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P Jenner

Publications and source records attributed to P Jenner.

At least 253 records · Page 14Linked to original sources
PubMed1989

Transient depletion of nucleus accumbens dopamine content may contribute to initial akinesia induced by MPTP in common marmosets.

Acute treatment of common marmosets with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) caused an initial profound akinesia and other motor deficits. However, over the following months akinesia gradually disappeared although the animals remained clumsy and poorly coordinated. At 10 days following MPTP treatment there was a profound decrease in the dopamine, HVA and DOPAC content of the caudate nucleus, putamen and nucleus accumbens. By 3-4 months following MPTP treatment the animals had largely recovered from their akinesia, but the caudate nucleus and putamen dopamine, HVA and DOPAC content remained low. In contrast, the dopamine content of the nucleus accumbens had returned towards normal and the metabolite levels were higher than at 10 days. No overall alterations in 5HT or 5HIAA levels were observed at either time point. The transient and reversible nature of dopamine loss in the nucleus accumbens may contribute to the initial profound akinesia exhibited by common marmosets treated with MPTP. The restoration of dopamine levels in the nucleus accumbens may be partially responsible for the subsequent recovery of motor function that occurs in MPTP-treated marmosets.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1989

Stereoselective reversal of MPTP-induced parkinsonism in the marmoset after dermal application of N-0437.

The selective dopamine D-2 receptor agonist N-0437 produced a rapid and dose-dependent reversal of motor deficits lasting 90-120 min following i.p. or oral administration of the racemate to MPTP-treated common marmosets. In contrast, topical application of (+/-)-, (+)- or (-)-N-0437 to the skin of MPTP-treated animals did not alter locomotor activity in the initial 4 h although other motor disabilities were reduced. However, 24 h following application of the racemate or the (-) enantiomer both locomotor activity and the other motor deficits induced by MPTP were improved. The increase in locomotor activity returned to basal values by 48-52 h following application of the racemate to the skin and by 72-76 h following administration of (-)-N-0437; the other motor deficits induced by MPTP were reduced for up to 72-76 h by both (+/-)- and (-)-N-0437. Application to skin of the (+) enantiomer produced no behavioural improvement or stimulation of locomotor activity. Transdermal administration of the active enantiomer of N-0437 may be of value in producing a prolonged reversal of parkinsonian motor deficits in man.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1989

Increased caudate dopamine turnover may contribute to the recovery of motor function in marmosets treated with the dopaminergic neurotoxin MPTP.

Administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to common marmosets initially impaired motor function, but a partial recovery occurred over the following weeks. At both 10 days and 4-6 weeks following MPTP treatment, [3H]dopamine ([3H]DA) uptake into synaptosomal preparations of putamen was markedly decreased. At 10 days and 4-6 weeks following MPTP treatment DA, homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) levels in the caudate nucleus and nucleus accumbens were substantially reduced. However, the levels of HVA and DOPAC in caudate nucleus were higher at 4-6 weeks than at 10 days. The ratio of (DOPAC + HVA)/DA in caudate nucleus was elevated at 10 days following MPTP treatment and even more so at 4-6 weeks. No change in Bmax or Kd values for [3H]spiperone binding to caudate preparations were observed. The recovery of motor function in marmosets observed following MPTP treatment may result partially from a compensatory increase in caudate DA turnover by remaining neurones.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1989

Induction of purposeless chewing behaviour in rats by 5-HT agonist drugs.

