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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

Abstract

Rationale

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.

Objective

(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.

Methods

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.

Results

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.

Conclusions

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.

Keywords

Dopamine transporter (R)-ketamine Neurotoxicity Striatum TrkB 

Notes

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.

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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

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