Biomedical subjects

P Jenner

Publications and source records attributed to P Jenner.

At least 73 records · Page 4Linked to original sources

PubMed2000

The copper transport protein Atox1 promotes neuronal survival.

Atox1, a copper transport protein, was recently identified as a copper-dependent suppressor of oxidative damage in yeast lacking superoxide dismutase. We have previously reported that Atox1 in the rat brain is primarily expressed in neurons, with the highest levels in distinct neuronal subtypes that are characterized by their high levels of metal, like copper, iron, and zinc. In this report, we have transfected the Atox1 gene into several neuronal cell lines to increase the endogenous level of Atox1 expression and have demonstrated that, under conditions of serum starvation and oxidative injury, the transfected neurons are significantly protected against this stress. This level of protection is comparable with the level of protection seen with copper/zinc superoxide dismutase and the anti-apoptotic gene bcl-2 that had been similarly transfected. Furthermore, neuronal cell lines transfected with a mutant Atox1 gene, where the copper binding domain has been modified to prevent metal binding, do not afford protection against serum starvation resulting in apoptosis. Therefore, Atox1 is a component of the cellular pathways used for protection against oxidative stress.

Amino Acid Sequence↗

PubMed2000

Endogenous dopaminergic tone and dopamine agonist action.

Dopamine receptor agonists provide symptomatic relief in the early stages of Parkinson's disease, but with disease progression, their efficacy decreases. The reason behind this decrease in effectiveness is unknown, but maximal efficacy may be dependent on endogenous dopaminergic tone to provide stimulation of D1 and D2 receptor subtypes. Therefore, we have investigated the effects of the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine (AMPT) on the actions of D1, D2, and D1/D2 agonists and levodopa (L-dopa) in common marmosets treated with 1 -methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Administration of AMPT alone further increased motor disability and decreased locomotor activity. Administration of L-dopa reversed motor disability and increased locomotor activity, and this reversal was not affected by previous AMPT treatment. The D1 agonist A-77636 and the D2 agonist quinpirole reversed motor deficits, but these effects were markedly inhibited by previous AMPT treatment. Administration of quinpirole with A-77636 produced a reversal of motor deficits that was more resistant to AMPT pretreatment than was the effect produced by quinpirole or A-77636 alone. These data suggest that D1 and D2 receptor stimulation are required for dopamine receptor agonists to produce a maximal antiparkinsonian response. The reversal of motor deficits produced by the mixed D1/D2 agonist apomorphine was more resistant to AMPT treatment than that produced by quinpirole or A-77636. However, the motor effects of A-77636 plus quinpirole and of apomorphine were still affected by AMPT treatment. This suggests that loss of tyrosine hydroxylase activity may also alter motor activity through inhibition of endogenous L-dopa or norepinephrine synthesis, because both are also involved in the genesis of motor activity.

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

PubMed2000

Combined use of the adenosine A(2A) antagonist KW-6002 with L-DOPA or with selective D1 or D2 dopamine agonists increases antiparkinsonian activity but not dyskinesia in MPTP-treated monkeys.

The novel selective adenosine A(2A) receptor antagonist KW-6002 improves motor disability in MPTP-treated parkinsonian marmosets without provoking dyskinesia. In this study we have investigated whether KW-6002 in combination with l-DOPA or selective D1 or D2 dopamine receptor agonists enhances antiparkinsonian activity in MPTP-treated common marmosets. Combination of KW-6002 with the selective dopamine D2 receptor agonist quinpirole or the D1 receptor agonist SKF80723 produced an additive improvement in motor disability. Coadministration of KW-6002 with a low dose of L-DOPA also produced an additive improvement in motor disability, and increased locomotor activity. The ability of KW-6002 to enhance antiparkinsonian activity was more marked with L-DOPA and quinpirole than with the D1 agonist. However, despite producing an enhanced antiparkinsonian response KW-6002 did not exacerbate L-DOPA-induced dyskinesia in MPTP-treated common marmosets previously primed to exhibit dyskinesia by prior exposure to L-DOPA. Selective adenosine A(2A) receptor antagonists, such as KW-6002, may be one means of reducing the dosage of L-DOPA used in treating Parkinson's disease and are potentially a novel approach to treating the illness both as monotherapy and in combination with dopaminergic drugs.

