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Therapeutic potential of α7 nicotinic receptor agonists to regulate neuroinflammation in neurodegenerative diseases

Neural Regeneration Research 2017年第9期12卷 1418-1421页

作者： laura foucault-fruchard Daniel Antier UMR INSERM U930 Université Fran?ois Rabelais CHRU de Tours H?pital Bretonneau

Neurodegenerative diseases, such as Alzheimer＇s, Parkinson＇s and Huntington＇s diseases, are all character- ized by a component of innate immunity called neuroinflammation. Neuronal loss and neuroinflammation are two phenomena closely linked. Hence, the neuroinflammation is a relevant target for the management of the neurodegenerative diseases given that, to date, there is no treatment to stop neuronal loss. Several studies have investigated the potential effects of activators of alpha 7 nicotinic acetylcholine receptors in animal models of neurodegenerative diseases. These receptors are widely distributed in the central nervous system. After activation, they seem to mediate the cholinergic anti-inflammatory pathway in the brain. This anti-inflammatory pathway, first described in periphery, regulates activation of microglial cells considered as the resident macrophage population of the central nervous system. In this article, we shortly review the agonists of the alpha 7 nicotinic acetylcholine receptors that have been evaluated in vivo and we focused on the selective positive allosteric modulators of these receptors. These compounds represent a key element to enhance receptor activity only in the presence of the endogenous agonist.

关键词： α7 nicotinic receptors cholinergic anti-inflammatory pathway Alzheimer's disease Huntington's disease Parkinson's disease neuroinflammation neurodegeneration positive allosteric modulators

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Alpha-7 nicotinic acetylcholine receptor agonist treatment in a rat model of Huntington's disease and involvement of heme oxygenase-1

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Neural Regeneration Research 2018年第4期13卷 737-741页

作者： laura foucault-fruchard Claire Tronel Sylvie Bodard Zuhal Gulhan Julie Busson Sylvie Chalon Daniel Antier UMR 1253 iBrainUniversité de Tours CHRU de Tours H?pital Bretonneau

Neuroinflammation is a common element involved in the pathophysiology of neurodegenerative *** recently reported that repeated alpha-7 nicotinic acetylcholine receptor（α7 n ACh R） activations by a potent agonist such as PHA 543613 in quinolinic acid-injured rats exhibited protective effects on *** further investigate the underlying mechanism,we established rat models of early-stage Huntington＇s disease by injection of quinolinic acid into the right striatum and then intraperitoneally injected 12 mg/kg PHA 543613 or sterile water,twice a day during 4 *** blot assay results showed that the expression of heme oxygenase-1（HO-1）,the key component of the cholinergic anti-inflammatory pathway,in the right striatum of rat models of Huntington＇s disease subjected to intraperitoneal injection of PHA 543613 for 4 days was significantly increased compared to the control rats receiving intraperitoneal injection of sterile water,and that the increase in HO-1 expression was independent of change in α7 n ACh R *** findings suggest that HO-1 expression is unrelated to α7 n ACh R density and the increase in HO-1 expression likely contributes to α7 n ACh R activation-related neuroprotective effect in early-stage Huntington＇s disease.

关键词： alpha 7 nicotinic receptor PHA 543613 quinolinic acid cholinergic anti-inflammatory pathway neuroinflammation neurodegenerative disease

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

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Neural Regeneration Research 2021年第6期16卷 1099-1104页

作者： Steven Vetel laura foucault-fruchard Claire Tronel Frédéric Buron Jackie Vergote Sylvie Bodard Sylvain Routier Sophie Sérrière Sylvie Chalon UMR 1253 iBrainUniversitéde ToursInsermToursFrance CHU Tours Service pharmacieToursFrance Institut de Chimie Organique et Analytique ICOAUMR CNRS 7311Universitéd’OrléansOrléansFrance

To date there is no treatment able to stop or slow down the loss of dopaminergic neurons that characterizes Parkinson’s *** 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 *** 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 aσ1-R agonist in a well-characterized 6-hydroxydopamine rat model of Parkinson’s *** animals received either vehicle separately or the dual therapy PHA/PRE once a day until day 14 *** 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 ***,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 ***,this study reports for the first time that concomitant activation of α7-nAChR andσ1-R can provide a partial recovery of the nigro-striatal dopaminergic neurons through the modulation of microglial *** 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.

关键词： 6-hydroxydopamine astrocytes microglial activation neurodegeneration neuroinflammation nicotinicα7 receptor Parkinson’s disease PHA 543613 PRE-084 sigma-1 receptor

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