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Activation of mGlu 2/3 receptors with the orthosteric agonist LY-404,039 alleviates dyskinesia in experimental parkinsonism.
- Source :
-
Behavioural pharmacology [Behav Pharmacol] 2024 Jun 01; Vol. 35 (4), pp. 185-192. Date of Electronic Publication: 2024 Mar 29. - Publication Year :
- 2024
-
Abstract
- LY-404,039 is an orthosteric agonist at metabotropic glutamate 2 and 3 (mGlu 2/3 ) receptors, with a possible additional agonist effect at dopamine D 2 receptors. LY-404,039 and its pro-drug, LY-2140023, have previously been tested in clinical trials for psychiatric indications and could therefore be repurposed if they were shown to be efficacious in other conditions. We have recently demonstrated that the mGlu 2/3 orthosteric agonist LY-354,740 alleviated L-3,4-dihydroxyphenylalanine (L-DOPA)-induced abnormal involuntary movements (AIMs) in the 6-hydroxydopamine (6-OHDA)-lesioned rat without hampering the anti-parkinsonian action of L-DOPA. Here, we seek to take advantage of a possible additional D 2 -agonist effect of LY-404,039 and see if an anti-parkinsonian benefit might be achieved in addition to the antidyskinetic effect of mGlu 2/3 activation. To this end, we have administered LY-404,039 (vehicle, 0.1, 1 and 10 mg/kg) to 6-OHDA-lesioned rats, after which the severity of axial, limbs and oro-lingual (ALO) AIMs was assessed. The addition of LY-404,039 10 mg/kg to L-DOPA resulted in a significant reduction of ALO AIMs over 60-100 min (54%, P < 0.05). In addition, LY-404,039 significantly enhanced the antiparkinsonian effect of L-DOPA, assessed through the cylinder test (76%, P < 0.01). These results provide further evidence that mGlu 2/3 orthosteric stimulation may alleviate dyskinesia in PD and, in the specific case of LY-404,039, a possible D 2 -agonist effect might also make it attractive to address motor fluctuations. Because LY-404,039 and its pro-drug have been administered to humans, they could possibly be advanced to Phase IIa trials rapidly for the treatment of motor complications in PD.<br /> (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)
- Subjects :
- Animals
Male
Rats
Amino Acids pharmacology
Antiparkinson Agents pharmacology
Bridged Bicyclo Compounds pharmacology
Disease Models, Animal
Dose-Response Relationship, Drug
Excitatory Amino Acid Agonists pharmacology
Levodopa pharmacology
Oxidopamine
Rats, Sprague-Dawley
Rats, Wistar
Dyskinesia, Drug-Induced drug therapy
Parkinsonian Disorders chemically induced
Parkinsonian Disorders drug therapy
Receptors, Metabotropic Glutamate agonists
Receptors, Metabotropic Glutamate metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1473-5849
- Volume :
- 35
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Behavioural pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 38563661
- Full Text :
- https://doi.org/10.1097/FBP.0000000000000765