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Biomedical subjects

M R Luquin

Publications and source records attributed to M R Luquin.

At least 37 records · Page 2Linked to original sources
PubMed1995

Effects of L-DOPA on preproenkephalin and preprotachykinin gene expression in the MPTP-treated monkey striatum.

The cellular expression of the genes encoding the neuropeptides enkephalin and substance P were examined in the caudate nucleus and putamen of parkinsonian 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated cynomolgus monkeys by in situ hybridization using radioactive antisense oligonucleotides coupled with computer-assisted image analysis. Behavioural evaluation of the animals revealed two levels of motor impairment; one group moderately impaired and the other severely disabled. A marked increase in the cellular content of preproenkephalin A messenger RNA was observed in medium-sized (106 +/- 9 microns2) cells in the caudate-putamen of all MPTP animals when compared with controls, the increase being greatest in the most severely impaired animals. By contrast, a marked reduction in the cellular abundance of preprotachykinin gene expression was detected in striatal cells (101 +/- 16 microns2) of these same MPTP animals. These changes in neuropeptide gene expression were not associated with a change in the density (approximately 10 cells per mm2) of messenger RNA-expressing cells. L-DOPA treatment of two of the severely-impaired MPTP monkeys resulted in a dissociation of expression of these two genes: the cellular abundance of preproenkephalin A remained elevated whilst preprotachykinin levels were normalized and comparable with controls. No change in the cellular abundance of preprotachykinin messenger RNA was observed in cells of the insular cortex or a small discrete population of large cells (208 +/- 27 microns2) in the ventral putamen. These results demonstrate that MPTP treatment of primates results in a marked potentiation in preproenkephalin messenger RNA coupled with a attenuation in preprotachykinin messenger RNA in the dopamine-denervated caudate-putamen. L-DOPA therapy given on an intermittent schedule reverses the decrease in preprotachykinin messenger RNA, but fails to reverse the increase in preproenkephalin messenger RNA in the same animal. These observations suggest that a dissociation of the activity of these two neuropeptide systems may underlie the improvement in motor skill that accompanies dopamine replacement therapy and that this dissociation may be instrumental in the long-term complications associated with L-DOPA therapy.

Animals↗
PubMed1994

MPTP-induced parkinsonism in primates: pattern of striatal dopamine loss following acute and chronic administration.

We analyzed the effect of two different schedules of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment on dopaminergic systems in the striatum of cynomolgus monkeys. Acute MPTP treatment produced a marked dopamine (DA) depletion, more severe in the caudate nucleus than in the putamen. Chronic MPTP induced a more pronounced reduction in DA levels, the putamen being slightly more affected than the caudate nucleus, in accord with immunohistochemical findings that showed a higher loss of tyrosine-hydroxylase positive neurons in ventral subpopulations of the substantia nigra pars compacta. A striking increment in the quotient DOPAC+HVA/DA was also observed in chronically but not in acutely treated monkeys, especially in the putamen. In chronically treated animals there was a nearly complete loss of DA in all subdivisions of the putamen. In the caudate nucleus, a rostrocaudal gradient of DA depletion was found, with a greater decrease in DA concentration in the rostral parts, especially in the dorsolateral portions. The pattern of striatal DA loss characteristic of Parkinson's disease can be reproduced to a certain extent in MPTP-intoxicated primates.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1994

Functional interaction between dopamine D1 and D2 receptors in 'MPTP' monkeys.

