Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2022.141
5-Hydroxytryptophan Reduces Levodopa-Induced Dyskinesia via Regulating AKT/mTOR/S6K and CREB/ΔFosB Signals in a Mouse Model of Parkinson’s Disease
Yujin Choi1, Eugene Huh2,ψ, Seungmin Lee1, Jin Hee Kim1, Myoung Gyu Park3, Seung-Yong Seo4, Sun Yeou Kim4 and Myung Sook Oh1,2,*
1Department of Biomedical and Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02447,
2Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 02447,
3MetaCen therapeutics Inc. R&D Center, Suwon 16229,
4College of Pharmacy, Gachon University, Incheon 21936, Republic of Korea
*E-mail: msohok@khu.ac.kr
Tel: +82-2-961-9436, Fax: +82-2-963-9436
ψPresent Address
Department of Formulae Pharmacology, College of Korean Medicine, Gachon University, Seongnam 13120, Republic of Korea
Received: November 8, 2022; Revised: January 17, 2023; Accepted: February 10, 2023; Published online: March 15, 2023.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Long-term administration of levodopa (L-DOPA) to patients with Parkinson’s disease (PD) commonly results in involuntary dyskinetic movements, as is known for L-DOPA-induced dyskinesia (LID). 5-Hydroxytryptophan (5-HTP) has recently been shown to alleviate LID; however, no biochemical alterations to aberrant excitatory conditions have been revealed yet. In the present study, we aimed to confirm its anti-dyskinetic effect and to discover the unknown molecular mechanisms of action of 5-HTP in LID. We made an LID-induced mouse model through chronic L-DOPA treatment to 6-hydroxydopamine-induced hemi-parkinsonian mice and then administered 5-HTP 60 mg/kg for 15 days orally to LID-induced mice. In addition, we performed behavioral tests and analyzed the histological alterations in the lesioned part of the striatum (ST). Our results showed that 5-HTP significantly suppressed all types of dyskinetic movements (axial, limb, orolingual and locomotive) and its effects were similar to those of amantadine, the only approved drug by Food and Drug Administration. Moreover, 5-HTP did not affect the efficacy of L-DOPA on PD motor manifestations.From a molecular perspective, 5-HTP treatment significantly decreased phosphorylated CREB and ΔFosB expression, commonly known as downstream factors, increased in LID conditions. Furthermore, we found that the effects of 5-HTP were not mediated by dopamine1 receptor (D1)/DARPP32/ERK signaling, but regulated by AKT/mTOR/S6K signaling, which showed different mechanisms with amantadine in the denervated ST. Taken together, 5-HTP alleviates LID by regulating the hyperactivated striatal AKT/mTOR/S6K and CREB/ΔFosB signaling.
Keywords: Parkinson’s disease, Levodopa, Levodopa-induced dyskinesia, 5-Hydroxytryptophan, Serotonin

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