The 5-HT agonist m-chlorophenylpiperazine (m-CPP; 1-16 mg/kg i.p. or s.c.), trifluoromethylphenylpiperazine (TFMPP; 2-16 mg/kg i.p.) and quipazine (2.5-20 mg/kg i.p.) increased purposeless chewing behaviour in rats. However, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.025-4 mg/kg s.c.) and 5-methoxy-N,N-dimethyltryptamine (5-MeODMT; 0.25-8 mg/kg s.c.) were without effect on chewing behaviour. Chewing behaviour induced by m-CPP (6 mg/kg s.c.) was antagonised by pretreatment with the 5-HT antagonists methiothepin and mianserin, but not by ketanserin or spiperone, or ICS 205-930. m-CPP (6 mg/kg s.c.)-induced chewing behaviour was also antagonised by pretreatment with (-)-propranolol (20 mg/kg). Pretreatment with the anticholinergic drugs benzhexol (2.5 mg/kg), and scopolamine (1 mg/kg) antagonised m-CPP (6 mg/kg s.c.)-induced chewing behaviour, but methylscopolamine (1 mg/kg) had no effect. These data support the role of 5-HT receptors in the mediation of purposeless chewing behaviour and suggest an interaction between brain 5-HT and acetylcholine systems.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1989

The evolution and distribution of morphological changes in the nervous system of the common marmoset following the acute administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

Six young adult marmosets received 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in multiple doses (total 8-16 mg/kg over 2-13 days) sufficient to produce a parkinsonian syndrome and were killed up to 3.5 months later. Cellular changes were found in the substantia nigra, ventral tegmental area, and hypothalamus. The earliest histological abnormalities were axonal swellings in proximal parts of nigrostriatal axons. Subsequent changes in the substantia nigra were reduced Nissl staining, reduced cell volume, and aggregation and loss of melanin granules. Other effects were reduced nuclear and nucleolar volumes, depletion of cells, and hyperplasia of glial cells. Shrunken cytoplasm and nuclei stained uniformly with eosin, and no cells showed cytoplasmic swellings or inclusions. These cellular alterations, with nuclear changes resembling karyolysis, do not occur in Parkinson's disease, which is characterised by Lewy body inclusions and signs of chromatolysis. The rapid appearance of axonal swellings, disruption of Nissl substance, and cell shrinkage suggest an insult to energy producing mechanisms. In this study, the absence of histological evidence of toxicity in the locus coeruleus and also in the substantia innominata and in serotonergic cell groups is unlike the more widespread degenerative changes of Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1989

Oxyferriscorbone elevates the total iron content of blood but not brain.

Following the intravenous infusion of oxyferriscorbone into the tail vein of the rat, the blood and brain metal ion content was measured over the following 72 h period. Administration of oxyferriscorbone increased the total iron content of blood for up to 24 h following intravenous infusion. In contrast, there was no increase in the total iron content of the cerebellum or striatum. Overall, there was no change in total zinc or copper content of the blood or brain following oxyferriscorbone administration. The effect of oxyferriscorbone in Parkinson's disease may not be related to any alteration in total iron content of the brain.

2,3-Diketogulonic Acid↗
PubMed1989

Assessment of the muscarinic receptor subtype involved in the mediation of pilocarpine-induced purposeless chewing behaviour.

