Ropinirole Cotreatment Prevents Perivascular Glial Recruitment in a Rat Model of L-DOPA-Induced Dyskinesia

Abstract

Dopamine replacement therapy for Parkinson’s disease is achieved using L-DOPA or dopamine D2/3 agonists, such as ropinirole. Here, we compare the effects of L-DOPA and ropinirole, alone or in combination, on patterns of glial and microvascular reactivity in the striatum. Rats with unilateral 6-hydroxydopamine lesions were treated with therapeutic-like doses of L-DOPA (6 mg/kg), an equipotent L-DOPA-ropinirole combination (L-DOPA 3 mg/kg plus ropinirole 0.5 mg/kg), or ropinirole alone. Immunohistochemistry was used to examine the reactivity of microglia (ionized calcium-binding adapter molecule 1, IBA-1) and astroglia (glial fibrillary acidic protein, GFAP), as well as blood vessel density (rat endothelial cell antigen 1, RECA-1) and albumin extravasation. L-DOPA monotreatment and L-DOPA–ropinirole cotreatment induced moderate-severe dyskinesia, whereas ropinirole alone had negligible dyskinetic effects. Despite similar dyskinesia severity, striking differences in perivascular microglia and astroglial reactivity were found between animals treated with L-DOPA vs. L-DOPA–ropinirole. The former exhibited a marked upregulation of perivascular IBA-1 cells (in part CD68-positive) and IBA-1–RECA-1 contact points, along with an increased microvessel density and strong perivascular GFAP expression. None of these markers were significantly upregulated in animals treated with L-DOPA–ropinirole or ropinirole alone. In summary, although ropinirole cotreatment does not prevent L-DOPA-induced dyskinesia, it protects from maladaptive gliovascular changes otherwise associated with this disorder, with potential long-term benefits to striatal tissue homeostasis.

Differential activation states of direct pathway striatal output neurons associated with the development of L-DOPA-induced dyskinesia

“…These data are likely indicative of the supportive network that is necessary for synaptic and cellular remodeling of neurons upon L-DOPA treatment that leads to LID and will require future investigation. In addition, glial activation has been indicated previously in similar LID models and suggests an immune and/or inflammatory reaction in response to L-DOPA treatment (Elabi et al, 2023;Ferrari et al, 2021;Kuter et al, 2020;Morissette et al, 2022;Nascimento et al, 2023;Pinna et al, 2021). Though the overall populations of MSNs were not affected by L-DOPA treatment, the proportion expressing marker genes consistent with activation were increased in terms of D1-MSNs, and reduced in terms of D2-MSNs, compared to L-DOPA-naïve mice (Figure 2B, Table S2).…”