Foliglurax, a positive allosteric modulator of the metabotrophic glutamate receptor 4, protects dopaminergic neurons in MPTP-lesioned male mice.
Animals
Male
Mice
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Allosteric Regulation
/ drug effects
Antiparkinson Agents
/ administration & dosage
Basal Ganglia
/ metabolism
Disease Models, Animal
Dopamine
/ metabolism
Dopaminergic Neurons
/ drug effects
Dose-Response Relationship, Drug
Mice, Inbred C57BL
Neuroprotective Agents
/ pharmacology
Receptors, Metabotropic Glutamate
/ agonists
Astrocytes
/ metabolism
Microglia
/ metabolism
Neostriatum
/ drug effects
Foliglurax
MPTP
Neuroprotection
Parkinson’s disease
mGlu4 receptor
Journal
Brain research
ISSN: 1872-6240
Titre abrégé: Brain Res
Pays: Netherlands
ID NLM: 0045503
Informations de publication
Date de publication:
15 06 2023
15 06 2023
Historique:
received:
31
01
2023
revised:
20
03
2023
accepted:
24
03
2023
medline:
8
5
2023
pubmed:
28
3
2023
entrez:
27
3
2023
Statut:
ppublish
Résumé
Overactivity of the corticostriatal glutamatergic pathway is documented in Parkinson's disease (PD) and stimulation of presynaptic metabotropic glutamate (mGlu) receptors 4 on these striatal afferents inhibits glutamate release normalizing neuronal activity in the basal ganglia. Moreover, mGlu4 receptors are also expressed in glial cells and are able to modulate glial function making this receptor a potential target for neuroprotection. Hence, we investigated whether foliglurax, a positive allosteric modulator of mGlu4 receptors with high brain exposure after oral administration, has neuroprotective effects in MPTP mice to model early PD. Male mice were treated daily from day 1 to 10 with 1, 3 or 10 mg/kg of foliglurax and administered MPTP on the 5th day then euthanized on the 11th day. Dopamine neuron integrity was assessed with measures of striatal dopamine and its metabolites levels, striatal and nigral dopamine transporter (DAT) binding and inflammation with markers of striatal astrocytes (GFAP) and microglia (Iba1). MPTP lesion produced a decrease in dopamine, its metabolites and striatal DAT specific binding that was prevented by treatment with 3 mg/kg of foliglurax, whereas 1 and 10 mg/kg had no beneficial effect. MPTP mice had increased levels of GFAP; foliglurax treatment (3 mg/kg) prevented this increase. Iba1 levels were unchanged in MPTP mice compared to control mice. There was a negative correlation between dopamine content and GFAP levels. Our results show that positive allosteric modulation of mGlu4 receptors with foliglurax provided neuroprotective effects in the MPTP mouse model of PD.
Identifiants
pubmed: 36972837
pii: S0006-8993(23)00120-8
doi: 10.1016/j.brainres.2023.148349
pii:
doi:
Substances chimiques
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
9P21XSP91P
Antiparkinson Agents
0
Dopamine
VTD58H1Z2X
glial fibrillary astrocytic protein, mouse
0
metabotropic glutamate receptor 4
YZN9W7P1BX
Neuroprotective Agents
0
Receptors, Metabotropic Glutamate
0
Aif1 protein, mouse
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
148349Informations de copyright
Copyright © 2023 Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Dr. Di Paolo received a contract from Prexton Therapeutics for this study that was performed by Drs. M. Bourque and M. Morissette. Drs. D. Charvin and F. Conquet were employed by Prexton Therapeutics now Lundbeck.