Allosteric and orthosteric activation of mGlu <sub>2</sub> receptors to alleviate dyskinesia and psychosis in the parkinsonian marmoset
Bibliographic record
Abstract
Objective To determine the effect of combined allosteric and orthosteric activation of metabotropic glutamate 2 (mGlu 2 ) receptors on L‐3,4‐dihydroxyphenylalanine (L‐DOPA)‐induced psychosis‐like behaviours (PLBs) and dyskinesia in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐lesioned marmoset model of Parkinson's disease (PD). Background We have previously demonstrated that activation of mGlu 2 receptors via positive allosteric modulation with LY‐487,379 or orthosteric stimulation with LY‐354,740 alleviates PLBs and dyskinesia in experimental parkinsonism. Here, we seek to determine if synergy ensues when mGlu 2 positive allosteric modulation and orthosteric stimulation are combined, in the MPTP‐lesioned marmoset. Methods Six common marmosets were rendered parkinsonian by MPTP injection. Following repeated administration of L‐DOPA/benserazide (L‐DOPA) to elicit stable PLBs and dyskinesia, they were administered acute challenges of LY‐487,379 (1 mg/kg), LY‐354,740 (1 mg/kg), LY‐487,379/LY‐354,740 (each 1 mg/kg) or vehicle, in combination with L‐DOPA, after which the severity of each of PLBs, dyskinesia and parkinsonian disability was rated. Results LY‐487,379, LY‐354,740 and LY‐487,379/LY‐354,740 each significantly reduced the severity of the global dyskinesia score, by ≈ 42%, 55% and 64% (each P < 0.001), when compared to L‐DOPA/vehicle. The combination LY‐487,379/LY‐354,740 was significantly more effective than either treatment alone (both P < 0.05). The severity of the global PLB score was also significantly reduced by each of LY‐487,379, LY‐354,740 and LY‐487,379/LY‐354,740, by ≈ 51%, 44% and 56% (each P < 0.001), when compared to L‐DOPA/vehicle. The combination LY‐487,379/LY‐354,740 was significantly more effective than LY‐487,379 ( P < 0.01), but not LY‐354,740 ( P > 0.05). The benefits on dyskinesia and PLBs were achieved without compromising the therapeutic effect of L‐DOPA on parkinsonism. Conclusions Our results confirm mGlu 2 activation, via both positive allosteric modulation and orthosteric stimulation, is a promising strategy to reduce dyskinesia and psychosis in PD. Moreover, they suggest that the combination of a positive allosteric modulator and an orthosteric agonist may lead to a synergistic effect, thereby providing greater anti‐dyskinetic and anti‐psychotic effects. Support or Funding Information Fonds de Recherche Québec ‐ Santé, Natural Sciences and Engineering Research Council of Canada, Parkinson Canada, Weston Brain Institute, Michael J Fox Foundation for Parkinson's Research, Healthy Brains for Healthy Lives. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".