Chronic L-DOPA administration is not toxic to the remaining dopaminergic nigrostriatal neurons, but instead may promote their functional recovery, in rats with partial 6-OHDA or FeCl(3) nigrostriatal lesions.

In this study, we have examined the effects of chronic L-3,4-dihydroxyphenylalanine (L-DOPA) administration on the remaining dopaminergic neurons in rats with 6-hydroxydopamine (6-OHDA) or buffered FeCl(3) partial lesions to the nigrostriatal tract. L-DOPA administration increased the turnover of dopamine in the striatum. L-DOPA administration for 1 week produced an increase in the level of striatal RTI-121 binding, a specific marker for dopamine uptake sites on the dopaminergic nerve terminals in the striatum. However, longer periods of L-DOPA treatment decreased the level of RTI-121 binding in the striatum. In the partial 6-OHDA lesion model, L-DOPA treatment had a time-dependent effect on the number of neurons demonstrating a dopaminergic phenotype i.e., neurons that are tyrosine hyrdoxylase (TH)-immunopositive, on the lesioned side of the brain. In the first few weeks of treatment, L-DOPA decreased the number of TH-positive neurons but with long-term treatment, i.e., 24 weeks, L-DOPA increased the number of neurons demonstrating a dopaminergic phenotype. Even in the buffered FeCl(3) infusion model, where the levels of iron were increased, L-DOPA treatment did not have any detrimental effects on the number of TH-positive neurons on the lesioned side of the brain. Consequently, chronic L-DOPA treatment does not have any detrimental effects to the remaining dopaminergic neurons in rats with partial lesions to the nigrostriatal tract; indeed in the 6-OHDA lesion model, long-term L-DOPA may increase the number of neurons, demonstrating a dopaminergic phenotype.

Measuring symptom change in patients with Parkinson's disease.

BACKGROUND: The 39-item Parkinson's disease questionnaire (PDQ-39) is more sensitive to functional change than other measures of health and disability. AIM: To determine the ability of this scale to change over time and the concurrent validity of some of its subscales. METHODS: We assessed a cohort of 67 Parkinson's patients for 18 months, using the PDQ-39, the GHQ-28 general health questionnaire and the Office of Population and Census Surveys disability instrument. RESULTS: The Office of Population and Census Surveys disability instrument and GHQ-28 recorded no significant change, but the PDQ-39 showed marked changes in levels of functioning. We also analysed changes on the PDQ-39 subscales as well as concurrent validity data for several subscales. This showed concurrent validity with the Beck depression and anxiety inventories, the Barthel index and the Royal Postgraduate Medical School severity scale. There was a high level of concurrent validity for all comparisons except for the Barthel index. CONCLUSION: The PDQ-39 is a sensitive tool for monitoring change in patients with Parkinson's disease. It has high levels of concurrent validity with established measures of mood and motor function.

Neuroprotective effects of growth/differentiation factor 5 depend on the site of administration.

Growth/differentiation factor 5 (GDF5) is a neurotrophin which protects the rat nigrostriatal dopaminergic pathway from 6-hydroxydopamine-induced damage. Here we used amphetamine-induced rotational testing, high-performance liquid chromatography and immunocytochemistry to investigate the minimum effective dose of GDF5. We also compared the effectiveness of injecting GDF5 into either the substantia nigra pars compacta (SNpc), the lateral ventricle (LV) or the striatum (or combinations of these sites).

Effects of pergolide treatment on in vivo hydroxyl free radical formation during infusion of 6-hydroxydopamine in rat striatum.