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

PubMed2000

Pathophysiology and biochemistry of dyskinesia: clues for the development of non-dopaminergic treatments.

Levodopa-induced dyskinesia is a major therapeutic problem in the long-term treatment of Parkinson's disease. The development of dyskinesia is dependent on the extent of nigral denervation but can be induced through both D-1 and D-2 dopamine receptors. Short-acting dopamine agonists producing pulsatile receptor stimulation are more likely to induce dyskinesia than long-acting drugs that produce continuous receptor stimulation. However, there are no consistent changes in dopamine receptors which explain the occurrence of dyskinesia. Rather, dyskinesia may originate from an imbalance between the major striatal output pathways. Indeed, levodopa and dopamine agonist drugs show a differential ability to alter striatal output as judged by mRNA for colocalised neuropeptides. The involvement of striatal output pathways raises the possibility of utilising a range of non-dopaminergic receptors within the striatum and in output nuclei as targets for novel drug therapies which may be antiparkinsonian without eliciting dyskinesia. For example, the A2a adenosine antagonist KW6002 reverses motor deficits in primates treated with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) without provoking an established dyskinesia. Similarly, manipulation of muscarinic cholinergic receptors in the striatum can alter the intensity and components of dyskinesia. Neurotrophic therapies diminish dyskinesia since glial cell line-derived neurotrophic factor (GDNF) produces a decrease in motor disability in MPTP-treated primates associated with a reduced intensity of levodopa-induced dyskinesia. The mechanisms underlying the manifestations and the priming process for dyskinesia remain unknown, but non-dopaminergic approaches to therapy may provide an effective way of preventing, or limiting, the expression of involuntary movements in Parkinson's disease.

Animals↗

PubMed2000

Antiparkinsonian and neuroprotective effects of modafinil in the mptp-treated common marmoset.

The psychostimulant drug, modafinil, protects rodents against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity, striatal ischemia and partial transection of the nigro-striatal pathway. We now report on the ability of modafinil to reverse motor disability in MPTP-treated common marmosets and to prevent MPTP-induced nigral cell death in this species. In the initial experiments, adult common marmosets were treated with MPTP to produce stable motor deficits. The subsequent administration of modafinil (10, 30 or 100 mg/kg/day, p.o.) produced a dose-dependent reversal of motor disability. In a subsequent experiment, normal common marmosets were concurrently treated with 10, 30 or 100 mg/kg of modafinil once daily by gavage during acute MPTP administration (daily for 5 days), continuing for 2 weeks after the last dose of MPTP. Modafinil dose-dependently prevented the decline in motor activity normally produced by MPTP treatment. MPTP treatment caused a 76% loss of nigral tyrosine-hydroxylase-immunoreactive cells in placebo-treated animals, and this was dose-dependently prevented by modafinil. At the highest dose (100 mg/kg/day) of modafinil, there was no significant loss of tyrosine-hydroxylase-immunoreactive cells in the substantia nigra compared with normal animals. MPTP treatment also reduced striatal dopamine uptake sites by 95%, as measured by specific [3H]-mazindol binding, compared with normal controls. Modafinil treatment dose-dependently reduced the loss of specific [3H]-mazindol binding. Behavioural and morphological evidence in the present study indicate a potential antiparkinsonian and neuroprotective role for modafinil, which may form a new pharmacological approach to the treatment of Parkinson's disease.

Animals↗

PubMed2000

Autoradiographic study of striatal dopamine re-uptake sites and dopamine D1 and D2 receptors in a 6-hydroxydopamine and quinolinic acid double-lesion rat model of striatonigral degeneration (multiple system atrophy) and effects of embryonic ventral mesencephalic, striatal or co-grafts.

