Objective: To determine the effects of chronic LD treatment and induction of dyskinesias on cerebral metabolism, blood flow and blood-brain barrier permeability in 6-OHDA rat models.

Background: Levodopa is an effective treatment for Parkinson’s disease, but its long-term use leads to abnormal movements known as Levodopa-Induced Dyskinesias, thought to result from swings in brain dopamine levels. The LD concentration in brain extracellular fluid is dependent on its influx across the blood brain barrier (BBB). Studies have shown that chronic LD treatment is associated with microvascular changes. This agrees well with imaging studies demonstrating LD-increases in cerebral blood flow (CBF) in dopa decarboxylase rich regions which are dissociated from reductions in cerebral metabolic rate for glucose (CMR) in the same regions in rat models (Ohlin et al., 2012) and human patients (Hirano et al., 2008).

Methods: We used triple-tracer microPET to assess the relationship between LD-mediated changes in CBF (measured with 15O-labeled water), CMR (measured with 18F-fluorodexyglucose), and BBB permeability (measured with 11C-alpha aminobutyric acid) in the unilateral 6OHDA rat model. Animals underwent scanning in three conditions: before (Baseline) and after three weeks of daily subcutaneous LD treatment (10mg/kg/15 mg/kg L-DOPA/benserazide-HCl), following final injections of saline (OFF LD) and LD (ON LD). Whole-brain voxel searches were performed to evaluate LD-mediated changes in CBF and CMR, and the relationship of these responses to BBB permeability in the same animals.

Results: Significant LD-related CBF and CMR dissociation was seen in the basal ganglia of the lesioned hemisphere (F1,7=17.471; p=0.001, group × tracer interaction) following chronic treatment and dyskinesia induction. A whole-brain voxel search revealed a significant LD-mediated increase in BBB permeability in the GP of the lesioned hemisphere (p=0.007, paired student t-test), but not in the unlesioned side (p=0.65, paired student t-test).

Conclusions: The results indicate that LD results in robust CBF/CMR dissociation after chronic treatment and dyskinesia induction. Chronic treatment was also associated with increased BBB permeability adjacent to the zone of LD-dissociation. LID may be triggered by localized increases in LD influx possible in these circumstances.

Udall Center Meeting.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/impact-of-chronic-ld-treatment-on-metabolism-blood-flow-and-blood-brain-barrier-permeability-in-the-6-ohda-rat-model/