Abstract
BackgroundWe evaluated the utility of L-3,4-dihydroxy-6-[18F]fluoro-phenylalanine ([18F]FDOPA) positron emission tomography (PET) as a method for assessing the severity of dopaminergic dysfunction in unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats by comparing it with quantitative biochemical, immunohistochemical, and behavioral measurements.MethodsDifferent doses of 6-OHDA (0, 7, 14, and 28 μg) were unilaterally injected into the right striatum of male Sprague-Dawley rats. Dopaminergic functional activity in the striatum was assessed by [18F]FDOPA-PET, measurement of striatal dopamine (DA) and DA metabolite levels, tyrosine hydroxylase (TH) immunostaining, and methamphetamine-induced rotational testing.ResultsAccumulation of [18F]FDOPA in the bilateral striatum was observed in rats pretreated with both aromatic L-amino acid decarboxylase and catechol-O-methyltransferase (COMT) inhibitors. Unilateral intrastriatal injection of 6-OHDA produced a significant site-specific reduction in [18F]FDOPA accumulation. The topological distribution pattern of [18F]FDOPA accumulation in the ipsilateral striatum agreed well with the pattern in TH-stained corresponding sections. A significant positive relationship was found between Patlak plot Ki values and striatal levels of DA and its metabolites (r = 0.958). A significant negative correlation was found between both Ki values (r = -0.639) and levels of DA and its metabolites (r = -0.719) and the number of methamphetamine-induced rotations.ConclusionsKi values determined using [18F]FDOPA-PET correlated significantly with the severity of dopaminergic dysfunction. [18F]FDOPA-PET makes it possible to perform longitudinal evaluation of dopaminergic function in 6-OHDA-lesioned rats, which is useful in the development of new drugs and therapies for Parkinson's disease (PD).
Highlights
We evaluated the utility of L-3,4-dihydroxy-6-[18F]fluoro-phenylalanine ([18F]FDOPA) positron emission tomography (PET) as a method for assessing the severity of dopaminergic dysfunction in unilaterally 6hydroxydopamine (6-OHDA)-lesioned rats by comparing it with quantitative biochemical, immunohistochemical, and behavioral measurements
Effect of carbidopa and entacapone on striatal accumulation of [18F]FDOPA [18F]FDOPA-PET studies using sham-operated, unlesioned control rats pretreated with carbidopa and entacapone indicated that [18F]FDOPA accumulates highly in the bilateral striatum rather than other regions, including the cerebellum
In rats unilaterally lesioned with 28 μg of 6-OHDA, [18F]FDOPA uptake in the striatum was significantly lower in the ipsilateral side compared to the contralateral side of the injection (Figure 1b, “C + E”)
Summary
We evaluated the utility of L-3,4-dihydroxy-6-[18F]fluoro-phenylalanine ([18F]FDOPA) positron emission tomography (PET) as a method for assessing the severity of dopaminergic dysfunction in unilaterally 6hydroxydopamine (6-OHDA)-lesioned rats by comparing it with quantitative biochemical, immunohistochemical, and behavioral measurements. Parkinson’s disease is a progressive, chronic neurodegenerative disorder with movement dysfunction that primarily affects the elderly [1]. L-DOPA remains the most effective therapy, chronic treatment causes adverse effects, such as wearing-off phenomenon and dyskinesia [2]. Gene and stem cell therapies have attracted attention as L-DOPA alternatives. Rats unilaterally lesioned with 6-hydroxydopamine (6-OHDA) are a useful hemi-Parkinson model for studying DA-related functions. This model aids new drug and novel therapy research because motor deficits (e.g., drug-induced rotation) can be quantified [10]. The MFB and SNc lesion models, and partial DA depletion in the CPu model, mimic advanced and global PD stages, respectively [11]
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