MPTP-induced dopaminergic neurotoxicity in mouse brain is attenuated after subsequent intranasal administration of (R)-ketamine: a role of TrkB signaling

  • Atsuhiro Fujita
  • Yuko Fujita
  • Yaoyu Pu
  • Lijia Chang
  • Kenji HashimotoEmail author
Original Investigation



Parkinson’s disease (PD) is characterized as a chronic and progressive neurodegenerative disorder, and PD patients have non-motor features such as depressive symptoms. Although there are several available medications to treat PD symptoms, these medications do not prevent the progression of the disease.


(R)-ketamine has greater and longer-lasting antidepressant effects than (S)-ketamine in animal models of depression. This study was undertaken to investigate whether two enantiomers of ketamine and its metabolite norketamine shows neuroprotective effects in an animal model of PD.


Effects of (R)-ketamine, (S)-ketamine, and their metabolites on MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced reduction of dopamine transporter (DAT) and tyrosine hydroxylase (TH) in the mouse striatum and substantia nigra (SNr) were examined.


MPTP-induced reduction of DAT in the striatum was attenuated by subsequent repeated intranasal administration of both enantiomers of ketamine although (R)-ketamine was more potent than (S)-ketamine. MPTP-induced reduction of TH in the striatum and SNr was attenuated by administration of (R)-ketamine, but not (S)-ketamine. Interestingly, MPTP-induced reduction of DAT in the striatum was also attenuated by a single intranasal administration of (R)-ketamine. In contrast, MPTP-induced reduction of DAT in the striatum was not attenuated by repeated intranasal administration of two enantiomers of norketamine. Furthermore, the pretreatment with TrkB antagonist ANA-12 significantly blocked the neuroprotective effects of (R)-ketamine in the MPTP-induced reduction of DAT in the striatum.


These findings suggest that (R)-ketamine can protect against MPTP-induced neurotoxicity in the mouse brain via TrkB activation. Therefore, (R)-ketamine could represent a therapeutic drug for neurodegenerative disorders such as PD.


Dopamine transporter (R)-ketamine Neurotoxicity Striatum TrkB 


Funding information

This study was supported by AMED (to K.H., JP19dm0107119).

Compliance with ethical standards

Conflict of interest

Dr. Hashimoto is an inventor on a filed patent application on “The use of (R)-ketamine in the treatment of psychiatric diseases,” “(S)-norketamine and salt thereof as pharmaceutical,” and “The use of (R)-ketamine in the treatment of neurodegenerative diseases” by Chiba University. Dr. Hashimoto has received research support from Dainippon-Sumitomo, Otsuka, and Taisho. Other authors declare no conflict of interest.


