Axon terminal hypertrophy of striatal projection neurons with levodopa-induced dyskinesia priming

BackgroundA rat model of levodopa-induced dyskinesia (LID) showed enlarged axon terminals of striatal direct pathway neurons in the internal segment of the globus pallidus (GPi) with excessive gamma-aminobutyric acid (GABA) storage in them. Massive GABA release to GPi upon levodopa administration determines the emergence of LID.ObjectivesWe examined whether LID and axon terminal hypertrophy gradually develop with repeated levodopa treatment in Parkinsonian rats to examine if the hypertrophy reflects dyskinesia priming.Methods6-hydroxydopamine-lesioned hemiparkinsonian rats were randomly allocated to receive saline injections (placebo group, 14 days; n = 4), injections of 6 mg/kg levodopa methyl ester combined with 12.5 mg/kg benserazide (levodopa-treated groups, 3-day-treatment; n = 4, 7-day-treatment; n = 4, 14-day-treatment; n = 4), or injections of 6 mg/kg levodopa methyl ester with 12.5 mg/kg benserazide and 1 mg/kg 8-hydroxy-2-(di-n-propylamino)tetralin for 14 days (8-OH-DPAT-treated group; n = 4). We evaluated abnormal involuntary movement (AIM) scores and axon terminals in the GPi.ResultsThe AIM score increased with levodopa treatment, as did the hypertrophy of axon terminals in the GPi, showing an increased number of synaptic vesicles in hypertrophied terminals.ConclusionIncreased GABA storage in axon terminals of the direct pathway neurons represents the priming process of LID

What mechanisms are responsible for the reuptake of levodopa-derived dopamine in parkinsonian striatum?

Levodopa is the most effective medication for motor symptoms in Parkinson’s disease. However, various motor and non-motor complications are associated with levodopa treatment, resulting from altered levodopa-dopamine metabolism with disease progression and long-term use of the drug. The present review emphasizes the role of monoamine transporters other than the dopamine transporter in uptake of extracellular dopamine in the dopamine-denervated striatum. When dopaminergic neurons are lost and dopamine transporters decreased, serotonin and norepinephrine transporters compensate by increasing uptake of excessive extracellular dopamine in the striatum. Organic cation transporter-3 and plasma membrane monoamine transporter, low affinity and high capacity transporters, also potentially uptake dopamine when high-affinity transporters do not work normally. Selective serotonin reuptake inhibitors and serotonin and norepinephrine reuptake inhibitors are often administered to patients with Parkinson’s disease presenting with depression, pain or other non-motor symptoms. Thus, it is important to address the potential of these drugs to modify dopamine metabolism and uptake through blockade of the compensatory function of these transporters, which could lead to changes in motor symptoms of Parkinson’s disease

Zonisamide Enhances Motor Effects of Levodopa, Not of Apomorphine, in a Rat Model of Parkinson’s Disease

Zonisamide is a relatively recent drug for Parkinson’s disease. Multiple hypotheses have been proposed to explain the antiparkinsonian effects of zonisamide. However, it is still unclear whether the effect of zonisamide is mainly due to dopaminergic modification in the striatum, or if zonisamide works through nondopaminergic pathways. We conducted the present study to determine the mechanism that is mainly responsible for zonisamide’s effects in Parkinson’s disease. We examined the effects of zonisamide on motor symptoms in a hemiparkinsonian rat model when administered singly, coadministered with levodopa, a dopamine precursor, or apomorphine, a D1 and D2 dopamine receptor agonist. We used 6-hydroxydopamine-lesioned hemiparkinsonian rats, which were allocated to one of five groups: 14 rats received levodopa only (6 mg/kg), 12 rats received levodopa (6 mg/kg) plus zonisamide (50 mg/kg), six rats received apomorphine only (0.05 mg/kg), six rats received apomorphine (0.05 mg/kg) plus zonisamide (50 mg/kg), and six rats received zonisamide only (50 mg/kg). The drugs were administered once daily for 15 days. We evaluated abnormal involuntary movement every 20 min during a 3 h period following the injection of drugs on treatment Days 1, 8, and 15. Western blot analyses for dopamine decarboxylase and vesicular monoamine transferase-2 were performed using striatal tissues in the lesioned side of rats in the levodopa only group (n = 6) and levodopa plus zonisamide group (n = 4). Levodopa-induced abnormal involuntary movement was significantly enhanced by coadministration of zonisamide. In contrast, zonisamide had no effect on apomorphine-induced abnormal involuntary movement. Zonisamide monotherapy did not induce abnormal involuntary movement. Zonisamide did not affect striatal expression of dopamine decarboxylase or vesicular monoamine transferase-2. In conclusion, zonisamide appears to generate its antiparkinsonian effects by modulating levodopa-dopamine metabolism in the parkinsonian striatum

Clinical Utility of Skin Biopsy in Differentiating between Parkinson’s Disease and Multiple System Atrophy

Background. It is often difficult to differentiate Parkinson’s disease (PD) from multiple system atrophy (MSA), especially in their early stages. Objectives. To examine the clinical utility of histopathological analysis of biopsied skin from the chest wall and/or leg in differentiating between the two diseases. Methods. Skin biopsies from the lower leg and/or anterior chest wall were obtained from 38 patients with idiopathic PD (26 treated with levodopa and 12 levodopa-naïve) and 13 age-matched patients with MSA. We sought aggregates of phosphorylated α-synuclein on cutaneous nerve fibers using double fluorescence immunohistochemistry and confocal microscopy and measured intraepidermal nerve fiber density (IENFD). Results. Phosphorylated α-synuclein aggregates were identified on cutaneous nerves in two patients with PD (5.3%) but in none of the patients with MSA, and IENFD was significantly lower in patients with PD when compared to those with MSA. There was no difference in IENFD between levodopa-treated and levodopa-naïve patients with PD. Conclusions. Our findings suggest that an assessment of IENFD in biopsied skin could be a useful means of differentiating between PD and MSA but that detection of α-synuclein aggregates on cutaneous nerves in the distal sites of the body is insufficiently sensitive

Evaluation of cerebral blood flow in older patients with status epilepticus using arterial spin labeling

Introduction: Although older patients with status epilepticus (SE) have a high mortality rate and poor outcome, it is difficult to perform emergent electroencephalography (EEG) to diagnose SE in community hospitals. Arterial spin labeling (ASL) is a non-invasive magnetic resonance imaging (MRI) technique that can rapidly assess cerebral blood flow (CBF). Further, ASL can detect increased CBF in the ictal period. Therefore, ASL may be a useful tool for diagnosing SE in older patients. However, its effectiveness in this population is unknown. Methods: We retrospectively investigated differences in CBF abnormalities between older patients (≥70 years) and non-older patients (<70 years) with SE using ASL. Participants were diagnosed with convulsive status epilepticus (CSE) or non-convulsive status epilepticus (NCSE) based on symptoms, brain MRI, and EEG. Results: ASL detected CBF abnormalities in 40% of older patients with CSE or NCSE. Rates of CBF abnormalities in older patients were not significantly different compared with that in non-older patients. Conclusions: ASL did not detect a higher rate of CBF abnormalities in older patients, but may help physicians diagnose SE in older patients in a community hospital setting if emergent EEG cannot be immediately performed. Keywords: Status epilepticus, Arterial spin labeling, Older patient, Non-convulsive status epilepticus, Magnetic resonance imagin