Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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5-Hydroxytryptophan Reduces Levodopa-Induced Dyskinesia via Regulating AKT/mTOR/S6K and CREB/ΔFosB Signals in a Mouse Model of Parkinson's Disease

  • Yujin Choi (Department of Biomedical and Pharmaceutical Sciences, Graduate School, Kyung Hee University) ;
  • Eugene Huh (Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University) ;
  • Seungmin Lee (Department of Biomedical and Pharmaceutical Sciences, Graduate School, Kyung Hee University) ;
  • Jin Hee Kim (Department of Biomedical and Pharmaceutical Sciences, Graduate School, Kyung Hee University) ;
  • Myoung Gyu Park (MetaCen therapeutics Inc. R&D Center) ;
  • Seung-Yong Seo (College of Pharmacy, Gachon University) ;
  • Sun Yeou Kim (College of Pharmacy, Gachon University) ;
  • Myung Sook Oh (Department of Biomedical and Pharmaceutical Sciences, Graduate School, Kyung Hee University)
  • Received : 2022.11.08
  • Accepted : 2023.02.10
  • Published : 2023.07.01
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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

References

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