The influence of embryonic mesencephalic, striatal and mesencephalic/striatal co-grafts on amphetamine- and apomorphine-induced rotation behaviour was assessed in a rat model of multiple system atrophy/striatonigral degeneration type using dopamine D1 ([3H]SCH23390) and D2 ([3H]spiperone) receptor and dopamine re-uptake ([3H]mazindol) autoradiography. Male Wistar rats subjected to a sequential unilateral 6-hydroxydopamine lesion of the medial forebrain bundle followed by a quinolinic acid lesion of the ipsilateral striatum were divided into four treatment groups, receiving either mesencephalic, striatal, mesencephalic/striatal co-grafts or sham grafts. Amphetamine- and apomorphine-induced rotation behaviour was recorded prior to and up to 10 weeks following transplantation. 6-Hydroxydopamine-lesioned animals showed ipsiversive amphetamine-induced and contraversive apomorphine-induced rotation behaviour. Amphetamine-induced rotation rates persisted after the subsequent quinolinic acid lesion, whereas rotation induced by apomorphine was decreased. In 11 of 14 animals receiving mesencephalic or mesencephalic/striatal co-grafts, amphetamine-induced rotation scores were decreased by >50% at the 10-week post-grafting time-point. In contrast, only one of 12 animals receiving non-mesencephalic (striatal or sham) grafts exhibited diminished rotation rates at this time-point. Apomorphine-induced rotation rates were significantly increased following transplantation of mesencephalic, striatal or sham grafts. The largest increase of apomorphine-induced rotation rates approaching post-6-hydroxydopamine levels were observed in animals with striatal grafts. In contrast, in the co-graft group, there was no significant increase of apomorphine-induced rotation compared to the post-quinolinic acid time-point. Morphometric analysis revealed a 63-74% reduction of striatal surface areas across the treatment groups. Striatal [3H]mazindol binding on the lesioned side (excluding the demarcated graft area) revealed a marked loss of dopamine re-uptake sites across all treatment groups, indicating missing graft-induced dopaminergic re-innervation of the host. In eight (73%) of the 11 animals with mesencephalic grafts and reduced amphetamine-induced circling, discrete areas of [3H]mazindol binding ("hot spots") were observed, indicating graft survival. Dopamine D1 and D2 receptor binding was preserved in the remaining lesioned striatum irrespective of treatment assignment, except for a significant reduction of D2 receptor binding in animals receiving mesencephalic grafts. "Hot spots" of dopamine D1 and D2 receptor binding were observed in 10 (83%) and nine (75%) of 12 animals receiving striatal grafts or co-grafts, consistent with survival of embryonic primordial striatum grafted into a severely denervated and lesioned striatum. Our study confirms that functional improvement may be obtained from embryonic neuronal grafts in a double-lesion rat model of multiple system atrophy/striatonigral degeneration type. Co-grafts appear to be required for reversal of both amphetamine- and apomorphine-induced rotation behaviour in this model. We propose that the partial reversal of amphetamine-induced rotation asymmetry in double-lesioned rats receiving mesencephalic or mesencephalic/striatal co-grafts reflects non-synaptic graft-derived dopamine release. The changes of apomorphine-induced rotation following transplantation are likely to reflect a complex interaction of graft- and host-derived striatal projection pathways and basal ganglia output nuclei. Further studies in a larger number of animals are required to determine whether morphological parameters and behavioural improvement in the neurotransplantation multiple system atrophy rat model correlate.

Amphetamine↗

PubMed2000

The effects of central aromatic amino acid DOPA decarboxylase inhibition on the motor actions of L-DOPA and dopamine agonists in MPTP-treated primates.

