David Peggs

Neural mechanisms underlying Parkinsonian symptoms based upon regional uptake of 2-deoxyglucose in monkeys exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

The 2-deoxyglucose metabolic mapping technique has been used to investigate the neural mechanisms which underlie the symptoms of Parkinsonism in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine primate model of Parkinsons disease. In six cynomolgus monkeys, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine was either (a) administered intravenously to induce generalized Parkinsonism, or (b) infused into one carotid artery to induce unilateral Parkinsonism. Post-mortem examination revealed profound cell loss from the substantia nigra, pars compacta either bilaterally or unilaterally in the two groups, respectively. In addition, there was pathological involvement of the ventral tegmental area and locus coeruleus in animals receiving intravenous 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. 2-Deoxyglucose autoradiography revealed widespread changes in 2-deoxyglucose uptake in the brains of parkinsonian animals when compared to controls. Most of these changes were in basal ganglia and related structures and were qualitatively similar in the two groups of experimental animals. Prominent increases in 2-deoxyglucose uptake were observed in the lateral segment of the globus pallidus (24-27%), the ventral anterior and ventral lateral nuclei of the thalamus (14-22%) and the nucleus tegmenti pedunculopontinus of the caudal midbrain (17-69%). A profound decrease (17-26%) in 2-deoxyglucose uptake was observed in the subthalamic nucleus. We propose these data to indicate that in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinsonism there is the following pattern of abnormal neuronal activity in basal ganglia circuitry: (i) increased activity in the projection from the putamen to the lateral segment of the globus pallidus; (ii) decreased activity in the projection from the putamen to the medial segment of the globus pallidus; (iii) decreased activity in the projection from the lateral segment of the globus pallidus to the subthalamic nucleus; (iv) increased activity in the projection from the subthalamic nucleus to the globus pallidus; and (v) increased activity in neurons of the medial segment of the globus pallidus projecting to the ventral anterior/ventral lateral thalamus and the pedunculopontine nucleus. These results are compared to the 2-deoxyglucose uptake findings in previous studies from this laboratory in hemiballism and hemichorea in the monkey. The central importance of the subthalamic nucleus in all three conditions is proposed, and supportive evidence for the excitatory nature of subthalamic efferent fibres is adduced.

The α2-adrenergic receptor antagonist idazoxan reduces dyskinesia and enhances anti-parkinsonian actions of L-dopa in the MPTP-lesioned primate model of Parkinson's disease

Dopamine replacement therapy in patients with Parkinsons disease is plagued by the emergence of abnormal involuntary movements known as L‐dopa‐induced dyskinesias. It has been demonstrated that yohimbine can reduce L‐dopa‐induced dyskinesia in the MPTP‐lesioned primate model of Parkinsons disease. Yohimbine is, among other things, an alpha‐adrenergic receptor antagonist. In this study, we demonstrate that the selective and potent α2‐adrenergic receptor antagonist idazoxan reduces L‐dopa‐induced dyskinesia in the MPTP‐lesioned marmoset model of Parkinsons disease. The α2‐adrenergic receptor antagonists rauwolscine and yohimbine also reduce L‐dopa‐induced dyskinesia. Furthermore, we demonstrate that coadministration of idazoxan with L‐dopa can provide an anti‐parkinsonian action more than twice the length of that seen with L‐dopa alone. However, idazoxan as a monotherapy displayed no anti‐parkinsonian actions. We propose that idazoxan in combination with L‐dopa may provide a novel approach to the treatment of Parkinsons disease that will not only reduce the dyskinetic side effects, but extend the anti‐parkinsonian actions of L‐dopa. Idazoxan, as an adjunct to dopamine replacement, may prove useful in the treatment of parkinsonian patients at all stages of disease progression.

Subthalamic nucleotomy alleviates parkinsonism in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-exposed primate.

Research into the neural mechanisms underlying the symptoms of parkinsonism utilizing the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-exposed primate model have shown that the subthalamic nucleus (STN) occupies a central role. As a logical development of this theory, we have studied the effects of thermocoagulative lesions of the STN in the primate model. Such lesions can cause remarkable symptom reversal in the experimental primate model.

Antiparkinsonian actions of ifenprodil in the MPTP-lesioned marmoset model of Parkinson's disease.

Dopamine-replacement strategies form the basis of most symptomatic treatments for Parkinsons disease. However, since long-term dopamine-replacement therapies are characterized by many side effects, most notably dyskinesia, the concept of a nondopaminergic therapy for Parkinsons disease has attracted great interest. To date, it has proved difficult to devise a nondopaminergic therapy with efficacy comparable to that of dopamine replacement. In animal models of Parkinsons disease, loss of striatal dopamine leads to enhanced excitation of striatal NR2B-containing NMDA receptors. This is responsible, in part at least, for generating parkinsonian symptoms. Here we demonstrate that, in the MPTP-lesioned marmoset, monotherapy with the NR2B-selective NMDA receptor antagonist, ifenprodil, administered de novo, has antiparkinsonian effects equivalent to those of l-DOPA (administered as its methyl ester form). In MPTP-lesioned marmosets, median mobility scores, following vehicle-treatment were 12.5/h (range 6-21), compared to 61/h (range 26-121) in normal, non-MPTP-lesioned animals. Following ifenprodil (10 mg/kg) treatment in MPTP-lesioned marmosets, the median mobility score was 66/h (range 34-93), and following l-DOPA (10 mg/kg i.p.) treatment 89/h (range 82-92). The data support the proposal that NR2B-selective NMDA receptor antagonists have potential as a nondopaminergic monotherapy for the treatment of parkinsonian symptoms when given de novo.