We have studied the motor response induced by independent administration of 4 different doses of a dopamine D2 [(+)-PHNO] and a dopamine D1 (CY 208-243) receptor agonist in 5 MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) monkeys. Both drugs had similar antiparkinsonian effects and both elicited choreic dyskinesias. Simultaneous administration of (+)-PHNO [(+)-4-propyl-9-hydroxynaphthoxazine] and CY 208-243 [(-)4,6,6a,7,8,12b-hexahydro-7-methylindolo[4,3a-b]phenan thyxidine] did not result in modification of the dose-response curve induced by each dopamine receptor agonist given alone. Pretreatment with the dopamine D1 receptor antagonist SCH 23390 (0.8 mg/kg) and the dopamine D2 receptor antagonist sulpiride (60 mg/kg) reduced the magnitude and the duration of the motor response induced by (+)-PHNO and CY 208-243, respectively, but did not modify the intensity and characteristics of choreic dyskinesias. These results demonstrate that the motor effects and the dyskinesias cannot be dissociated by selective dopamine D1 and D2 receptor stimulation. It appears that stimulation of dopamine D1 and D2 receptors by endogenous dopamine is required to obtain the full motor response induced by selective dopamine receptor agonists as demonstrated by the reduction of the motor improvement found after pretreatment with SCH 23390 and sulpiride.

Animals↗
PubMed1994

Decreased tyrosine hydroxylase content in the dopaminergic neurons of MPTP-intoxicated monkeys: effect of levodopa and GM1 ganglioside therapy.

Parkinson's disease is characterized by the degeneration of melanized dopaminergic neurons of the substantia nigra. The functional capacity of the surviving dopaminergic neurons is affected, as suggested by the subnormal levels of tyrosine hydroxylase messenger RNA and protein found in the remaining cells. The reduced expression of tyrosine hydroxylase may be due to either the evolving neurodegenerative process or its downregulation, possibly secondary to chronic levodopa treatment. The cellular content of tyrosine hydroxylase was determined in the mesencephalon from 16 Macaca fascicularis monkeys, using a semiquantitative immunocytochemical method. Thirteen monkeys were rendered parkinsonian by weekly intravenous injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 2 (subacute treatment) or 20 (chronic treatment) weeks. Three of the monkeys received levodopa and 3 others received GM1 ganglioside. The loss of dopaminergic neurons in the mesencephalon of the MPTP-intoxicated monkeys was severe in the substantia nigra, intermediate in cell groups A8 and A10, and almost undetectable in the central gray substance. After both subacute and chronic treatment, the cellular content of tyrosine hydroxylase was reduced by 40% in the surviving neurons of the lesioned substantia nigra, but by less in the other mesencephalic dopaminergic regions. Neuronal survival and tyrosine hydroxylase content in monkeys that had received levodopa were not significantly different. The cellular content of tyrosine hydroxylase was increased in the substantia nigra of the monkeys that received GM1 ganglioside injections. The results show that the decreased expression of tyrosine hydroxylase found in nigral dopaminergic neurons after partial degeneration of the mesostriatal dopaminergic system is not influenced by levodopa treatment and is partially reversed by GM1 ganglioside administration.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1994

Motor response to apomorphine and levodopa in asymmetric Parkinson's disease.

The motor responses of 14 patients with Parkinson's disease (six previously untreated and eight chronically receiving levodopa) with pronounced asymmetry in the severity of motor signs between the left and right sides of the body were studied. The effects of a short (60 minutes) and a long (16-22 hours) intravenous levodopa infusion as well as of subcutaneous apomorphine (1-6 mg bolus) were assessed. Four different tapping tests were used to measure motor function. For all pharmacological tests, the more affected side showed a shorter response duration, increased latency, and greater response magnitude than the less affected side. These differences were more pronounced in those patients receiving chronic levodopa treatment. As apomorphine is not dependent on dopamine storage capacity, these findings suggest that postsynaptic mechanisms play an important part in the origin of motor fluctuations in Parkinson's disease.

Apomorphine↗
PubMed1993

The AMPA receptor antagonist NBQX does not alter the motor response induced by selective dopamine agonists in MPTP-treated monkeys.

We studied the motor response induced by the administration of the AMPA receptor antagonist, NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f]quinoxaline(1H,4H)dione sodium salt), in two parkinsonian monkeys and its interaction with the selective D-2 dopamine receptor agonist, (+)-PHNO [(+)-4-propyl-9-hydroxynaphthoxazine], and the partial dopamine D-1 receptor agonist, CY 208-243 [(-)-4,6,6a,7,8,12b-hexahydro-7-methyl-indolo[4,3a-b]phen anthyxidine]. NBQX treatment did not reverse the parkinsonism or change the responses previously induced by dopamine agonists. These results do not support an antiparkinsonian effect of the AMPA receptor antagonist, NBQX. In addition they indicate that there is no functional interaction between AMPA and dopamine receptors in monkeys with a substantia nigra lesion.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1993

The subthalamic nucleus: a possible target for stereotaxic surgery in Parkinson's disease.