  1. Ascherio PA, Schwarzschild MA (2016) The epidemiology of Parkinson’s disease: risk factors and prevention. Lancet Neurol 15:1257–1272CrossRefGoogle Scholar
  2. Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH (2000) Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 47:351–354CrossRefGoogle Scholar
  3. Booij J, Tissingh G, Boer GJ, Speelman D, Stoof JC, Janssen AG, Woilters EC, van Royen EA (1997) [123I]FP-CIT SPECT shows a pronounced decline of striatal dopamine transporter labelling in early and advanced Parkinson’s disease. J Neurol Neurosurg Psychiatry 62:133–140CrossRefGoogle Scholar
  4. Cazorla M, Prémont J, Mann A, Girard N, Kellendonk C, Rognan D (2011) Identification of a low–molecular weight TrkB antagonist with anxiolytic and antidepressant activity in mice. J Clin Invest 121:1846–1857CrossRefGoogle Scholar
  5. Chang L, Zhang K, Pu Y, Qu Y, Wang SM, Xiong Z, Ren Q, Dong C, Fujita Y, Hashimoto K (2019) Comparison of antidepressant and side effects in mice after intranasal administration of (R,S)-ketamine, (R)-ketamine, and (S)-ketamine. Pharmacol Biochem Behav 181:53–59CrossRefGoogle Scholar
  6. Cummings JL (1992) Depression and Parkinson’s disease: a review. Am J Psychiatry 149:443–454CrossRefGoogle Scholar
  7. Dehay B, Bourdenx M, Gorry P, Przedborski S, Vila M, Hunot S, Singleton A, Olanow CW, Merchant KM, Bezard E, Petsko GA, Meissner WG (2015) Targeting α-synuclein for treatment of Parkinson’s disease: mechanistic and therapeutic considerations. Lancet Neurol 14:855–866CrossRefGoogle Scholar
  8. Ebert B, Mikkelsen S, Thorkildsen C, Borgbjerg FM (1997) Norketamine, the main metabolite of ketamine, is a non-competitive NMDA receptor antagonist in the rat cortex and spinal cord. Eur J Pharmacol 333:99–104CrossRefGoogle Scholar
  9. Fukumoto K, Toki H, Iijima M, Hashihayata T, Yamaguchi JI, Hashimoto K, Chaki S (2017) Antidepressant potential of (R)-ketamine in rodent models: comparison with (S)-ketamine. J Pharmacol Exp Ther 361:9–16CrossRefGoogle Scholar
  10. Goodarzi Z, Mrklas KJ, Roberts DJ, Jette N, Pringsheim T, Holroyd-Leduc J (2016) Detecting depression in Parkinson disease: a systematic review and meta-analysis. Neurology 87:426–437CrossRefGoogle Scholar
  11. Hashimoto K (2010) Brain-derived neurotrophic factor as a biomarker for mood disorders: an historical overview and future directions. Psychiatry Clin Neurosci 64:341–357CrossRefGoogle Scholar
  12. Hashimoto K (2016a) Letter to the editor: R-ketamine: a rapid-onset and sustained antidepressant without risk of brain toxicity. Psychol Med 46:2449–2451CrossRefGoogle Scholar
  13. Hashimoto K (2016b) Ketamine’s antidepressant action: beyond NMDA receptor inhibition. Expert Opin Ther Targets 20:1389–1392CrossRefGoogle Scholar
  14. Hashimoto K (2016c) Detrimental side effects of repeated ketamine infusions in the brain. Am J Psychiatry 173:1044–1045CrossRefGoogle Scholar
  15. Hashimoto K (2019) Rapid-acting antidepressant ketamine, its metabolites and other candidates: a historical overview and future perspective. Psychiatry Clin Neurosci 2019.
  16. Hashimoto K, Yang C (2019) Is (S)-norketamine an alternative antidepressant for esketamine? Eur Arch Psychiatry Clin Neurosci 2018.
  17. Hashimoto K, Shimizu E, Iyo M (2004) Critical role of brain-derived neurotrophic factor in mood disorders. Brain Res Brain Res Rev 45:104–114CrossRefGoogle Scholar
  18. Hashimoto K, Kakiuchi T, Ohba H, Nishiyama S, Tsukada H (2017) Reduction of dopamine D2/3 receptor binding in the striatum after a single administration of esketamine, but not R-ketamine: a PET study in conscious monkeys. Eur Arch Psychiatry Clin Neurosci 267:173–176CrossRefGoogle Scholar
  19. Innis RB, Seibyl JP, Scanley BE, Laruelle M, Abi-Dargham A, Wallace E, Baldwin RM, Zea-Ponce Y, Zoghbi S, Wang S (1993) Single photon emission computed tomographic imaging demonstrates loss of striatal dopamine transporters in Parkinson disease. Proc Natl Acad Sci U S A 90:11965–11969CrossRefGoogle Scholar
  20. Jackson-Lewis V, Przedborski S (2007) Protocol for the MPTP mouse model of Parkinson’s disease. Nat Protoc 2:141–151CrossRefGoogle Scholar
  21. Kaasinen V, Vahlberg T (2017) Striatal dopamine in Parkinson disease: a meta-analysis of imaging studies. Ann Neurol 82:873–882CrossRefGoogle Scholar
