PT320, Sustained-Release Exendin-4, Mitigates L-DOPA-Induced Dyskinesia in a Rat 6-Hydroxydopamine Model of Parkinson’s Disease

Seong Jin Yu, Shuchun Chen, Yung Yung Yang, Elliot J. Glotfelty, Jin Jung, Hee Kyung Kim, Ho Il Choi, Doo Sup Choi, Barry J. Hoffer, Nigel H. Greig, Yun Wang

Research output: Contribution to journalArticlepeer-review

Abstract

Background: We previously demonstrated that subcutaneous administration of PT320, a sustained-release (SR) form of exendin-4, resulted in the long-term maintenance of steady-state exenatide (exendin-4) plasma and target levels in 6-hydroxydopamine (6-OHDA)-pretreated animals. Additionally, pre- or post-treatment with PT320 mitigated the early stage of 6-OHDA-induced dopaminergic neurodegeneration. The purpose of this study was to evaluate the effect of PT320 on L-3,4-dihydroxyphenylalanine (L-DOPA)-induced abnormal involuntary movements (AIMs) in the rat 6-OHDA model of Parkinson’s disease. Methods: Adult male Sprague–Dawley rats were unilaterally lesioned in the right medial forebrain bundle by 6-OHDA. L-DOPA and benserazide were given daily for 22 days, starting from 4 weeks after lesioning. PT320 was co-administered weekly for 3 weeks. AIM was evaluated on days 1, 16, and 22 after initiating L-DOPA/benserazide + PT320 treatment. Brain tissues were subsequently collected for HPLC measurements of dopamine (DA) and metabolite concentrations. Results: L-DOPA/benserazide increased AIMs of limbs and axial as well as the sum of all dyskinesia scores (ALO) over 3 weeks. PT320 significantly reduced the AIM scores of limbs, orolingual, and ALO. Although PT320 did not alter DA levels in the lesioned striatum, PT320 significantly attenuated 6-OHDA-enhanced DA turnover. Conclusion: PT320 attenuates L-DOPA/benserazide-induced dyskinesia in a 6-OHDA rat model of PD and warrants clinical evaluation to mitigate Parkinson’s disease in humans.

Original languageEnglish (US)
Article number785
JournalFrontiers in Neuroscience
Volume14
DOIs
StatePublished - Aug 11 2020

Keywords

  • exenatide
  • exendin-4
  • glucagon-like peptide-1
  • L-DOPA-induced dyskinesia
  • levodopa
  • Parkinson’s disease
  • PT302
  • PT320

ASJC Scopus subject areas

  • Neuroscience(all)

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