Hyperactivity in the subthalamic nucleus (STN) projections to the globus pallidus medialis (GPM) has been established as a crucial feature of parkinsonism in animal models of Parkinson's disease (PD). Recent experiments blocking the STN glutamatergic output to GPM or lesioning the STN support this concept by showing a dramatic reversal of parkinsonism. We review the role of stereotaxic surgery in the past and the possible future application of subthalamotomy for PD.

Animals↗
PubMed1993

Behavioral tolerance to repeated apomorphine administration in parkinsonian monkeys.

Four consecutive injections (s.c.) of apomorphine (Apo) were given to 5 parkinsonian monkeys after i.v. MPTP administration. The minimal effective dose (MED) of Apo was defined as that capable of reducing motor disability by 50% or more for a minimum period of 30 min. Repeated apomorphine injections were given with an interval of 30 min after the motor effect of the previous injection had worn off or with a separation of 3 h between injections. The doses used in different experiments were the MED (2.4 micrograms/kg), 4 MED and 8 MED. In every experiment the duration of motor benefit was longest with the first Apo injection. There was a decay in the duration of the response elicited by consecutive Apo injections when given 30 min after the previous effect had waned. This was significant for the MED and 4 MED (ANOVA, P < 0.01). When Apo boluses were given with an interval of 3 h there was a significant reduction in the duration of the response elicited by the MED, 4 MED and 8 MED of apomorphine. For the MED the reduction in the duration of the motor response was significantly greater for injections given with a 30-min interval than 3-h interval. These findings indicate that behavioral hyposensitivity to repeated Apo administration in parkinsonian monkeys occurs preferentially when near threshold doses are given with short intervals.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1993

GM-1 ganglioside promotes the recovery of surviving midbrain dopaminergic neurons in MPTP-treated monkeys.

We have examined the influence of chronic GM-1 treatment (20 mg/kg i.m. for 16 consecutive days) on the extent of dopaminergic damage induced by acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration in cynomolgus monkeys using immunohistochemical and neurochemical analysis. The total number of tyrosine hydroxylase-immunoreactive neurons was reduced in different catecholaminergic mesencephalic regions of MPTP-treated monkeys such as substantia nigra pars compacta, mainly in the ventral portion of the nucleus (39% reduction), substantia nigra pars lateralis (31%), peri- and retrorubral catecholaminergic cell group and ventral tegmental area (A8 and A10 respectively, 20% reduction). A similar degree of neuronal loss was observed in the MPTP+GM-1-treated animals, suggesting that GM-1 ganglioside does not exert a protective effect against MPTP-induced dopaminergic cell loss. Moreover, no neurochemical recovery from the striatal dopaminergic depletion induced by MPTP was found after GM-1 treatment. However, the optical density of tyrosine hydroxylase fibers and the cellular tyrosine hydroxylase content were increased in the substantia nigra pars compacta and ventral tegmental area of the MPTP-treated monkeys which received GM-1 ganglioside, compared with animals treated only with the neurotoxin. These results indicate that GM-1 does not protect against cell death but exerts a neurotrophic effect on surviving dopaminergic neurons in the midbrain of MPTP-lesioned monkeys, suggesting that GM-1 ganglioside may be potentially useful for the treatment of neurodegenerative disorders such as Parkinson's disease.

Animals↗
PubMed1993

Does neuromelanin contribute to the vulnerability of catecholaminergic neurons in monkeys intoxicated with MPTP?

