Tetrabenazine Mitigates Aberrant Release and Clearance of Dopamine in the Nigrostriatal System, and Alleviates L-DOPA-Induced Dyskinesia in a Mouse Model of Parkinson’s Disease

Article type: Research Article

Authors: Tseng, Kuan-Yin^{a; b} | Kuo, Tung-Tai^b | Wang, Vicki^c | Huang, Eagle Yi-Kung^d | Ma, Kuo-Hsing^e | Olson, Lars^f | Hoffer, Barry J.^g | Chen, Yuan-Hao^{a; b; *}

Affiliations: [a] National Defense Medical Center, Taipei, Taiwan, R.O.C | [b] Department of Neurological Surgery, Tri-Service General Hospital, Taipei, Taiwan, R.O.C | [c] Ph.D. Program in Translational Medicine, National Defense Medical Center and Academia Sinica, Taipei, Taiwan | [d] Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan, R.O.C | [e] Graduate Institute of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan, R.O.C | [f] Department of Neuroscience, Karolinska Institute, Stockholm, Sweden | [g] Department of Neurosurgery, University Hospitals of Cleveland, Case Western Reserve University School of Medicine, Cleveland, OH, USA

Correspondence: [*] Correspondence to: Yuan-Hao Chen, MD, PhD, Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, 4F, No.325, 2nd Sec., Cheng-Kung Road, Nei-Hu District, Taipei City, 114, Taiwan, R.O.C. Tel.: +886 2 8792 7177; Fax: +886 2 8792 7178; E-mail: [email protected].

Abstract: Background:L-DOPA-induced dyskinesia (LID), occurring with aberrant processing of exogenous L-DOPA in the dopamine-denervated striatum, is a main complication of levodopa treatment in Parkinson’s disease. Objective:To characterize the effects of the vesicular antagonist tetrabenazine (TBZ) on L-DOPA-induced behavior, neurochemical signals, and underlying protein expressions in an animal model of Parkinson’s disease. Methods:20-week-old MitoPark mice were co-treated or separately administered TBZ and L-DOPA for 14 days. Abnormal involuntary movements (AIMs) and locomotor activity were analyzed. To explore dopamine (DA) transmission, fast scan cyclic voltammetry was used to assess presynaptic DA dynamics in striatal slices following treatments. PET imaging with 4-[18F]-PE2I, ADAM and immunoblotting assays were used to detect receptor protein changes in the DA-denervated striatum. Finally, nigrostriatal tissues were collected for HPLC measures of DA, serotonin and their metabolites. Results:A single injection of TBZ given in the interval between the two L-DOPA/Carbidopa treatments significantly attenuated L-DOPA-induced AIMs expression and locomotor hyperactivity. TBZ was shown to reduce tonic and phasic release of DA following L-DOPA treatment in DA-denervated striatal tissue. In the DA-depleted striatum, TBZ decreased the expression of L-DOPA-enhanced D1 receptors and the serotonin reuptake transporter. Neurochemical analysis indicated that TBZ attenuated L-DOPA-induced surges of DA levels by promoting DA turnover in the nigrostriatal system. Conclusions:Our findings demonstrate that TBZ diminishes abnormal striatal DA transmission, which involves the ability of TBZ to modulate the presymptomatic dynamics of DA, and then mitigate aberrant release of exogenous L-DOPA from nerve terminals. The results support the potential of repositioning TBZ to counteract LID development.

Keywords: Parkinson’s disease, dopamine, L-DOPA-induced dyskinesia, tetrabenazine, serotonin transporter

DOI: 10.3233/JPD-223195

Journal: Journal of Parkinson's Disease, vol. 12, no. 5, pp. 1545-1565, 2022