CAS  PubMed  Google Scholar 

  15. Bordia T, Campos C, McIntosh JM, Quik M (2010) Nicotinic receptor-mediated reduction in l-DOPA-induced dyskinesia may occur via desensitization. J Pharmacol Exp Ther 333:929–938

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Quik M, Park KM, Hrachova M, Mallela A, Huang LZ, McIntosh JM, Grady SR (2012) Role for alpha6 nicotinic receptors in l-dopa-induced dyskinesia in parkinsonian mice. Neuropharmacology 63:450–459

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Chen L (2012) Effects of nicotine on the behavior of l-DOPA-induced dyskinesia in PD rat model and the possible mechanisms. Master’s degree thesis, Huazhong University of science and technology

  18. Quik M, Campos C, Grady SR (2013) Multiple CNS nicotinic receptors mediate l-dopa-induced dyskinesia: studies with parkinsonian nicotinic receptor knockout mice. Biochem Pharmacol 86:1153–1162

    Article  CAS  PubMed  Google Scholar 

  19. Quik M, Mallela A, Ly J, Zhang D (2013) Nicotine reduces established levodopa-induced dyskinesia in a monkey model of Parkinson’s disease. Mov Disord 28:1398–1406

    CAS  PubMed  Google Scholar 

  20. Zhang D, Mallela A, Sohn D, Carroll FI, Bencherif M, Letchworth S, Quik M (2013) Nicotinic receptor agonists reduce l-DOPA-induced dyskinesia in a monkey model of Parkinson’s disease. J Pharmacol Exp Ther 347:225–234

    Article  CAS  PubMed  Google Scholar 

  21. Bordia T, McIntosh JM, Quik M (2013) The nicotine-mediated decline in l-dopa-induced dyskinesia is associated with a decrease in striatal dopamine release. J Neurochem 125:291–302

    Article  CAS  Google Scholar 

  22. Hackam DG, Redelmeier DA (2006) Translation of research evidence from animals to humans. JAMA 296:1731–1732

    CAS  PubMed  Google Scholar 

  23. van der Worp HB, Howells DW, Sena ES, Porritt MJ, Rewell S, O’Collins V, Macleod MR (2010) Can animal models of disease reliably inform human studies? PLoS Med 7:e1000245

    Article  PubMed Central  PubMed  Google Scholar 

  24. Begley CG, Ellis LM (2012) Drug development: raise standards for preclinical cancer research. Nature 483:531–533

    Article  CAS  PubMed  Google Scholar 

  25. Cook N, Jodrell DI, Tuveson DA (2012) Predictive in vivo animal models and translation to clinical trials. Drug Discov Today 17:253–260

    Article  PubMed  Google Scholar 

  26. Paz R, Barsness B, Martenson T, Tanner D, Allan AM (2007) Behavioral teratogenicity induced by nonforced maternal nicotine consumption. Neuropsychopharmacology 32:693–699

    Article  CAS  PubMed  Google Scholar 

  27. Sparks JA, Pauly JR (1999) Effects of continuous oral nicotine administration on brain nicotinic receptors and responsiveness to nicotine in C57Bl/6 mice. Psychopharmacology 141:145–153

    Article  CAS  PubMed  Google Scholar 

  28. Alsharari SD, Siu EC, Tyndale RF, Damaj MI (2014) Pharmacokinetic and pharmacodynamics studies of nicotine after oral administration in mice: effects of methoxsalen, a CYP2A5/6 inhibitor. Nicotine Tob Res 16:18–25

    Article  CAS  PubMed  Google Scholar 

  29. Romano C, Goldstein A (1980) Stereospecific nicotine receptors on rat brain membranes. Science 210:647–650

    Article  CAS  PubMed  Google Scholar 

  30. Millar NS, Gotti C (2009) Diversity of vertebrate nicotinic acetylcholine receptors. Neuropharmacology 56:237–246

    Article  CAS  PubMed  Google Scholar 

  31. Millar NS, Harkness PC (2008) Assembly and trafficking of nicotinic acetylcholine receptors (review). Mol Membr Biol 25:279–292

