Neural Regeneration Research ›› 2021, Vol. 16 ›› Issue (6): 1099-1104.doi: 10.4103/1673-5374.300451

Previous Articles     Next Articles

Neuroprotective and anti-inflammatory effects of a therapy combining agonists of nicotinic α7 and σ1 receptors in a rat model of Parkinson’s disease

Steven Vetel1, Laura Foucault-Fruchard1, 2, #, Claire Tronel1, #, Frédéric Buron3, Jackie Vergote1, Sylvie Bodard1, Sylvain Routier3, Sophie Sérrière1, Sylvie Chalon1, *   

  1. 1 UMR 1253, iBrain, Université de Tours, Inserm, Tours, France;  2 CHU Tours, Service pharmacie, Tours, France;  3 Institut de Chimie Organique et Analytique, ICOA, UMR CNRS 7311, Université d’Orléans, Orléans, France
  • Online:2021-06-15 Published:2020-12-31
  • Contact: Sylvie Chalon, PhD, sylvie.chalon@univ-tours.fr.
  • Supported by:
    This work was supported  by Inserm (to SV, LFF, CT, JV, SB, SS, SC) and by the Labex IRON (ANR-11-LABX-18-01: to all authors).

PDF

136

Abstract: To date there is no treatment able to stop or slow down the loss of dopaminergic neurons that characterizes Parkinson’s disease. It was recently observed in a rodent model of Alzheimer’s disease that the interaction between the α7 subtype of nicotinic acetylcholine receptor (α7-nAChR) and sigma-1 receptor (σ1-R) could exert neuroprotective effects through the modulation of neuroinflammation which is one of the key components of the pathophysiology of Parkinson’s disease. In this context, the aim of the present study was to assess the effects of the concomitant administration of N-(3R)-1-azabicyclo[2.2.2]oct-3-yl-furo[2,3-c]pyridine-5-carboxamide (PHA) 543613 as an α7-nAChR agonist and 2-(4-morpholinethyl) 1-phenylcyclohexanecarboxylate (PRE)-084 as a σ1-R agonist in a well-characterized 6-hydroxydopamine rat model of Parkinson’s disease. The animals received either vehicle separately or the dual therapy PHA/PRE once a day until day 14 post-lesion. Although no effect was noticed in the amphetamine-induced rotation test, our data has shown that the PHA/PRE treatment induced partial protection of the dopaminergic neurons (15–20%), assessed by the dopamine transporter density in the striatum and immunoreactive tyrosine hydroxylase in the substantia nigra. Furthermore, this dual therapy reduced the degree of glial activation consecutive to the 6-hydroxydopamine lesion, i.e, the 18 kDa translocation protein density and glial fibrillary acidic protein staining in the striatum, and the CD11b and glial fibrillary acidic protein staining in the substantia nigra. Hence, this study reports for the first time that concomitant activation of α7-nAChR and σ1-R can provide a partial recovery of the nigro-striatal dopaminergic neurons through the modulation of microglial activation. The study was approved by the Regional Ethics Committee (CEEA Val de Loire n°19) validated this protocol (Authorization N°00434.02) on May 15, 2014.

Key words: 6-hydroxydopamine, astrocytes, microglial activation, neurodegeneration, neuroinflammation, nicotinic α7 receptor, Parkinson’s disease, PHA 543613, PRE-084, sigma-1 receptor