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

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 antiinflammatory 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 RT-PCR of striatal tissue implicated a role for IL-1β 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, IL-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.

Differential Involvement of D1 and D2 Dopamine Receptors in L-DOPA-Induced Angiogenic Activity in a Rat Model of Parkinson's Disease

“…Similar to the situation reported in other neurological conditions (Ivens et al, 2007;van Vliet et al, 2007), angiogenesis and altered BBB permeability may, however, itself contribute to the abnormal neuronal activities and (in the case of PD) it may also alter the kinetics of L-DOPA entry into the brain. In support of this contention, the development of L-DOPA-induced AIMs can be delayed by corticosterone co-treatment (Barnum et al, 2008), which is known to inhibit brain angiogenesis (Ekstrand et al, 2008b) and to stabilize the BBB. It is presently unknown whether BBB dysfunction contributes to human LID.…”

The Pharmacology of l-DOPA-Induced Dyskinesia in Parkinson’s Disease

“…In a study performed in the 6-OHDA-lesioned rat, systemic administration of the endogenous steroid corticosterone and intrastriatal administration of an interleukin-1 receptor antagonist both attenuated the expression of established LI-AIMs (Barnum et al, 2008). In that study, de novo treatment with corticosterone also attenuated the development of LI-AIMs (Barnum et al, 2008).…”

“…In that study, de novo treatment with corticosterone also attenuated the development of LI-AIMs (Barnum et al, 2008). Striatal levels of interleukin-1b were also found to be elevated in the dopaminedepleted striatum of dyskinetic rats killed 2 hours after last L-DOPA dose (Barnum et al, 2008). The mechanisms by which anti-inflammatory agents alleviate LID are far from being elucidated.…”

Are cyclooxygenase-2 and nitric oxide involved in the dyskinesia of Parkinson's disease induced byl-DOPA?

“…Recently, non-neuronal factor such as inflammation have been suggested to be involved in L-DOPA-induced dyskinesia [36,46]. The anti-dyskinetic effects of anti-inflammatory treatments with either corticosterone [46] or IRC-82451 (a multitargeting molecule [47]) support the hypothesis.…”