    Article  CAS  PubMed  Google Scholar 

  32. Huang LZ, Campos C, Ly J, Ivy Carroll F, Quik M (2011) Nicotinic receptor agonists decrease l-dopa-induced dyskinesia most effectively in partially lesioned parkinsonian rats. Neuropharmacology 60:861–868

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Huang LZ, Campos C, Ly J, Ivy Carroll F, Quik M (2011) Nicotinic receptor agonists decrease l-dopa-induced dyskinesias most effectively in partially lesioned parkinsonian rats. Neuropharmacology 60:861–868

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Henderson LP, Gdovin MJ, Liu C, Gardner PD, Maue RA (1994) Nerve growth factor increases nicotinic ACh receptor gene expression and current density in wild-type and protein kinase A-deficient PC12 cells. J Neurosci 14:1153–1163

    CAS  PubMed  Google Scholar 

  35. Toulorge D, Guerreiro S, Hild A, Maskos U, Hirsch EC, Michel PP (2011) Neuroprotection of midbrain dopamine neurons by nicotine is gated by cytoplasmic Ca2+. FASEB 25:2563–2573

    Article  CAS  Google Scholar 

  36. Quik M, Perez XA, Bordia T (2012) Nicotine as a potential neuroprotective agent for Parkinson’s disease. Mov Disord 27:947–957

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Shimohama S (2009) Nicotinic receptor-mediated neuroprotection in neurodegenerative disease models. Biol Pharm Bull 32:332–336

    Article  CAS  PubMed  Google Scholar 

  38. Kjaergard LL, Villumsen J, Gluud C (2011) Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses. Ann Intern Med 135:982–989

    Article  Google Scholar 

  39. Campbell MJ, Julious SA, Altman DG (1995) Estimating sample sizes for binary, ordered categorical, and continuous outcomes in two group comparisons. BMJ 311:1145–1148

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Schulz KF, Grimes DA (2005) Sample size calculations in randomised trials: mandatory and mystical. Lancet 365:1348–1353

    Article  PubMed  Google Scholar 

  41. Xie CL, Gu Y, Wang WW, Lu L, Fu DL, Liu AJ, Li HQ, Li JH, Lin Y, Tang WJ, Zheng GQ (2013) Efficacy and safety of Suanzaoren decoction for primary insomnia: a systematic review of randomized controlled trials. BMC Complement Altern Med 22:13–18

    Google Scholar 

  42. Guyatt GH, Oxman AD, Montori V, Vist G, Kunz R, Brozek J (2011) GRADE guidelines: 5. Rating the quality of evidence––publication bias. J Clin Epidemiol 64:1277–1282

    Article  PubMed  Google Scholar 

  43. Vesterinen HM, Sena ES, Egan KJ, Hirst TC, Churolov L, Currie GL, Antonic A, Howells DW, Macleod MR (2014) Meta-analysis of data from animal studies: a practical guide. J Neurosci Methods 221:92–102

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We gratefully acknowledge Professor Zhen-Guo Liu for his help in guiding and revising the manuscript. We also thank all the study participants. This study was supported by grants from the National Science Foundation of China (81171203), the Shanghai Committee of Science and Technology (12XD1403800).

Conflict of interest

The authors declared that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Neurology, Xinhua Hospital affiliated to the Medical School of Shanghai Jiaotong University, 1665 Kongjiang Road, Shanghai, 200092, China

    Cheng-long Xie, Su-fang Zhang, Jing Gan & Zhen-Guo Liu

  2. Department of Internal Medicine, The Second Affiliated Hospital of Wenzhou Medical College, Wenzhou, 325027, People’s Republic of China

    Jia-Lin Pan

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  1. Cheng-long Xie
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Correspondence to Zhen-Guo Liu.

Additional information

C. Xie and J.-L. Pan contributed equally to this work.

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Xie, Cl., Pan, JL., Zhang, Sf. et al. Effect of nicotine on l-dopa-induced dyskinesia in animal models of Parkinson’s disease: a systematic review and meta-analysis. Neurol Sci 35, 653–662 (2014). https://doi.org/10.1007/s10072-014-1652-5

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