  22. Kalia LV, Lang AE (2015) Parkinson’s disease. Lancet 386:896–912CrossRefGoogle Scholar
  23. Kieburtz K, Katz R, Olanow CW (2018) New drugs for Parkinson’s disease: the regulatory and clinical development pathways in the United States. Mov Disord 33:920–927CrossRefGoogle Scholar
  24. Kishimoto T, Chawia JM, Hagi K, Zarate CA, Kane JM, Bauer M, Correll CU (2016) Single-dose infusion ketamine and non-ketamine N-methyl-D-aspartate receptor antagonists for unipolar and bipolar depression: a meta-analysis of efficacy, safety and time trajectories. Psychol Med 46:1459–1472CrossRefGoogle Scholar
  25. Martini A, Dal Lago D, Edelstyn NMJ, Salgarello M, Lugoboni F, Tamburin S (2018) Dopaminergic neurotransmission in patients with Parkinson’s disease and impulse control disorders: a systematic review and meta-analysis of PET and SPECT studies. Front Neurol 9:1018CrossRefGoogle Scholar
  26. Miller GW, Staley JK, Heilman CJ, Perez JT, Mash DC, Eye DB, Levey AI (1997) Immunochemical analysis of dopamine transporter protein in Parkinson’s disease. Ann Neurol 41:530–539CrossRefGoogle Scholar
  27. Murrough JW, Abdallah CG, Mathew SJ (2017) Targeting glutamate signaling in depression: progress and prospects. Nat Rev Drug Discov 16:472–486CrossRefGoogle Scholar
  28. Nagatsu T, Sawada M (2007) Biochemistry of postmortem brains in Parkinson’s disease: historical overview and future prospects. J Neural Transm Suppl 72:113–120Google Scholar
  29. Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM (2002) Neurobiology of depression. Neuron 34:13–25CrossRefGoogle Scholar
  30. Newport DJ, Carpenter LL, McDonald WM, Potash JB, Tohen M, Nemeroff CB, APA Council of Research Task Force on Novel Biomarkers and Treatments (2015) Ketamine and other NMDA antagonists: early clinical trials and possible mechanisms in depression. Am J Psychiatry 172:950–966CrossRefGoogle Scholar
  31. Paxinos G, Franklin K (2002) Paxinos and Franklin’s the mouse brain in stereotaxic coordinates, 4th edn. Academic Press, CambridgeGoogle Scholar
  32. Pu Y, Qu Y, Chang L, Wang SM, Zhang K, Ushida Y, Suganuma H, Hashimoto K (2019) Dietary intake of glucoraphanin prevents the reduction of dopamine transporter in the mouse striatum after repeated administration of MPTP. Neuropsychopharmacol Rep 2019.
  33. Ren Q, Zhang JC, Ma M, Fujita Y, Wu J, Hashimoto K (2014) 7,8-Dihydroxyflavone, a TrkB agonist, attenuates behavioral abnormalities and neurotoxicity in mice after administration of methamphetamine. Psychopharmacology 231:159–166CrossRefGoogle Scholar
  34. Ren Q, Ma M, Yang C, Zhang JC, Yao W, Hashimoto K (2015) BDNF–TrkB signaling in the nucleus accumbens shell of mice has key role in methamphetamine withdrawal symptoms. Transl Psychiatry 5:e666CrossRefGoogle Scholar
  35. Ren Q, Ma M, Yang J, Nonaka R, Yamaguchi A, Ishikawa KI, Kobayashi K, Murayama S, Hwang SH, Saiki S, Akamatsu W, Hattori N, Hammock BD, Hashimoto K (2018) Soluble epoxide hydrolase plays a key role in the pathogenesis of Parkinson’s disease. Proc Natl Acad Sci U S A 115:E5815–E5823CrossRefGoogle Scholar
  36. Sanacora G, Frye MA, McDonald W, Mathew SJ, Turner MS, Schatzberg AF, Summergrad P, Nemeroff CB, American Psychiatric Association (APA) Council of Research Task Force on Novel Biomarkers and Treatments (2017) A consensus statement on the use of ketamine in the treatment of mood disorders. JAMA Psychiatry 74:399–405CrossRefGoogle Scholar
  37. Schapira AHV, Chaudhuri KR, Jenner P (2017) Non-motor features of Parkinson disease. Nat Rev Neurosci 18:435–450CrossRefGoogle Scholar
  38. Shirayama Y, Hashimoto K (2018) Lack of antidepressant effects of (2R,6R)-hydroxynorketamine in a rat learned helplessness model: comparison with (R)-ketamine. Int J Neuropsychopharmacol 21:84–88CrossRefGoogle Scholar
  39. Short B, Fong J, Galvez V, Shelker W, Loo CK (2018) Side-effects associated with ketamine use in depression: a systematic review. Lancet Psychiatry 5:65–78CrossRefGoogle Scholar
  40. Singh I, Morgan C, Curran V, Nutt D, Schlag A, McShane R (2017) Ketamine treatment for depression: opportunities for clinical innovation and ethical foresight. Lancet Psychiatry 4:419–426CrossRefGoogle Scholar
  41. Takahashi H, Watanabe Y, Tanaka H, Mochizuki H, Kato H, Hatazawa J, Tomiyama N (2019) Quantifying the severity of Parkinson disease by use of dopaminergic neuroimaging. AJR Am J Roentgenol 213:163–168. CrossRefGoogle Scholar