The question has been raised as to whether neuromelanin, a by-product of catecholamine metabolism which accumulates during aging in primate midbrain neurons, contributes to the selective vulnerability of subgroups of dopaminergic neurons in Parkinson's disease. 1-Methyl-4-phenylpyridinium (MPP+) a metabolite of 1-methyl, 4-phenyl, 1,2,3,6-tetrahydropyridine (MPTP) is toxic to dopaminergic neurons, particularly in primates, producing a motor syndrome similar to that observed in Parkinson's disease. To test whether this neurotoxin preferentially affects melanized neurons, the survival of melanized and non-melanized catecholaminergic neurons was analysed after MPTP intoxication in the midbrain of the cynomolgus monkey (Macaca fascicularis). Experiments were performed on six animals chronically treated with MPTP (two were severely disabled, four moderately affected) and two age-matched control monkeys. Two populations of neurons were examined on regularly spaced sections throughout the midbrain: catecholaminergic neurons, identified by tyrosine hydroxylase immunohistochemistry and neuromelanin-containing neurons, visualized by Masson's method. The total number of neurons of each type was estimated in the different midbrain catecholaminergic cell groups using computer assisted image analysis. In the midbrains of control animals not all catecholaminergic neurons contained neuromelanin. The percentage of melanized neurons compared to the total population of tyrosine hydroxylase-positive neurons was high in the substantia nigra pars compacta (81.5%) and in the locus coeruleus (98%), intermediate in the substantia nigra pars lateralis (70%), in the catecholaminergic cell group A8 (50%), and in the ventral tegmental area (41.5%) and almost nil in the central gray substance. In MPTP-treated monkeys, the severity of the loss of catecholaminergic neurons was variable within the different midbrain cell groups, though of similar intensity in severely and mildly disabled monkeys. A relationship was found between the loss of dopaminergic neurons in the different mesencephalic cell groups of MPTP-intoxicated animals and the percentage of melanized neurons they normally contain (r = 0.98; P = 0.04). The percentage loss of catecholaminergic neurons in the locus coeruleus, the only noradrenergic cell group studied, was lower than expected from the correlation curve obtained for dopaminergic cell groups. Altogether, these findings indicate: (i) that dopaminergic neurons are more vulnerable to MPTP-toxicity than noradrenergic neurons; and (ii) that among dopaminergic neurons, those containing neuromelanin are more susceptible, indicating a possible role of neuromelanin in MPTP-toxicity.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

Palatal myoclonus and opioid peptides.

We report a patient who presented palatal myoclonus (PM) after anoxic brain damage that was completely abolished by the administration of opioid agonists. This suggests the involvement of peptide systems in the development of PM.

Carcinoma↗
PubMed1993

Neuromelanin accumulation with age in catecholaminergic neurons from Macaca fascicularis brainstem.

Neuromelanin (NM) is an auto-oxidation by-product of catecholamine synthesis which is observed almost exclusively in primates. We have estimated the distribution and the number of NM-positive neurons of the upper brainstem and the degree of their melanization from birth to the onset of senescence in 5 monkeys (Macaca fascicularis) aged 0, 1.5, 3.5, 8 and 13 years. Series of sections taken at 640-microns intervals were examined either unstained to detect unstained NM, stained for NM with Masson silver impregnation or processed by tyrosine hydroxylase (TH) immunohistochemistry to analyze catecholaminergic neurons. The proportion of NM-containing cells among TH-positive neurons varied from one catecholaminergic region to another: low in the hypothalamus and central gray substance (cgs); moderate in the cell group A8, and high in the ventral tegmental area (VTA), locus coeruleus (LC) and substantia nigra (SN). TH-positive neurons were detected in the SN, VTA, catecholaminergic cell group A8, LC, cgs and hypothalamus. At birth, although no unstained NM-positive neurons were detected, Masson-stained cells were observed, though only in the LC. At 1.5 and 3.5 years, Masson-positive neurons were observed despite the absence of visible pigment. At 8 and 13 years, unstained NM was present in Masson-positive neurons. The number of unstained NM-positive neurons and Masson-positive neurons and the amount of NM per neuron increased with age in each subregion studied. Nevertheless, some TH-positive neurons were found to be without NM. The data indicate a differential increased NM content with age in the neurons of midbrain catecholaminergic cell groups. However, its functional significance remains to be determined.