1. Endogenous L-DOPA may act as a neuromodulator contributing to the production of motor activity. We now investigate the effects of the centrally acting aromatic amino acid dopa decarboxylase (AADC) inhibitor NSD-1015 (3-hydroxybenzyl hydrazine) on the motor actions of L-DOPA and dopamine agonist drugs in MPTP treated common marmosets. 2. Pretreatment with NSD-1015 (10 - 50 mg kg(-1); i.p.) worsened baseline motor deficits in MPTP-treated common marmosets. Similarly, it abolished L-DOPA (5 - 18 mg kg(-1) s.c.) induced locomotor activity and reversal of disability. NSD-1015 pretreatment inhibited dopamine formation and elevated L-DOPA levels in plasma. 3. The increase in locomotor activity and improvement in disability produced by the administration of the D-1 agonist A-86929 (0.03 - 0. 04 mg kg(-1) s.c.) or the D-2 agonist quinpirole (0.05 - 0.3 mg kg(-1) i.p.) was abolished by NSD-1015 (25 mg kg(-1) i.p.) pretreatment. While the effects of a low dose combination of A-86929 (0.04 mg kg(-1) s.c.) and quinpirole (0.05 mg kg(-1) i.p.) were inhibited by NSD-1015 (25 mg kg(-1) i.p.), there was little effect on the action of a high dose combination of these drugs (0.08 mg kg(-1) A-86929 and 0.1 mg kg(-1) quinpirole). 4. Following central AADC inhibition with NSD-1015 (25 mg kg(-1) i.p.), locomotor behaviour induced by administration of high dose combinations of A-86929 (0.08 mg kg(-1) s.c.) and quinpirole (0.1 mg kg(-1) i.p.) was unaffected by L-DOPA (5 mg kg(-1) s.c.) pretreatment. 5. These results do not support a role for endogenous L-DOPA in spontaneous or drug induced locomotor activity. Rather, they strengthen the argument for the importance of endogenous dopaminergic tone in the motor actions of dopamine agonists.

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

PubMed2000

Alterations in preproenkephalin and adenosine-2a receptor mRNA, but not preprotachykinin mRNA correlate with occurrence of dyskinesia in normal monkeys chronically treated with L-DOPA.

Chronic treatment with L-DOPA induces dyskinesia in patients with Parkinson's disease (PD) and 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP)-treated monkeys, but is not thought to do so in normal humans or primates. However, we have shown that chronic oral high dose L-DOPA administration, with the peripheral decarboxylase inhibitor, carbidopa and with or without the peripherally acting catechol-O-methyl transferase (COMT) inhibitor, entacapone, to normal macaque monkeys for 13 weeks induced dyskinesia in a proportion of animals. In the present study, in situ hybridization histochemistry was used to investigate the effect of chronic L-DOPA administration on the activity of the direct and indirect striatal output pathways by measuring striatal preprotachykinin (PPT), preproenkephalin-A (PPE-A) and adenosine-2a (A2a) receptor gene expression in these monkeys. Overall there was no significant difference in striatal PPT, PPE-A and A2a receptor mRNA levels between normal animals and all L-DOPA (plus carbidopa and/or entacapone)-treated animals irrespective of whether or not dyskinesia occurred. However, when the level of PPE-A and A2a receptor mRNA was analysed in eight monkeys displaying marked dyskinesias as a result of L-DOPA (plus carbidopa with or without entacapone) treatment, there was a significant increase in PPE-A and A2a receptor mRNA message levels in the striatum compared with animals receiving identical treatment, but displaying few or no involuntary movements, and compared with normal controls. There was no difference in striatal PPT mRNA levels in monkeys exhibiting severe dyskinesia compared with those showing little or no dyskinesia after L-DOPA treatment or to normal controls. These results suggest that prolonged L-DOPA treatment alone has no consistent effect on either the direct or indirect pathways, as judged by striatal PPT, PPE-A or A2a receptor mRNA levels in normal monkeys. However, in monkeys exhibiting marked dyskinesia resulting from chronic L-DOPA treatment, abnormal activity is detected in the indirect striato-pallidal output pathway, as judged by striatal PPE-A and A2a receptor mRNA levels, indicating an imbalance between the direct and indirect striatal pathway which may explain the emergence of dyskinesia in these animals.

Animals↗

PubMed2000

No evidence for increased oxidative damage to lipids, proteins, or DNA in Huntington's disease.