This study focused on the early neurochemical events involved in 6-hydroxydopamine (6-OHDA) neurotoxicity and the putative neuroprotective effects of pergolide. 6-OHDA in 0.1% ascorbic acid/saline was delivered into rat striatum by means of microdialysis and 2,3-dihydroxybenzoic acid (2,3-DHBA) was measured as an index of hydroxyl free radical formation using salicylate trapping. Infusion of 6-OHDA (2-20 mM) via the dialysis probe for 15 min was associated with an immediate and striking increase in the extracellular levels of 2,3-DHBA and dopamine, and this effect was dose-dependent. An infusion of 10 mM 6-OHDA, equivalent to a direct injection of approximately 4 microgram free base, resulted in dopamine overflow with a maximum approx. 200-fold above the baseline. This massive overflow of toxic amounts of dopamine, much greater than expected of reuptake inhibition, seems to be the earliest response of nigrostriatal neurones to 6-OHDA. In rats treated with pergolide mesylate (7 days 0.5 mg/kg/day, i.p.), the average amount of 2, 3-DHBA associated with 6-OHDA striatal infusion was significantly smaller than that in controls. This suggests that pergolide treatment leads to an increased ability of striatal tissue to quench hydroxyl radical formation in vivo.

Long-term protection of the rat nigrostriatal dopaminergic system by glial cell line-derived neurotrophic factor against 6-hydroxydopamine in vivo.

Glial cell-line-derived neurotrophic factor (GDNF) has been shown to enhance the survival of dopaminergic neurones both in vitro and in vivo, and to protect the rodent dopaminergic system from neurotoxic damage. However, most previous studies have only examined the short-term protective effects of GDNF. We have investigated the long-term effects of GDNF on a 6-hydroxydopamine (6-OHDA)-induced lesion of the rat medial forebrain bundle (MFB), which results in complete and irreversible destruction of the nigrostriatal pathway, and is a robust model of Parkinson's disease. GDNF was administered ipsilaterally above the substantia nigra and into the lateral ventricle immediately before a unilateral 6-OHDA injection into the MFB. The effects of GDNF were examined in vivo by behavioural testing and positron emission tomography (PET) at weekly intervals, for 12 weeks. GDNF prevented the development of amphetamine-induced rotations at all time-points. PET studies, using [11C]-RTI-121 as a tracer for the dopamine transporter, indicated that GDNF prevented 6-OHDA-induced reduction of dopamine reuptake sites in the ipsilateral striatum. Post-mortem neurochemical analysis at 13 weeks after surgery found that GDNF significantly inhibited 6-OHDA-induced loss of dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid in the ipsilateral striatum. Immunocytochemistry showed that GDNF reduced 6-OHDA-induced loss of tyrosine hydroxylase-positive neurones in both the substantia nigra pars compacta and ventral tegmental area. We have shown that a single treatment with GDNF can confer long-term protective effects against a 6-OHDA lesion, which suggests that this factor may be useful for the treatment of Parkinson's disease.

Glial pathology but absence of apoptotic nigral neurons in long-standing Parkinson's disease.

The cause and mechanism of neuronal cell death in the substantia nigra of patients with Parkinson's disease (PD) are unknown. There is also controversy about whether the cell death results from a single event followed by cell loss consistent with aging or whether there is an ongoing pathologic process. Using postmortem tissue obtained from the Parkinson's Disease Society Brain Tissue Bank in London, we have sought to establish whether apoptosis, or more specifically DNA fragmentation of neurons, is a prominent feature of nigral pathology. In addition, we have studied microglial activation in the substantia nigra as an indicator of ongoing pathology using the highly sensitive markers CR3/43 and EBM11. Reactive astrocytes have been assessed using immunostaining for glial fibrillary acidic protein (GFAP). Ten patients with pathologically proven PD were studied. In all cases, regardless of disease duration, severity, drug treatment, or age of the patient, there was no evidence of apoptosis in the substantia nigra as assessed by in situ end-labeling of DNA fragments using biotinylated dUTP and terminal deoxynucleotidyl transferase (TdT). In contrast, a case of multiple system atrophy (MSA) served as a positive control for the technique. In this case, positive DNA end-labeling could be found in neurons and non-neuronal cells in the brain stem. In the PD cases, there was, however, localized pathology in the substantia nigra as revealed by the CR3/ 43 and EBM11 markers for activated microglia. This process seemed independent of disease duration and was florid even in patients with severe neuronal loss. It remains to be determined to what extent the activation of glial cells reflects progressive nigral pathology, and whether those factors which are classically associated with prominent apoptotic neuronal cell death in vivo, such as neurotrophic factor deprivation, are prime causes of nigral neuronal loss in PD. Future studies should focus on recent-onset PD or incidental Lewy body disease to further address these questions.

