In:
European Journal of Neuroscience, Wiley, Vol. 51, No. 12 ( 2020-06), p. 2412-2422
Abstract:
l ‐3,4‐Dihydroxyphenylalanine ( l ‐DOPA) is the most effective treatment for Parkinson's disease (PD), but its use over a long period is marred by motors complications such as dyskinesia. We previously demonstrated that selective metabotropic glutamate 2/3 (mGlu 2/3 ) receptor activation with LY‐354,740 alleviates dyskinesia in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐lesioned marmoset and the 6‐hydroxydopamine (6‐OHDA)‐lesioned rat. Here, we sought to determine the role played by selective mGlu 2 activation in the anti‐dyskinetic effect of mGlu 2/3 stimulation and have investigated the effect of the highly selective mGlu 2 positive allosteric modulator LY‐487,379 at alleviating established, and preventing the development of, l ‐DOPA‐induced dyskinesia in the 6‐OHDA‐lesioned rat. First, dyskinetic 6‐OHDA‐lesioned rats were administered l ‐DOPA in combination with LY‐487,379 (0.1, 1 and 10 mg/kg) or vehicle, and the severity of dyskinesia was determined. Second, 6‐OHDA‐lesioned rats were administered LY‐487,379 (0.1 or 1 mg/kg), started concurrently with l ‐DOPA, once daily for 22 days, and dyskinesia severity was evaluated weekly for four consecutive weeks. We also assessed the effect of LY‐487,379 on l ‐DOPA anti‐parkinsonian effect. We found that acute challenges of LY‐487,379 0.1 mg/kg in combination with l ‐DOPA, significantly diminished dyskinesia severity, by ≈54% ( p 〈 .01), when compared to vehicle. Moreover, animals treated with l ‐DOPA/LY‐487,379 0.1 and 1 mg/kg during the dyskinesia induction phase exhibited milder dyskinesia, by ≈74% and ≈61%, respectively (both p 〈 .01), when compared to l ‐DOPA/vehicle. LY‐487,379 did not impair l ‐DOPA anti‐parkinsonian activity. These results suggest that mGlu 2 activation may be an effective and promising therapeutic strategy to alleviate the severity and prevent the development of dyskinesia.
Type of Medium:
Online Resource
ISSN:
0953-816X
,
1460-9568
Language:
English
Publisher:
Wiley
Publication Date:
2020
detail.hit.zdb_id:
2005178-5
SSG:
12
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