It has been proposed that mitochondrial dysfunction and excitotoxic mechanisms lead to oxidative damage in the brain of Huntington;s disease patients. We sought evidence that increased oxidative damage occurs by examining postmortem brain material from patients who had died with clinically and pathologically diagnosed Huntington's disease. Oxidative damage was measured using methods that have already demonstrated the presence of increased oxidative damage in Parkinson's disease, Alzheimer's disease, and senile dementia of the Lewy body type. No alterations in the levels of lipid peroxidation (as measured by lipid peroxides and thiobarbituric acid-malondialdehyde adducts) were found in the caudate nucleus, putamen, or frontal cortex of patients with Huntington's disease compared with normal controls. Similarly, there were no elevations in the levels of 8-hydroxyguanine or of a wide range of other markers of oxidative DNA damage. Levels of protein carbonyls in these tissues were also unaltered. Our data suggest that oxidative stress is not a major component of the degenerative processes occurring in Huntington's disease, or at least not to the extent that occurs in other neurodegenerative disorders.

Adult↗

PubMed2000

In-vitro inhibition of human erythrocyte acetylcholinesterase by salvia lavandulaefolia essential oil and constituent terpenes.

Sage (Salvia spp) is reputed in European herbal encyclopaedias to enhance memory, and current memory-enhancing/anti-dementia drugs are based on enhancing cholinergic activity by inhibiting cholinesterase. In this study the effects of Salvia lavandulaefolia Vahl. (Spanish sage) essential oil and some of its constituent terpenes on human erythrocyte acetylcholinesterase were examined in-vitro. The main constituents in the essential oil batch used for analysis of cholinesterase inhibition were camphor (27%), 1,8-cineole (13%), alpha- and beta-pinene (10-15%) and bornyl acetate (10%) with other minor constituents (1% or less) including geraniol, limonene, linalool, terpineol and gamma-terpinene. Using the Ellman spectrophotometric method, kinetic analysis was conducted on the interaction of the essential oil and the main monoterpenoids, camphor, 1,8-cineole and alpha-pinene. IC50 values were obtained for the essential oil, 1,8-cineole and alpha-pinene and were 0.03 microL [corrected] mL(-1), 0.67 mM and 0.63 mM, respectively. Camphor and other compounds tested (geraniol, linalool and gamma-terpinene) were less potent (camphor IC50: >10mM). The essential oil, alpha-pinene, 1,8-cineole and camphor were found to be uncompetitive reversible inhibitors. These findings suggest that if the inhibitory activity of the essential oil is primarily due to the main inhibitory terpenoid constituents identified, there is a major synergistic effect among the constituents. Since no single constituent tested was particularly potent, it remains to be determined whether these in-vitro cholinesterase inhibitory activities are relevant to in-vivo effects of the ingestion of S. lavandulaefolia essential oil on brain acetylcholinesterase activity.

Acetylcholinesterase↗

PubMed2000

Factors influencing the onset and persistence of dyskinesia in MPTP-treated primates.

The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treated primate model of Parkinson's disease provides a unique opportunity to study factors influencing the onset and persistence of dyskinesia induced by levodopa or dopamine agonist treatment. Contrary to popular belief, denervation is not essential for the induction of dyskinesia, and both D1 and D2 dopamine agonist drugs are able to initiate dyskinetic movements. However, their ability to do so is currently attributed to their pharmacokinetic and pharmacodynamic properties rather than to their receptor selectivity, although this view is challenged in this article. Short-acting pulsatile dopamine agonists are more likely to induce dyskinesia than drugs that have a long duration of effect and produce continuous receptor stimulation. The induction of dyskinesia does not seem to be associated with any obvious change in the number or sensitivity of post-synaptic dopamine receptors, but rather to downstream events associated with the indirect and direct output pathways. Currently, there is evidence for the involvement of both pathways in the genesis of dyskinesia and so there is no clear explanation for the onset of involuntary movements or for the priming process that initiates dyskinesia. However, a variety of therapeutic strategies primarily related to the use of non-dopaminergic agents may be able to prevent dyskinesia from occurring, and the actions of neurotropic factors, such as glial-derived neurotropic factor, may be effective in reversing established involuntary movements.

