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Hydroxychloroquine antiparkinsonian potential: Nurr1 modulation versus autophagy inhibition

Shireen A Hedya1, Marwa M Safar2, Ashraf K Bahgat1

  • 1Pharmacology & Toxicology Department, Faculty of Pharmacy, Cairo University, Egypt.

Behavioural Brain Research
|February 25, 2019
PubMed

Insights

Hydroxychloroquine improved Parkinson's disease (PD) motor symptoms by boosting Nurr1 expression and reducing inflammation. However, it also inhibited autophagy and increased apoptosis, suggesting complex therapeutic effects.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Cell Biology

Background:

  • Parkinson's disease (PD) pathophysiology involves autophagy dysregulation.
  • Nurr1 (nuclear orphan receptor) is a potential therapeutic target for PD.
  • Hydroxychloroquine (HCQ) is an antimalarial and anti-rheumatic drug with controversial neuroprotective potential.

Purpose of the Study:

  • To investigate if hydroxychloroquine (HCQ) exhibits antiparkinsonian activity via Nurr1 modulation.
  • To assess HCQ's effects on neuroinflammation, autophagy, and apoptosis in a rat rotenone model of PD.

Main Methods:

  • Utilized a rat rotenone model to induce Parkinson's-like pathology.
  • Administered hydroxychloroquine (HCQ) and assessed its impact on Nurr1 expression, pro-inflammatory cytokines, GSK-3β activity, and tyrosine hydroxylase content.
  • Evaluated autophagy markers (LC3-II, P62, sirtuin 1) and apoptotic biomarkers.

Main Results:

  • HCQ boosted Nurr1 expression, reduced inflammation, and decreased GSK-3β activity, leading to improved motor function.
  • HCQ increased striatal tyrosine hydroxylase content, enhancing locomotion and muscle coordination.
  • HCQ induced autophagic inhibition and elevated apoptosis, potentially linked to reduced sirtuin 1 levels.

Conclusions:

  • Hydroxychloroquine ameliorated motor dysfunction in a rat PD model through Nurr1 modulation.
  • Despite positive motor effects, HCQ deregulated autophagy and apoptosis, indicating a complex therapeutic profile.
  • Further research is needed to balance the benefits of Nurr1 modulation with the adverse effects on autophagy and apoptosis.
Keywords:
GSK-3βHydroxychloroquineLC3-IINurr1RotenoneSIRT-1

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