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<p><span>l</span>-3,4-dihydroxyphenylalanine (<span>l</span>-DOPA) remains the main treatment for motor symptoms of Parkinson’s disease (PD). However, chronic use is associated with the development of complications such as <span>l</span>-DOPA-induced dyskinesia. We previously demonstrated that LY-487,379, a highly selective metabotropic glutamate receptor 2 (mGluR2) positive allosteric modulator (PAM), reduces the severity of <span>l</span>-DOPA-induced abnormal involuntary movements (AIMs) in the 6-hydroxydopamine (6-OHDA)-lesioned rat model of PD, without interfering with the anti-parkinsonian action of <span>l</span>-DOPA. Here, we seek to determine the effect of AZD8529, another highly selective mGluR2 PAM, on <span>l</span>-DOPA-induced AIMs in the 6-OHDA-lesioned rat. Unlike LY-487,379, AZD8529 has previously undergone clinical trials and could therefore be repurposed if proven efficacious in pre-clinical studies. We first determined the pharmacokinetic (PK) profile of AZD8529 to administer doses leading to clinically relevant plasma levels in the behavioural studies. Then, dyskinetic 6-OHDAlesioned rats were administered AZD8529 (0.1, 0.3, and 1 mg/kg) or vehicle in combination with <span>l</span>-DOPA followed by assessment of AIMs severity. The cylinder test was then used to evaluate the effect of AZD8529 on the anti-parkinsonian action of <span>l</span>-DOPA. We found that AZD8529 (0.1, 0.3 and 1 mg/kg) in combination with <span>l</span>-DOPA significantly reduced the severity of AIMs duration (<i>P</i> &lt; 0.05), but not amplitude, when compared to <span>l</span>-DOPA/vehicle. AZD8529 administration did not interfere with <span>l</span>-DOPA anti-parkinsonian action. Our results provide evidence that mGluR2 positive allosteric modulation with AZD8529 may be a viable, yet relatively modest, treatment strategy to alleviate <span>l</span>-DOPA-induced.</p>

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The anti-dyskinetic effect of the clinic-ready mGluR2 positive allosteric modulator AZD8529 in the 6-OHDA-lesioned rat

  • 期刊论文

  • 发表日期：

    2025年1月22日

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  • Judy Shaqfah,
  • Woojin Kang,
  • Fleur Gaudette,
  • Marianne Khalil,
  • Cynthia Kwan,
  • Sébastien Belliveau,
  • Élodie Bourgeois-Cayer,
  • Adjia Hamadjida,
  • Dominique Bédard,
  • Francis Beaudry,
  • Philippe Huot

摘要

l-3,4-dihydroxyphenylalanine (l-DOPA) remains the main treatment for motor symptoms of Parkinson’s disease (PD). However, chronic use is associated with the development of complications such as l-DOPA-induced dyskinesia. We previously demonstrated that LY-487,379, a highly selective metabotropic glutamate receptor 2 (mGluR2) positive allosteric modulator (PAM), reduces the severity of l-DOPA-induced abnormal involuntary movements (AIMs) in the 6-hydroxydopamine (6-OHDA)-lesioned rat model of PD, without interfering with the anti-parkinsonian action of l-DOPA. Here, we seek to determine the effect of AZD8529, another highly selective mGluR2 PAM, on l-DOPA-induced AIMs in the 6-OHDA-lesioned rat. Unlike LY-487,379, AZD8529 has previously undergone clinical trials and could therefore be repurposed if proven efficacious in pre-clinical studies. We first determined the pharmacokinetic (PK) profile of AZD8529 to administer doses leading to clinically relevant plasma levels in the behavioural studies. Then, dyskinetic 6-OHDAlesioned rats were administered AZD8529 (0.1, 0.3, and 1 mg/kg) or vehicle in combination with l-DOPA followed by assessment of AIMs severity. The cylinder test was then used to evaluate the effect of AZD8529 on the anti-parkinsonian action of l-DOPA. We found that AZD8529 (0.1, 0.3 and 1 mg/kg) in combination with l-DOPA significantly reduced the severity of AIMs duration (P < 0.05), but not amplitude, when compared to l-DOPA/vehicle. AZD8529 administration did not interfere with l-DOPA anti-parkinsonian action. Our results provide evidence that mGluR2 positive allosteric modulation with AZD8529 may be a viable, yet relatively modest, treatment strategy to alleviate l-DOPA-induced.