Animals↗

PubMed1999

Chronic L-DOPA treatment increases striatal cannabinoid CB1 receptor mRNA expression in 6-hydroxydopamine-lesioned rats.

The effect of a unilateral 6-hydroxydopamine (6-OHDA) lesion of the left medial forebrain bundle and 3 weeks treatment with L-DOPA of normal and 6-OHDA lesioned rats on CB1r mRNA expression was investigated by in situ hybridization. A 6-OHDA lesion of nigrostriatal pathway alone, confirmed by the loss of nigral tyrosine hydroxylase mRNA, did not alter CB1r mRNA levels in the dopamine depleted striatum. Similarly, chronic L-DOPA treatment of normal rats had no effect on striatal CB1r mRNA expression. In contrast, chronic L-DOPA treatment of 6-OHDA-lesioned rats significantly increased CB1r mRNA expression in the denervated striatum. These results suggest that the CB1r activity may be altered by L-DOPA's action and this may be related to the treatment of Parkinson's disease.

Adrenergic Agents↗

PubMed1999

Effects of desferrithiocin and its derivatives on peripheral iron and striatal dopamine and 5-hydroxytryptamine metabolism in the ferrocene-loaded rat.

Iron overload disorders, such as beta-thalassaemia, are currently treated with the iron chelator desferrioxamine (DFO) or 1,2-dimethyl-3-hydroxypyridin-4-one (L1), which is currently under clinical evaluation. However, DFO is inactive orally and needs to be administered by intramuscular infusion, whilst there are concerns over the long-term effectiveness and toxicity of L1. In addition, both DFO and L1 affect brain dopamine (DA) and 5-hydroxytryptamine (5-HT) metabolism. In this study, the 3,5,5-trimethylhexanoyl ferrocene rat model of iron overload was used to compare the iron-chelating capabilities of a novel orally active siderophore, desferrithiocin (DFT) and its desmethyl derivatives DFT-D and DFT-L, to that of DFO, along with their ability to affect brain DA and 5-HT metabolism. Chronic administration of ferrocene produced a 12-fold increase in liver iron levels, as assessed by electrothermal atomic absorption. Subsequent treatment with DFT over a two-week period produced a 37% reduction in liver iron levels, whereas similar treatment with DFT-D and DFT-L produced a more marked reduction in these levels (65% and 59%, respectively) in the ferrocene-treated animals. In contrast, using the same dosing regimen, DFO and L1 only produced a 16% and 18% reduction, respectively, in liver iron levels. Both DFT and its derivatives failed to affect either striatal DA or 5-HT metabolism when assessed by HPLC. In view of the previously described oral bioavailability of DFT, the marked ability of DFT and its derivatives to chelate hepatic iron, and their inability to affect brain DA or 5-HT metabolism, such siderophores appear potentially useful clinical iron chelators.

Administration, Oral↗

PubMed1999

Expression and localisation of CYP2D enzymes in rat basal ganglia.

P450 enzymes in the CYP2D subfamily have been suggested to contribute to the susceptibility of individuals in developing Parkinson's disease. We have used specific anti-peptide antisera and peroxidase immunohistochemistry to investigate the expression of CYP2D enzymes in the rat brain and some possible factors that may affect their regulation. In male Wistar rats, CYP2D1 was not detected in the basal ganglia or in any other brain region. CYP2D2 was weakly expressed within neurones of the subthalamic nucleus, substantia nigra and interpeduncular nucleus as well as in the hippocampus, dentate gyrus, red nucleus and pontine nucleus. CYP2D3 and CYP2D4 were absent from the basal ganglia, although moderate amounts of CYP2D3 were detected within fibres of the oculomotor root, and very low levels of CYP2D4 were present in white matter tracts. In contrast, CYP2D5 was extensively expressed in the basal ganglia, including neurones in the subthalamic nucleus, substantia nigra and interpeduncular nucleus, as well as other areas of the brain, including the ventral tegmental area, piriform cortex, hippocampus, dentate gyrus, medial habenular nucleus, thalamic nucleus and pontine nucleus. Lesioning of the nigro-striatal tract to cause almost a complete loss of tyrosine hydroxylase containing neurones in the substantia nigra, also reduced the number of neurones expressing CYP2D5 by 50%, indicating that CYP2D5 is expressed in dopaminergic neurones. Castration of pre-pubertal or adult Wistar rats had no effect on the number of CYP2D5-positive neurones in the substantia nigra. Although Dark Agouti rats lack hepatic CYP2D2, expression in the midbrain was similar to that of Wistar rats; furthermore, there was no difference in expression or distribution between male and female rats. In contrast to naive rats, extensive expression of CYP2D4 was found throughout the basal ganglia and in other brain nuclei in Wistar rats treated with not only clozapine, but also saline, suggesting that CYP2D4 may be induced as a result of mild stress. The function of CYP2D enzymes in the brain remains unknown, but their selective localisation suggests a physiological role in neuronal activity and in adaptation to abnormal situations.