Aging↗
PubMed1993

Gangliosides and parkinsonism.

The protective effect of GM1 ganglioside against nerve cell death induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was analyzed in monkey mesencephalon. Administration of GM1 before and during MPTP treatment improved motor performances compared with MPTP-treated animals that received saline rather than GM1. Postmortem analysis revealed that GM1 did not protect dopaminergic cell bodies from MPTP intoxication but resulted in an increased immunoreactivity of tyrosine hydroxylase in the perikarya and processes of the surviving neurons. These data suggest that GM1 may be potentially used as a palliative rather than a curative therapy in Parkinson's disease.

Animals↗
PubMed1992

Chronic MPTP treatment reduces substance P and met-enkephalin content in the basal ganglia of the marmoset.

Common marmosets were treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 1.25-2.5 mg/kg s.c., twice a week) for 5-10 consecutive months. The initial doses of MPTP produced a severe parkinsonian syndrome but motor activity was partially recovered at the end of treatment. Fifteen days or 6 months after the last MPTP dose, monkeys were sacrificed. In addition to a strong decrease of dopamine in the striatum, there were significant reductions in substance P and Met-enkephalin content in the substantia nigra, caudate nucleus and putamen. In the globus pallidus, the reduction in peptide levels did not reach statistical significance as compared to controls. Neurotensin levels were also decreased in the caudate nucleus. The chronic administration of MPTP for 5-10 months induces changes in substance P and Met-enkephalin systems which resemble the degeneration found in brains from parkinsonian patients.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1992

Neurotoxic effect of prenatal exposure to MPTP on the dopaminergic systems of the marmoset brain.

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) was incidentally administered to pregnant marmosets during the whole gestational period, except for the last 15 days before term. The infant monkeys were killed 5 months after birth, and dopamine and its metabolites were measured in the striatum and the nucleus accumbens. Prenatal exposure to MPTP produced a marked dopamine depletion in these brain regions of the offspring, showing that MPTP is able to cross the placental barrier in primates.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1992

Selective D2 receptor stimulation induces dyskinesia in parkinsonian monkeys.

Stimulation of D1 striatal receptors has been proposed as the main mechanism mediating levodopa-induced dyskinesia in Parkinson's disease. We used (+)-PHNO, a selective D2 agonist, as the only treatment in 6 cynomolgus monkeys made parkinsonian by repeated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration. All animals developed choreic dyskinesia after a mean treatment period of 12.8 days (range, 1-29). Administration of the D1 antagonist SCH-23390 1 hour before administration of (+)-PHNO did not change the dyskinesia. These results indicate that drug-induced dyskinesia in a primate model of Parkinson's disease is not solely induced by D1 receptor activation.

Animals↗
PubMed1992

Levodopa-induced dyskinesias in Parkinson's disease: clinical and pharmacological classification.

Levodopa-induced dyskinesias (LID) in Parkinson's disease (PD) may be classified into three main categories: "On" dyskinesias, diphasic dyskinesias (DD), and "off" periods. The study of 168 parkinsonian patients showed that about half (n = 84) showed one pattern of LID only. A combination of two was present in 68, and 16 had the three presentation patterns. A fairly good correlation between type of dyskinesia and presentation pattern was established. Chorea, myoclonus, and dystonic movements occurred during the "on" period. Dystonic postures, particularly affecting the feet, were mainly present in the "off" period, but a few patients had a diphasic presentation. Repetitive stereotyped movements of the lower limbs always corresponded to DD. Acute pharmacological tests using dopamine agonists (subcutaneous apomorphine 3-8 mg; intravenous lisuride 0.1-0.15 mg) and dopamine antagonists (intravenous sulpiride 200-400 mg and intravenous chlorpromazine 25 mg) were performed in 40 patients. Dopamine agonists enhanced "on" dyskinesias and markedly reduced or abolished "off" period dystonia and DD. Dopamine antagonists reduced all types of LID but usually aggravated parkinsonism. These clinical and pharmacological results indicate that LID in PD are a heterogeneous phenomenon difficult to explain on the basis of a single pathophysiological mechanism.

Aged↗