Elsevier

Neuroscience

Volume 156, Issue 1, 22 September 2008, Pages 30-41
Neuroscience

Behavioural neuroscience
Exogenous corticosterone reduces l-DOPA-induced dyskinesia in the hemi-parkinsonian rat: Role for interleukin-1β

https://doi.org/10.1016/j.neuroscience.2008.07.016Get rights and content

Abstract

While the etiology of Parkinson's disease (PD) remains unknown, there is overwhelming evidence that neuroinflammation plays a critical role in the progressive loss of dopamine (DA) neurons. Because nearly all persons suffering from PD receive l-DOPA, it is surprising that inflammation has not been examined as a potential contributor to the abnormal involuntary movements (AIMs) that occur as a consequence of chronic l-DOPA treatment. As an initial test of this hypothesis, we examined the effects of exogenously administered corticosterone (CORT), an endogenous anti-inflammatory agent, on the expression and development of l-DOPA-induced dyskinesia (LID) in unilateral DA-depleted rats. To do this, male Sprague–Dawley rats received unilateral medial forebrain bundle 6-hydroxydopamine lesions. Three weeks later, l-DOPA primed rats received acute injections of CORT (0–3.75 mg/kg) prior to l-DOPA to assess the expression of LID. A second group of rats was used to examine the development of LID in l-DOPA naïve rats co-treated with CORT and l-DOPA for 2 weeks. AIMs and rotations were recorded. Exogenous CORT dose-dependently attenuated both the expression and development of AIMs without affecting rotations. Real-time reverse-transcription polymerase chain reaction of striatal tissue implicated a role for interleukin-1 (IL-1) β in these effects as its expression was increased on the lesioned side in rats treated with l-DOPA (within the DA-depleted striatum) and attenuated with CORT. In the final experiment, interleukin-1 receptor antagonist (IL-1ra) was microinjected into the striatum of l-DOPA-primed rats to assess the impact of IL-1 signaling on LID. Intrastriatal IL-1ra reduced the expression of LID without affecting rotations. These findings indicate a novel role for neuroinflammation in the expression of LID, and may implicate the use of anti-inflammatory agents as a potential adjunctive therapy for the treatment of LID.

Section snippets

Animals

Adult male Sprague–Dawley rats were used (225–250 g upon arrival; Taconic Farms, Hudson, NY, USA). Animals were housed in plastic cages (22 cm high, 45 cm deep and 23 cm wide) and had free access to standard laboratory chow (Rodent Diet 5001; Laboratory Diet, Brentwood, MO, USA) and water. The colony room was maintained on a 12-h light/dark cycle (lights on at 07:00 h) at a temperature of 22–23 °C. Animals and all experiments were maintained and conformed to international and local

Monoamine and metabolite levels

The effects of the 6-OHDA lesion on concentrations of monoamine and metabolite levels and turnover ratios (metabolite/monoamine) in the intact (right) versus lesioned (left) striata were examined using HPLC across all experiments (see Table 2). Unilateral 6-OHDA injection into the medial forebrain bundle produced significant reductions in striatal DOPAC and DA levels (P<0.05), 88% and 96% respectively, compared with intact striatum. The denervated side also showed an increased DOPAC/DA turnover

Discussion

Convergent evidence supports the hypothesis that neuroinflammation contributes to the progressive loss of DA neurons in PD by direct recruitment of apoptotic pathways or through increased production of reactive oxygen species (Schulz et al 1995, He et al 2000, Anderson 2001). While DA replacement therapy with l-DOPA provides unique symptomatic relief of PD-related movement disability, repeated administration leads to the development of LID (Jankovic, 2005). Traditional investigations of LID

Acknowledgments

This work was supported by grants from the American Parkinson Disease Association (C. Bishop), NIH NS059600 (C. Bishop), National Science Foundation grant No. 0549987 (T. Deak), and Center for Development and Behavioral Neuroscience at Binghamton University (C. Bishop and T. Deak). The authors would especially like to thank Sheri Zola for her excellent technical assistance during the running of these studies. We would also like to thank Kayla Wilt, Amy Steiniger, and Anna Klioueva for their

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      There is evidence that IL-10 can down-regulate the expression of TNF-α and other pro-inflammatory cytokines and growth factors (John et al., 2003; Majumder et al., 2012), which may promote the occurrence of LID. Also, it was found that the development of LID was accompanied by an increase in interleukin-1β (IL-1β), cyclooxygenase 2 (COX2), neuronal NOS (nNOS), and NF-κB levels in the dorsolateral striatum (Barnum et al., 2008; Bortolanza et al., 2015a, b; Dos-Santos-Pereira et al., 2016). Reducing the expression of various inflammatory factors was reported beneficial to improve the symptoms of dyskinesia (Boi et al., 2019; Del-Bel et al., 2015; Dos-Santos-Pereira et al., 2016).

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