Animals↗

PubMed1999

Actions of the D1 agonists A-77636 and A-86929 on locomotion and dyskinesia in MPTP-treated L-dopa-primed common marmosets.

Common marmosets show parkinsonian motor deficits following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration and develop dyskinesias during chronic L-dopa exposure. The D1 agonists A-77636 [(1R, 3S) 3-(1'-adamantyl)-1-aminomethyl-3, 4-dihydro-5, 6-dihydroxy-1H-2-benzopyran HCl] and A-86929 [(-)-trans 9, 10-hydroxy-2-propyl-4, 5, 5a, 6, 7, 11b-hexahydro-3-thia-5-azacyclopent-1-ena[c]phenanthrene hydrochloride] possess potent antiparkinsonian activity in the MPTP-treated marmoset and we now assess their influence on L-dopa-induced dyskinesias. MPTP-treated marmosets with stable motor deficits were treated with L-dopa plus carbidopa for 28 days to induce dyskinesias. Subsequently, they received A-86929 for 10 days, initially at 0.5 micromol/kg and then at 1.0 micromol/kg for a further 5 days. Several months later, L-dopa 12.5 mg/kg plus carbidopa 12.5 mg/kg was given orally twice daily for 7 days, followed by A-77636 1 micromol/kg for 10 days, and then both A-77636 and L-dopa plus carbidopa were given concurrently for 3 further days. In these L-dopa-primed animals, A-86929 effectively reversed akinesia and produced dose-dependent dyskinesias which were significantly less intense than those produced by L-dopa administration. A degree of behavioral tolerance was encountered, but antiparkinsonian activity was preserved and elicited behaviour was free of hyperkinesis and stereotypy and more naturalistic than that seen with L-dopa. After a week of twice-daily L-dopa dosing, administration of the long-acting D1 agonist A-77636 initially dramatically enhanced locomotion and reproduced dyskinesia with prominent dystonia, but after repeated administration of A-77636, dyskinesia and in particular chorea, gradually disappeared. Tolerance to locomotor stimulation greater than with A-86929 occurred, although activity remained significantly above baseline levels. There was a marked reduction in L-dopa-induced climbing, stereotypy and hyperkinesis and behaviour more closely resembled that of normal unlesioned marmosets. Upon reintroduction of L-dopa concurrently with continued A-77636 administration, dystonic, but virtually no choreic dyskinesias appeared and behaviour was once again free of stereotypy and hyperkinesis, contrasting dramatically with the presence of these behaviours along with abundant chorea when L-dopa is given alone. These results show a lesser liability of A-86929 and A-77636 to reproduce dyskinesia in L-dopa-primed MPTP-lesioned subjects while maintaining effective antiparkinsonian activity and producing a more naturalistic motor response. The differential effects of A-77636 on chorea and dystonia, with suppression of chorea and stereotypy on co-administration with L-dopa, may reflect an altered balance of activity in the direct and indirect striatofugal pathways. These results suggest a possible role for D1 agonists in the treatment of Parkinson's disease.