Purposeless chewing behaviour in rats was enhanced by intraperitoneal administration of the muscarinic agonists pilocarpine (1.0-8.0 mg/kg), RS 86 (0.5-0.8 mg/kg), oxotremorine (1-2 mg/kg) and arecoline (2-32 mg/kg), but not by nicotine (0.1-3.2 mg/kg). Chewing behaviour was also induced by the ICV administration of the muscarinic agonists carbachol (12.5-100 micrograms) and pilocarpine (50-200 micrograms), but not by the putative M-1 receptor agonist McN-A-343 (50-200 micrograms) or AH 6405 (100-200 micrograms). The muscarinic receptor antagonists scopolamine (0.01-0.1 mg/kg SC), benzhexol (0.075-2.5 mg/kg SC), secoverine (1-10 mg/kg SC), and dicyclomine (1.25-10 mg/kg SC) antagonised purposeless chewing behaviour induced by pilocarpine (4 mg/kg IP). AF-DX 116 (2.5-100 mg/kg SC), an M-2 antagonist, partially inhibited the actions of pilocarpine (4 mg/kg IP). Based on ED40 values the rank order of potency following IP administration was scopolamine greater than benzhexol greater than secoverine greater than dicyclomine greater than AF-DX 116. The ICV administration of the muscarinic antagonists N-methylscopolamine (2.5-10 micrograms) and oxyphenonium (10-40 micrograms) antagonised chewing behaviour induced by pilocarpine (4 mg/kg IP) in a dose-related manner. The M-2 antagonist 4-DAMP (40-160 micrograms ICV), as well as AF-DX 116 (40-160 micrograms ICV), also inhibited the effects of pilocarpine (40-160 micrograms ICV). The putative M-1 receptor antagonist pirenzepine (80-320 micrograms ICV) did not antagonise chewing behaviour induced by pilocarpine (4 mg/kg IP).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Further treatment with MPTP does not produce parkinsonism in marmosets showing behavioural recovery from motor deficits induced by an earlier exposure to the toxin.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), or 0.9% saline, was administered to a group of common marmosets initially treated with the toxin 12-18 months previously. Initial treatment had consisted of a cumulative dose of 6-22 mg/kg (i.p.) which caused marked parkinsonism. Subsequently, the animals gradually recovered normal motor function. Further treatment consisted of a cumulative dose of MPTP of 78-83 mg/kg (i.p.) but this produced only modest akinesia. At 12-18 months after the initial treatment with MPTP, the content of dopamine, HVA and DOPAC in the caudate and putamen was markedly reduced. However, levels of dopamine, HVA and DOPAC in the nucleus accumbens were normal. Three months after the second treatment with MPTP there was no further decrease in the content of dopamine in the caudate-putamen. However, in the nucleus accumbens the content of dopamine, HVA and DOPAC was now reduced. The initial treatment with MPTP substantially decreased the binding of [3H]mazindol in the caudate-putamen but less so in the nucleus accumbens. Only a small additional decrease occurred upon further treatment with MPTP. The density of tyrosine hydroxylase (TH) immunoreactive cells in substantia nigra was reduced after the initial treatment with MPTP. However, the cell loss was far less marked than the decrease in terminal density, assessed by the binding of [3H]mazindol. Subsequent treatment with MPTP caused a small further loss of tyrosine hydroxylase-positive cells. Initial treatment with MPTP may kill the majority of MPTP-sensitive dopamine cells in the nigra. Compensation by the remaining nigrostriatal neurones may account for the behavioural recovery observed.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1989

Behavioural and morphological changes following treatment with GM-1 ganglioside of rats with an electrolytic lesion of the substantia nigra.

The effects of daily treatment with GM-1 ganglioside (30 mg/kg i.p.) or saline (1 ml/kg i.p.) in rats with discrete unilateral electrolytic lesions of the dorsal substantia nigra were investigated. Treatment with GM-1 ganglioside, beginning 3 days prior to surgery and continuing for 33 days post-operatively, caused reductions in the total ipsilateral turns and peak turning rates induced by apomorphine (0.75 mg/kg s.c.) between 7 and 31 days post-operatively, without altering the time course of the effect of apomorphine. No effects of GM-1 on lesion-induced changes in synaptosomal uptake of [3H]dopamine, dopamine, serotonin in the striatum or corresponding levels of metabolites were found. Treatment with GM-1 ganglioside had no effect on the rostrocaudal extent of the electrolytic lesion, but caused morphological changes at the site of the lesion, including a reduction in the density of glial cells. Treatment with GM-1 ganglioside resulted in a relative preservation of cell bodies, staining immunocytochemically for tyrosine hydroxylase, in the substantia nigra pars compacta (expressed as a percentage of the intact side), when compared with saline-treated rats. The results showed that GM-1 ganglioside promoted a partial functional recovery from apomorphine-induced circling, which may be due in part to a reduction in the extent of damage at the lesion site.

