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