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

PubMed1999

Neuronal nitric oxide synthase inhibition reduces MPP+-evoked hydroxyl radical formation but not dopamine efflux in rat striatum.

Nigral cell degeneration induced by 1-methyl-4-phenyl-1,2,3,6-tertrahydropyridine (MPTP) or its metabolite 1-methyl-4-phenyl pyridinium (MMP+) may involve toxicity induced by nitric oxide. In the present study a microdialysis procedure incorporating salicylate hydroxylation was used to measure striatal hydroxyl radical production through the formation of 2,3-dihydroxybenzoic acid (2,3-DHBA). MPP+ (5-20mM for 20 min) increased 2,3-DHBA formation in the rat striatum in a concentration-dependent manner with a concomitant increase in dopamine release and decrease in 3,4-dihydroxyphenyl acetic acid (DOPAC) formation. Inhibition of NO synthesis following N(G)-nitro-L-arginine methyl ester (L-NAME; 1 mM) and 7-nitroindazole monosodium salt (7-NINA; 1 mM), but not N(G)-nitro-D-arginine methyl ester (D-NAME; 1 mM) attenuated the MPP+-induced increase in hydroxyl radical formation. However, neither L-NAME nor 7-NINA had any effect on the MPP+-induced increase in dopamine efflux measured in vivo by microdialysis or in vitro using superfused striatal slices, although nomifensine (10 microM) abolished the MPP+-evoked dopamine efflux in vitro. These data suggest that NO formation is necessary for the production of hydroxyl radical following MPP+ treatment, but is not involved in the MPP+-evoked dopamine release.

1-Methyl-4-phenylpyridinium↗

PubMed1999

Chronic supranigral infusion of BDNF in normal and MPTP-treated common marmosets.

BDNF or vehicle were administered by unilateral supranigral infusion in normal and chronically lesioned MPTP-treated common marmosets (Callithrix jacchus) for four weeks and locomotor activity, disability and response to apomorphine were assessed with nigral TH, GFAP and GAD immunoreactivity and striatal [3H]mazindol autoradiography. Selective contraversive orientation and ipsilateral neglect evolved in MPTP-treated marmosets receiving BDNF with no significant difference in disability or locomotor activity when compared to the vehicle-infused group. Apomorphine produced an ipsiversive rotational bias in BDNF-treated animals. In normal animals infused with BDNF contralateral neglect, ipsiversive turning, postural instability and ataxia rapidly evolved. In MPTP-treated marmosets BDNF caused increased ipsilateral striatal [3H]mazindol binding with increased somatic size and staining intensity in GAD-immunoreactive cells and a 10-20% loss of nigral TH-immunoreactive cells with increased GFAP staining. In normal common marmosets, both vehicle and BDNF infusion decreased nigral TH-immunoreactivity. Chronic supranigral infusion of BDNF alters motor behaviour and spatial attention in MPTP-treated marmosets which may reflect altered function in residual nigral dopaminergic neurons and brainstem GABAergic neurons and in normal animals produces behavioural and histological signs of nigrostriatal hypofunction.

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

PubMed1999

The neuronal toxicity of sulfite plus peroxynitrite is enhanced by glutathione depletion: implications for Parkinson's disease.

In Parkinson's disease (PD) and incidental Lewy body disease glutathione levels in the substantia nigra are decreased by 40-50%. Both peroxynitrite (ONOO ) and alterations in the metabolism of sulfur-containing amino acids have been implicated in PD and we have previously shown that sulfite and ONOO- exert synergistic toxicity to a neuronal cell line. This article presents data to show that this synergistic toxicity of sulfite and ONOO- is greatly enhanced by 50% depletion of cellular glutathione levels. The toxicity of sulfite is also slightly enhanced. Neurones with decreased glutathione may be at increased risk from sulfite and especially from the synergistic damaging effects of ONOO- and sulfite. Because sulfite is present normally in the brain as a product of cysteine metabolism, and because increased ONOO- formation has been reported in PD, these events might contribute to neuronal cell death.

Animals↗