  42. Tian Z, Dong C, Fujita A, Fujita Y, Hashimoto K (2018) Expression of heat shock protein HSP-70 in the retrosplenial cortex of rat brain after administration of (R,S)-ketamine and (S)-ketamine, but not (R)-ketamine. Pharmacol Biochem Behav 172:17–21CrossRefGoogle Scholar
  43. Vollenweider FX, Leenders KL, Øye I, Hell D, Angst J (1997) Differential psychopathology and patterns of cerebral glucose utilization produced by (S)- and (R)-ketamine in healthy volunteers using positron emission tomography (PET). Eur Neuropsychopharmacol 7:25–38CrossRefGoogle Scholar
  44. Yang C, Shirayama Y, Zhang JC, Ren Q, Yao W, Ma M, Hashimoto K (2015) R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects. Transl Psychiatry 5:e632CrossRefGoogle Scholar
  45. Yang C, Han M, Zhang JC, Ren Q, Hashimoto K (2016) Loss of parvalbumin-immunoreactivity in mouse brain regions after repeated intermittent administration of esketamine, but not R-ketamine. Psychiatry Res 239:281–283CrossRefGoogle Scholar
  46. Yang C, Qu Y, Abe M, Nozawa D, Chaki S, Hashimoto K (2017a) (R)-ketamine shows greater potency and longer lasting antidepressant effects than its metabolite (2R,6R)-hydroxynorketamine. Biol Psychiatry 82:e43–e44CrossRefGoogle Scholar
  47. Yang C, Qu Y, Fujita Y, Ren Q, Ma M, Dong C, Hashimoto K (2017b) Possible role of the gut microbiota-brain axis in the antidepressant effects of (R)-ketamine sin a social defeat stress model. Transl Psychiatry 7:1294CrossRefGoogle Scholar
  48. Yang C, Ren Q, Qu Y, Zhang JC, Ma M, Dong C, Hashimoto K (2018a) Mechanistic target of rapamycin–independent antidepressant effects of (R)-ketamine in a social defeat stress model. Biol Psychiatry 83:18–28CrossRefGoogle Scholar
  49. Yang C, Kobayashi S, Nakao K, Dong C, Han M, Qu Y, Ren Q, Zhang JC, Ma M, Toki H, Yamaguchi JI, Chaki S, Shirayama Y, Nakazawa K, Manabe T, Hashimoto K (2018b) AMPA receptor activation-independent antidepressant actions of ketamine metabolite (S)-norketamine. Biol Psychiatry 84:591–600CrossRefGoogle Scholar
  50. Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, Alkondon M, Yuan P, Pribut HJ, Singh NS, Dossou KS, Fang Y, Huang XP, Mayo CL, Wainer IW, Albuquerque EX, Thompson SM, Thomas CJ, Zarate CA Jr, Gould TD (2016) NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature 533:481–486CrossRefGoogle Scholar
  51. Zanos P, Moaddel R, Morris PJ, Riggs LM, Highland JN, Georgiou P, Pereira EFR, Albuquerque EX, Thomas CJ, Zarate CA Jr, Gould TD (2018) Ketamine and ketamine metabolite pharmacology: insights into therapeutic mechanisms. Pharmacol Rev 70:621–660CrossRefGoogle Scholar
  52. Zarate CA, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK (2006) A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 63:856–864CrossRefGoogle Scholar
  53. Zhang K, Hashimoto K (2019) An update on ketamine and its two enantiomers as rapid-acting antidepressants. Expert Rev Neurother 19:83–92CrossRefGoogle Scholar
  54. Zhang L, Kitaichi K, Fujimoto Y, Nakayama H, Shimizu E, Iyo M, Hashimoto K (2006) Protective effects of minocycline on behavioral changes and neurotoxicity in mice after administration of methamphetamine. Prog Neuro-Psychopharmacol Biol Psychiatry 30:1381–1393CrossRefGoogle Scholar
  55. Zhang JC, Li SX, Hashimoto K (2014) R (−)-ketamine shows greater potency and longer lasting antidepressant effects than S (+)-ketamine. Pharmacol Biochem Behav 116:137–141CrossRefGoogle Scholar
  56. Zhang JC, Yao W, Dong C, Yang C, Ren Q, Ma M, Han M, Hashimoto K (2015) Comparison of ketamine, 7, 8-dihydroxyflavone, and ANA-12 antidepressant effects in the social defeat stress model of depression. Psychopharmacology 232:4325–4335CrossRefGoogle Scholar
  57. Zhang JC, Yao W, Hashimoto K (2016) Brain-derived neurotrophic factor (BDNF)-TrkB signaling in inflammation-related depression and potential therapeutic targets. Curr Neuropharmacol 14:721–731CrossRefGoogle Scholar
  58. Zhu G, Li J, He L, Wang X, Hong X (2015) MPTP-induced changes in hippocampal synaptic plasticity and memory are prevented by memantine through the BDNF-TrkB pathway. Bri J Pharmacol 172:2354–2368CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Division of Clinical NeuroscienceChiba University Center for Forensic Mental HealthChibaJapan

Personalised recommendations