The highly selective mGlu₂ receptor positive allosteric modulator LY‐487,379 alleviates l‐DOPA‐induced dyskinesia in the 6‐OHDA‐lesioned rat model of Parkinson's disease

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 (mGlu2/3) 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 mGlu2 activation in the anti‐dyskinetic effect of mGlu2/3 stimulation and have investigated the effect of the highly selective mGlu2 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 mGlu2 activation may be an effective and promising therapeutic strategy to alleviate the severity and prevent the development of dyskinesia.

Activation of mGlu2/3 receptors with the orthosteric agonist LY-404,039 alleviates dyskinesia in experimental parkinsonism

“…It is possible that this antiparkinsonian effect may be mediated by its purported interactions with the dopamine D 2 receptor. Whereas head-to-head comparisons were not made, in the previous work we conducted in the 6-OHDA-lesioned rat with the mGlu 2/3 OA LY-354,740 (Frouni et al ., 2019) and the mGlu 2 positive allosteric modulator LY-487,379 (Hamadjida et al ., 2020), which reportedly do not interact with D 2 receptors (Monn et al ., 1997; Johnson et al ., 2003), we did not find that LY-354,740 and LY-487,379 enhanced the antiparkinsonian action of L-DOPA to such an extent. This possible D 2 -agonist effect of LY-404,039 might explain why it increased the therapeutic effect of L-DOPA on parkinsonism to a seemingly greater extent than LY-354,740 and LY-487,379.…”

“…We have recently identified activation of metabotropic glutamate 2/3 (mGlu 2/3 ) receptors as a novel therapeutic approach in PD, either via orthosteric stimulation (Frouni et al ., 2019) or positive allosteric modulation (Hamadjida et al ., 2020; Frouni et al ., 2021) to reduce dyskinesia in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. mGlu 2/3 receptors appear as a target of interest based on their regulatory role in glutamatergic neurotransmission.…”

[3H]-NFPS binding to the glycine transporter 1 in the hemi-parkinsonian rat brain

“…Hemi-parkinsonism was induced by unilateral injection of 6-OHDA, as previously described (Frouni et al 2019 , 2022 ; Hamadjida et al 2020 ). Initially, animals were administered desipramine (10 mg/kg subcutaneously [s.c.], MilliporeSigma, Oakville, ON, Canada) and pargyline (5 mg/kg s.c., MilliporeSigma) to prevent noradrenergic neuron damage (Ungerstedt 1968 ).…”