Animals↗
PubMed1989

Treatment with a selective MAO B inhibitor prevents loss of dopamine in the nucleus accumbens of MPTP-treated common marmosets.

Administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to common marmosets induced motor deficits, associated with a marked decrease in the uptake of [3H]dopamine into synaptosomes in the putamen and a reduction in the content of dopamine in both caudate nucleus and nucleus accumbens. Histological analysis showed a marked loss of dopamine-containing cells in the zona compacta of the substantia nigra and less loss in the ventral tegmental area. Treatment of animals with the selective monoamine oxidase (MAO) B inhibitor, MDL 72145 (0.5 or 2.0 mg/kg) prior to, during and following administration of MPTP partially protected animals from the motor abnormalities induced by administration of MPTP alone. Both doses inhibited the onset of akinesia but only the large dose of MDL 72145 prevented the occurrence of other motor abnormalities. Moreover, while MDL 72145 (2.0 mg/kg) prevented the loss in uptake of [3H]dopamine into synaptosomes of the putamen, this was only partly prevented using the smaller dose. Similarly, while MDL 72145 (2.0 mg/kg) prevented loss of dopamine in the caudate, only partial protection was afforded by the smaller dose. However, in the nucleus accumbens, both doses of MDL 72145 prevented the depletion of dopamine, occurring in this region. Histological examination of the substantia nigra showed little or no cell loss in animals receiving the larger dose of MDL 72145 but a moderate cell loss in animals receiving the smaller dose. No damage was observed in the ventral tegmental area of animals treated with MDL 72145 (2.0 mg/kg) and only mild cell loss in those receiving the smaller dose.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1989

Increased nigral iron content and alterations in other metal ions occurring in brain in Parkinson's disease.

Levels of iron, copper, zinc, manganese, and lead were measured by inductively coupled plasma spectroscopy in parkinsonian and age-matched control brain tissue. There was 31-35% increase in the total iron content of the parkinsonian substantia nigra when compared to control tissue. In contrast, in the globus pallidus total iron levels were decreased by 29% in Parkinson's disease. There was no change in the total iron levels in any other region of the parkinsonian brain. Total copper levels were reduced by 34-45% in the substantia nigra in Parkinson's disease; no difference was found in the other brain areas examined. Zinc levels were increased in substantia nigra in Parkinson's disease by 50-54%, and the zinc content of the caudate nucleus and lateral putamen was also raised by 18-35%. Levels of manganese and lead were unchanged in all areas of the parkinsonian brain studied when compared to control brains, except for a small decrease (20%) in manganese content of the medial putamen. Increased levels of total iron in the substantia nigra may cause the excessive formation of toxic oxygen radicals, leading to dopamine cell death.

Aged↗
PubMed1989

Basal lipid peroxidation in substantia nigra is increased in Parkinson's disease.

Polyunsaturated fatty acid (PUFA) levels (an index of the amount of substrate available for lipid peroxidation) were measured in several brain regions from patients who died with Parkinson's disease and age-matched control human postmortem brains. PUFA levels were reduced in parkinsonian substantia nigra compared to other brain regions and to control tissue. However, basal malondialdehyde (MDA; an intermediate in the lipid peroxidation process) levels were increased in parkinsonian nigra compared with other parkinsonian brain regions and control tissue. Expressing basal MDA levels in terms of PUFA content, the difference between parkinsonian and control substantia nigra was even more pronounced. Stimulating MDA production by incubating tissue with FeSO4 plus ascorbic acid, FeSO4 plus H2O2, or air alone produced lower MDA levels in the parkinsonian substantia nigra, probably reflecting the lower PUFA content. These results may indicate that an increased level of lipid peroxidation continues to occur in the parkinsonian nigra up to the time of death, perhaps because of continued exposure to excess free radicals derived from some endogenous or exogenous neurotoxic species.

