Neuroinflammation and L-dopa-induced abnormal involuntary movements in 6-hydroxydopamine-lesioned rat model of Parkinson's disease are counteracted by combined administration of a 5-HT1A/1B receptor agonist and A2A receptor antagonist

Neuropharmacology. 2021 Sep 15:196:108693. doi: 10.1016/j.neuropharm.2021.108693. Epub 2021 Jul 3.

Abstract

Several lines of evidence have strongly implicated neuroinflammation in Parkinson's disease (PD) progression and l-dopa-induced dyskinesia. The present study investigated whether early subchronic pretreatment with the serotonin 5-HT1A/1B receptor agonist eltoprazine plus the adenosine A2A receptor antagonist preladenant counteracted l-dopa-induced abnormal involuntary movements (AIMs, index of dyskinesia), and neuroinflammation, in unilateral 6-hydroxydopamine(6-OHDA)-lesioned rat model of PD. The immunoreactivity of glial fibrillary acidic protein (GFAP), and the colocalization of ionized calcium binding adaptor molecule-1 (IBA-1), with interleukin (IL)-1β, tumor-necrosis-factor-α (TNF-α) and IL-10 were evaluated in the denervated caudate-putamen (CPu) and substantia nigra pars-compacta (SNc). The combined subchronic pretreatment with l-dopa plus eltoprazine and preladenant reduced AIMs induced by acute l-dopa challenge in these rats and decreased GFAP and IBA-1 immunoreactivity induced by the drug in both CPu and SNc, with reduction in IL-1β in IBA-1-positive cells in both CPu and SNc, and in TNF-α in IBA-1-positive cells in SNc. Moreover, a significant increase in IL-10 in IBA-1-positive cells was observed in SNc. Evaluation of immediate early-gene zif-268 (index of neuronal activation) after l-dopa challenge, showed an increase in its expression in denervated CPu of rats pretreated with l-dopa or l-dopa plus preladenant compared with vehicle, whereas rats pretreated with eltoprazine, with or without preladenant, had lower zif-268 expression. Finally, tyrosine hydroxylase and dopamine transporter examined to evaluate neurodegeneration, showed a significant equal decrease in all experimental groups. The present findings suggest that combination of l-dopa with eltoprazine and preladenant may be promising therapeutic strategy for delaying the onset of dyskinesia, preserving l-dopa efficacy and reducing neuroinflammation markers in nigrostriatal system of 6-OHDA-lesioned rats.

Keywords: Abnormal involuntary movements; Astroglia; Dyskinesia; GFAP; IBA-1; Microglia; Neuroinflammation; Nigrostriatal system; Zif-268.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine A2 Receptor Antagonists / pharmacology*
  • Animals
  • Antiparkinson Agents / adverse effects*
  • Calcium-Binding Proteins / drug effects
  • Calcium-Binding Proteins / metabolism
  • Caudate Nucleus / drug effects
  • Caudate Nucleus / metabolism
  • Dyskinesia, Drug-Induced / etiology
  • Dyskinesia, Drug-Induced / metabolism
  • Dyskinesia, Drug-Induced / physiopathology*
  • Glial Fibrillary Acidic Protein / drug effects
  • Glial Fibrillary Acidic Protein / metabolism
  • Interleukin-10 / metabolism
  • Interleukin-1beta / drug effects
  • Interleukin-1beta / metabolism
  • Levodopa / adverse effects*
  • Microfilament Proteins / drug effects
  • Microfilament Proteins / metabolism
  • Neuroinflammatory Diseases / metabolism
  • Oxidopamine / toxicity
  • Parkinsonian Disorders / chemically induced
  • Parkinsonian Disorders / drug therapy
  • Parkinsonian Disorders / metabolism
  • Parkinsonian Disorders / physiopathology*
  • Pars Compacta / drug effects
  • Pars Compacta / metabolism
  • Piperazines / pharmacology*
  • Putamen / drug effects
  • Putamen / metabolism
  • Pyrimidines / pharmacology*
  • Rats
  • Receptor, Serotonin, 5-HT1A
  • Receptor, Serotonin, 5-HT1B
  • Serotonin 5-HT1 Receptor Agonists / pharmacology*
  • Triazoles / pharmacology*
  • Tumor Necrosis Factor-alpha / drug effects
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Adenosine A2 Receptor Antagonists
  • Aif1 protein, rat
  • Antiparkinson Agents
  • Calcium-Binding Proteins
  • GFAP protein, rat
  • Glial Fibrillary Acidic Protein
  • IL1B protein, rat
  • Interleukin-1beta
  • Microfilament Proteins
  • Piperazines
  • Pyrimidines
  • Receptor, Serotonin, 5-HT1B
  • Serotonin 5-HT1 Receptor Agonists
  • Triazoles
  • Tumor Necrosis Factor-alpha
  • Receptor, Serotonin, 5-HT1A
  • Interleukin-10
  • Levodopa
  • eltoprazine
  • Oxidopamine
  • 2-(2-furanyl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)-1-piperazinyl)ethyl)-7H-pyrazolo(4,3-e)(1,2,4)triazolo(1,5-c)pyrimidine-5-amine