Growth/differentiation factor 5 and glial cell line-derived neurotrophic factor enhance survival and function of dopaminergic grafts in a rat model of Parkinson's disease.

Growth/differentiation factor 5 is a member of the transforming growth factor beta superfamily, which has neurotrophic and neuroprotective effects on dopaminergic neurons both in vitro and in vivo. Here we investigate the effects of growth/differentiation factor 5 on foetal mesencephalic grafts transplanted into a rat model of Parkinson's disease, and compare them with those of glial cell line-derived neurotrophic factor. Mesencephalic tissue was suspended in solutions containing either growth/differentiation factor 5 or glial cell line-derived neurotrophic factor prior to transplantation into the left striatum of rats with 6-hydroxydopamine lesions of the left medial forebrain bundle. Both proteins enhanced graft-induced compensation of amphetamine-stimulated rotations. Positron emission tomography studies showed that both neurotrophins increased graft-induced recovery of striatal binding of [11C]RTI-121, a marker for dopaminergic nerve terminals. Post mortem analysis at 8 weeks after transplantation showed that both neurotrophins significantly increased the survival of grafted dopaminergic neurons. This study shows that growth/differentiation factor 5 is at least as effective as glial cell line-derived neurotrophic factor in enhancing the survival and functional activity of mesencephalic grafts, and thus is an important candidate for use in the treatment of Parkinson's disease.

Growth/differentiation factor 5 protects nigrostriatal dopaminergic neurones in a rat model of Parkinson's disease.

Growth/differentiation factor 5 (GDF5), a novel member of the transforming growth factor beta superfamily, promotes the survival of dopaminergic neurones in vitro. We present here the first evidence for a neuroprotective action of GDF5 in vivo. We investigated the effects of intracerebral administration of GDF5 on a rat model of Parkinson's disease. GDF5 was administered just above the substantia nigra and into the lateral ventricle immediately before ipsilateral injection of 6-hydroxydopamine into the medial forebrain bundle. GDF5 prevented the development of amphetamine-induced rotations and preserved the integrity of striatal dopaminergic nerve terminals, as measured by positron emission tomography. Post-mortem studies showed that GDF5 spared dopamine levels in the striatum and tyrosine hydroxylase positive neurones in the midbrain. This study suggests that GDF5 has potential for the treatment of Parkinson's disease.

Clinical features and management of two cases of encephalitis lethargica.

Two patients with presumed encephalitis lethargica are presented with clinical features suggestive of two forms of the disease described by Von Economo: One patient had a psychosis and a mute-akinetic syndrome associated with myoclonus. The second patient presented with a psychosis and fever, developing severe dyskinesias involving the mouth, trunk and limbs, together with respiratory irregularities and presumed hypothalamic disturbance and disturbance of consciousness. In both cases, initial cerebrospinal fluid (CSF) examination revealed an elevated white cell count (predominantly lymphocytes), elevated protein in case 2, and oligoclonal bands in both cases. Computed tomography (CT) brain scan was normal but in both cases EEG revealed diffuse slow wave activity. A 18F-Dopa positron emission tomography (PET) scan in case 2 was normal. The medical management of both patients is discussed. In case 1, L-Dopa improved the akinesia, while the myoclonus responded to clonazepam. In case 2, the severe dyskinesias failed to respond to a number of drugs, and she ultimately required paralysis to relieve her almost continuous movements. Both patients responded rapidly and dramatically to intravenous methylprednisolone. We suggest that steroid treatment should be considered in the acute phase of patients with features suggestive of encephalitis lethargica.

Facial myokymia in multiple system atrophy.

Two patients are described with clinical and neuroimaging features consistent with a diagnosis of multiple system atrophy (MSA). The patients are unusual in that facial myokymia became apparent clinically at some stage in their illness. In each patient, the nature and severity of the involuntary facial movements evolved over the course of the illness. Electrophysiologically the movement pattern was consistent with myokymia, and studies of blink-reflex responses suggested that the myokymic discharges were of brainstem origin. Involuntary facial movements described as facial action myoclonus with electrical characteristics consistent with myoclonus have been described previously in hereditary olivopontocerebellar atrophy (OPCA). Our report describes electrical and clinical features of facial myokymia in MSA with electrical features suggesting hyperexcitability of the facial motorneurons in the brainstem. Such myokymic movements may occur more frequently in MSA than previously recognised but may be missed clinically because of their evolving nature.