Aged↗
PubMed1989

A selective increase in particulate superoxide dismutase activity in parkinsonian substantia nigra.

The total activity of superoxide dismutase (SOD) and cytosolic and particulate activity of SOD in human substantia nigra and cerebellum were measured by a spectrophotometric method based on the ability of SOD to inhibit the autoxidation of adrenaline. The cytosolic and particulate isoenzymes of SOD were differentiated by the inclusion of potassium cyanide which selectively inhibits cytosolic copper/zinc-dependent SOD activity. In autopsied human brains, there was no difference in total SOD activity, or the activity of SOD in cytosol in substantia nigra of patients dying with Parkinson's disease compared to age-matched controls. However, the activity of the particulate form of SOD was higher in the parkinsonian substantia nigra compared to control tissue. In the cerebellum there was no difference in the total, cytosolic, or particulate activity of SOD between parkinsonian patients and age-matched controls. Increased activity of SOD in particulate fraction may be a protective response to elevated levels of toxic free radicals in the parkinsonian substantia nigra. Alternatively, increased SOD activity may induce cell death through the accumulation of hydrogen peroxide.

Aged↗
PubMed1989

Definition of the in-vivo binding of [3H]spiperone in rat brain using substituted benzamide drugs.

The ability of some substituted benzamide drugs to define in-vivo the binding of [3H]spiperone to brain dopamine receptors in rats was assessed using behaviourally effective doses in comparison with haloperidol. As judged using haloperidol, [3H]spiperone identified dopamine receptors in the substantia nigra, striatum, tuberculum olfactorium and hypothalamus, but not in frontal cortex or nucleus accumbens. The substituted benzamide compounds alizapride, metoclopramide, clebopride and YM 09151-2 prevented the accumulation of [3H]spiperone in the substantia nigra, striatum, tuberculum olfactorium and hypothalamus. However, YM 09151-2 also caused displacement of [3H]spiperone accumulation in the nucleus accumbens and frontal cortex. (+/- )-Sulpiride, (+/- )-sultopride, amisulpiride and prosulpride all prevented the accumulation of [3H]spiperone in the hypothalamus but were ineffective in one or more of the other regions containing dopamine receptors defined by [3H]spiperone. The isomers of sulpiride and sultopride stereoselectively defined the accumulation of [3H]spiperone in dopamine containing brain regions. The (-)-isomers of both drugs prevented the accumulation of [3H]spiperone in the substantia nigra, striatum, tuberculum olfactorium and hypothalamus. In contrast, (+)-sulpiride and (+)-sultopride were ineffective. Selected substituted benzamide drugs can be used to define the interaction of ligands with dopamine receptors in-vivo. These substances may be useful in PET studies in man. The isomers of some substituted benzamine drugs may be used to define dopamine receptors in-vivo by enantiomeric selectivity.

Amisulpride↗
PubMed1989

Clues to the mechanism underlying dopamine cell death in Parkinson's disease.

The primary pathological change in Parkinson's disease is the destruction of dopamine containing cells in the zona compacta of substantia nigra. The cause of nigral cell death and the underlying mechanism remains elusive. However, the discovery of the selective nigral neurotoxin MPTP and its ability to inhibit mitochondrial energy metabolism via its metabolite MPP+ and to generate superoxide radicals suggests processes by which nigral cell death might occur. Recent postmortem evidence in brain tissue from patients dying with Parkinson's disease also suggests the occurrence of some on-going toxic mechanism. This may be a free radical process stimulated by an excess of iron within substantia nigra coupled to a generalised decrease in brain ferritin content. These data suggest altered iron handling occurs in Parkinson's disease which may lead to the generation of toxic oxygen species such as superoxide radicals. There is also evidence for an inhibition of mitochondrial function in the substantia nigra in patients with Parkinson's disease. So there may be a close association between the actions of the synthetic neurotoxin MPTP and the underlying cause of idiopathic Parkinson's disease.

Animals↗