Neural mechanisms underlying peak-dose dyskinesia induced by levodopa and apomorphine are distinct : Evidence from the effects of the Alpha2 adrenoceptor antagonist idazoxan

Dyskinesia, secondary to dopamine replacement therapy, is the major complication of currently available therapies for Parkinsons disease. Alpha2 adrenoceptor antagonists, such as idazoxan, can significantly reduce levodopa‐induced dyskinesia in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐lesioned, nonhuman primate model of Parkinsons disease and in human. This action of adrenoceptor antagonists may involve blockade of the actions of noradrenaline synthesised from levodopa. We hypothesise that, because dopamine receptor agonists, such as apomorphine, cannot be metabolised to produce noradrenaline, activation of adrenoceptors may not be involved in dyskinesia produced by such agents. If this were the case, idazoxan would not be expected to reduce apomorphine‐induced dyskinesia.

Effect of the NMDA antagonist MK-801 on MPTP-induced parkinsonism in the monkey

Current evidence suggests that the motor symptoms of parkinsonism are due to abnormal overactivity of the medial segment of the globus pallidus, brought about by overactivity of the subthalamic nucleus, from which it receives an excitatory amino acid-mediated projection. The possibility exits, therefore, that excitatory amino acid antagonists might have an anti-parkinson effect by normalising medial pallidal activity. The NMDA antagonist MK-801 was administered i.m. to a single cynomolgus monkey with parkinsonism induced by the neurotoxin MPTP. In fact, MK-801 exacerbated the symptoms of parkinsonism. When administered after a therapeutic dose of L-DOPA it antagonised the anti-parkinson action of L-DOPA. The results suggest that any potential anti-parkinson action of excitatory amino acid antagonists will depend upon an action at non-NMDA sites. The administration of the selective neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to produce a primate model of Parkinsons disease is well-documented (Burns, Markey, Phillips & Chiuch, 1984; Crossman, 1987; Langston, Forno, Rebert & Irwin, 1984). Intravenous injection of MPTP, titrated judiciously over a period of several weeks, can produce a stable manifestation of the motor disability seen in the idiopathic disease of man, with a remarkable correspondence of both symptoms and pathology. Additionally, primates rendered parkinsonian by MPTP respond well to L-DOPA treatment. As in human Parkinsons disease, long-term L-DOPA therapy of MPTP-induced parkinsonism tends to be complicated by the emergence of choreiform movements and dystonic postures (Boyce, Clarke, Luquin, Peggs, Robertson, Mitchell, Sambrook & Crossman, 1989; Clarke, Sambrook, Mitchell & Crossman, 1987).(ABSTRACT TRUNCATED AT 250 WORDS)

Hydrostatic and osmotic pressures in the heart and pericardium of Mya arenaria and Anodonta cygnea

Abstract 1. 1. Simultaneous and consecutive pressure recordings from the ventricle, auricles and pericardium have been made from representative bivalves. At all stages of the heart-beat cycle the hydrostatic pressure of the blood exceeds that of the pericardial fluid. 2. 2. Osmotic concentrations and pH of blood and pericardial fluid were determined, the former by freezing-point depression. Differences between blood and pericardial fluid are insignificant in each species. 3. 3. These measurements support the contention that the hydrodynamic conditions will permit primary ultrafiltration to take place across the wall of the heart. 4. 4. The circulatory pressure gradient is established for both species and the constant volume hypothesis of auricular refilling is confirmed.

The Role of the Internal Segment of the Globus Pallidus in Mediating Dyskinesias

Changes in neuronal activity within the internal segment of the globus pallidus (GPi), which subsequently influence thalamo-cortical pathways, are believed to reflect movement-related information processed within the basal ganglia. Previous work from this laboratory would support the view that in the hypokinetic movement disorder of Parkinson’s disease, the GPi is overactive, being driven by a disinhibited subthalamic nucleus (STN) mediating excitatory transmission. In contrast it is well documented that lesion or damage within the STN in man gives rise to choreic or ballistic dyskinesias (hyperkinesias), which, if STN output is reduced, would imply the presence of an underactivity of GPi neurones in the production of these movements. Therefore the current view is that an overall increase or decrease in GPi neuronal activity explains the two extremes of the movement spectrum. In this chapter we examine the sufficiency of this view by discussing more specifically the role of the GPi in mediating dyskinesias (chorea, ballism and dystonia), by drawing upon results from our own and other related studies.