Foot dystonia and lumbar canal stenosis.

We describe a patient who developed involuntary, painless, dystonic contraction of the toes of the right foot on standing or walking. The development of this abnormal movement had been preceded by sensory disturbance on the soles of both feet, triggered by dorsiflexion of the feet. Examination showed that weight bearing on the right foot and walking brought on clawing of the toes of the right foot, which was relieved within seconds of taking pressure off the right foot. There was sensory and reflex evidence of bilateral S1 root disturbance confirmed by electrophysiology. Magnetic resonance imaging of the lumbar spine showed marked stenosis of the lumbar canal with compression of the L5 and S1 nerve roots bilaterally. The patient underwent a lumbar laminectomy with nerve root exit foramina decompression, which abolished the foot dystonia and has considerably improved the sensory disturbance. This case demonstrates that lumbar canal stenosis and/or nerve root compression, may be responsible for foot dystonia. Amelioration of the abnormal movement by surgical decompression argues strongly in favour of this hypothesis.

Lack of permanent nigrostriatal dopamine deficit following 6-hydroxydopamine injection into the rat striatum. Short communication.

The lesion caused by a single 6-hydroxydopamine injection into rat striatum was evaluated. In vivo positron emission tomography using a dopamine reuptake tracer revealed no consistent reduction in striatal dopamine transporter. Amphetamine rotation test was negative up to 18 weeks. A 21% reduction in striatal dopamine seen at 11 weeks was not detectable at 18 weeks. Tyrosine hydroxylase-positive neurone counts showed no decline in substantia nigra. Our results suggest that this lesion may be subject to compensation and therefore should be used with caution in studies on neuroprotective treatments of Parkinson' disease.

GDNF protects against 6-OHDA nigrostriatal lesion: in vivo study with microdialysis and PET.

We have investigated whether glial cell line-derived neurotrophic factor (GDNF) protects against a complete unilateral 6-hydroxydopamine (6-OHDA) nigrostriatal lesion, a robust rat model of Parkinson's disease. GDNF or vehicle were administered above the rat substantia nigra and into the lateral ventricle immediately before an ipsilateral 6-OHDA injection into the medial forebrain bundle. In vivo tests were employed to assess the effects of the treatment: microdialysis to measure striatal dopamine release, amphetamine challenge to estimate turning behaviour, and positron emission tomography (PET) to image dopamine reuptake sites. The present results show that GDNF can protect dopaminergic neurones against an acute and irreversible 6-OHDA lesion. They are encouraging for potential use of GDNF in Parkinson's disease.

Suppressive effect of L-dopa on dopamine cells remaining in the ventral tegmental area of rats previously exposed to the neurotoxin 6-hydroxydopamine.

Ever since the introduction of levo-3,4-dihydroxyphenylalanine (L-dopa) for the treatment of Parkinson's disease, there has been concern that it might accelerate the degeneration of dopamine neurones. Using rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the medial forebrain bundle (MFB), we have studied the effect of chronic L-dopa treatment on the survival of dopamine cells which remain in the ventral tegmental area (VTA) ipsilateral to a 6-OHDA lesion. Following lesion surgery, rats were treated with L-dopa and carbidopa administered in the drinking water for 27 weeks. At the end of the treatment period, the number of dopamine cells remaining in each of the lesioned and intact substantia nigra (SN) and VTA were assessed, using tyrosine hydroxylase immunohistochemistry. Chronic L-dopa treatment resulted in an apparent reduction in the number of dopamine neurones remaining in the VTA ipsilateral to the lesion, whereas it had no effect on the number of dopamine cells remaining in the intact SN and VTA. This finding suggests a possible suppressive effect in vivo of L-dopa on dopamine cells in the midbrain of adult animals that have been previously exposed to 6-OHDA.