Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several studies suggest that nitric oxide (NO.) contributes to cell death following activation of NMDA receptors in cultured cortical, hippocampal, and striatal neurons. In the present study we investigated whether 7-nitroindazole (7-NI), a specific neuronal nitric oxide synthase inhibitor, can block dopaminergic neurotoxicity seen in mice after systemic administration of MPTP. 7-NI dose-dependently protected against MPTP-induced dopamine depletions using two different dosing regimens of MPTP that produced varying degrees of dopamine depletion. At 50 mg/kg of 7-NI there was almost complete protection in both paradigms. Similar effects were seen with MPTP-induced depletions of both homovanillic acid and 3,4-dihydroxyphenylacetic acid. 7-NI had no significant effect on dopamine transport in vitro and on monoamine oxidase B activity both in vitro and in vivo. One mechanism by which NO. is thought to mediate its toxicity is by interacting with superoxide radical to form peroxynitrite (ONOO-), which then may nitrate tyrosine residues. Consistent with this hypothesis, MPTP neurotoxicity in mice resulted in a significant increase in the concentration of 3-nitrotyrosine, which was attenuated by treatment with 7 NI. Our results suggest that NO. plays a role in MPTP neurotoxicity as well as novel therapeutic strategies for Parkinson's disease.
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PMID:Inhibition of neuronal nitric oxide synthase by 7-nitroindazole protects against MPTP-induced neurotoxicity in mice. 753 Feb 97

The aim of this article was to review the recent literature on the role of excitatory amino acids in Parkinson's disease and in animal equivalents of parkinsonian symptoms. Effects of NMDA and AMPA antagonists on the reserpine-induced akinesia, catalepsy and rigidity, on the neuroleptic-induced catalepsy, on the turning behaviour of 6-OHDA-lesioned rats, as well as on the parkinsonian symptoms evoked by MPTP in monkeys were analysed. Moreover, the role of NMDA antagonists in Parkinson's disease was discussed. Data concerning the protective influence of these drugs on degenerative properties of methamphetamine, MPTP and 6-OHDOPA were also presented. On the basis of the above findings, the following conclusions may be drawn: (1) disturbances in the glutamatergic transmission in various brain structures seem to play a significant role in the development of symptoms of Parkinson's disease; (2) the NMDA-receptor blocking component may make a substantial contribution to the therapeutic effect of antiparkinsonian drugs; a similar contribution of AMPA-receptor blocking component has not been sufficiently documented, so far; (3) compounds blocking NMDA receptors may possibly prevent the development of Parkinson's disease; this presumption needs, however further studies; (4) side effects of NMDA receptor antagonists may be a limiting factor in the use of these compounds in humans.
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PMID:The role of excitatory amino acids in experimental models of Parkinson's disease. 753 62

The development of drug-induced behavioral sensitization is thought to underlie many of the motor complications that accompany chronic L-DOPA treatment of patients with Parkinson's disease. As the development of sensitization to some dopaminergic behaviors has been linked to alterations in NMDA neurotransmission in animal models, we sought to determine whether or not NMDA antagonists can block the development of sensitization to rotational effects of dopamine agonists in rodents with unilateral nigrostriatal lesions. Rats with unilateral 6-hydroxydopamine lesions received either a single dose or eight daily doses of apomorphine, each dose preceded by the NMDA antagonists MK-801 or CPP. Three days after the last apomorphine dose, the circling behavior produced by the D1 agonist SKF 38393 was measured. A single dose of MK-801 (0.1 mg/kg) prevented the subsequent response to SKF 38393 but neither repeated treatment with MK-801 (0.1 or 0.3 mg/kg) nor CPP (0.1 mg/kg) preceding apomorphine prevented the subsequent response to SKF 38393 or attenuated the response in comparison to a control group. Each of the chronic treatment groups exhibited an increase in rotational effects of apomorphine despite MK-801 or CPP pretreatment. These data suggest behavioral sensitization in unilateral nigrostriatally lesioned rats chronically treated with apomorphine is not dependent upon stimulation of NMDA receptors.
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PMID:Sensitization to apomorphine-induced rotational behavior in 6-OHDA-lesioned rats: effects of NMDA antagonists on drug response. 755 28

The distribution of somatostatin in both the human and rat brain suggests that it is involved in numerous functions, including endocrine regulation, cognition and memory, autonomic regulation and motor activity. We have examined the regulation of somatostatin mRNA in the striatum, a brain region involved in motor and cognitive behaviour. Somatostatin and its mRNA are expressed in this region in interneurons which are resistant to ischaemia, excitotoxicity and Huntington's disease, possibly because they express high levels of superoxide dismutase. Striatal somatostatin mRNA is increased by stimulation of NMDA (N-methyl-D-aspartate) receptors. Ischaemia-induced cortical lesions also increase somatostatin gene expression in the striatum. In contrast, the levels of striatal somatostatin mRNA decrease after treatment with haloperidol, an antipsychotic agent that produces extrapyramidal symptoms, but not clozapine, which does not. Further evidence for a role for striatal somatostatin in extrapyramidal symptoms includes the observation that somatostatin mRNA levels decrease in the striatum after lesions are made in the dopaminergic pathway, a feature of Parkinson's disease. The largest change in somatostatin gene expression after dopaminergic lesions is the increase in somatostatin mRNA level sin neurons of the internal pallidum and lateral hypothalamus projecting to the lateral habenula. The results suggest that changes in brain somatostatin gene expression occur in pathological conditions and may be related to their symptoms.
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PMID:Anatomical localization and regulation of somatostatin gene expression in the basal ganglia and its clinical implications. 758 52

The administration to rats of different doses of the non competitive NMDA receptor blocker MK-801 (0.03-1 mg/kg IP) induced stimulation or reduction of locomotor activity, depending on the dose, whereas the competitive NMDA antagonists CGP 43487 (0.188-6 mg/kg IP) and APV (2.5-20 micrograms/rat ICV) inhibited locomotion at the highest doses. Unlike MK-801 and APV treatment, the administration of CGP 43487 did not induce impairment of rota-rod test performance. Both competitive and non-competitive NMDA antagonists, at doses devoid of any behavioral effect per se, potentiated the responses elicited by apomorphine (0.25 mg/kg SC). In particular, the occurrence of episodes of licking was weakly affected by MK-801 administration, but significantly increased by CGP 43487 and APV treatment; the presence of gnawing was augmented by all the pretreatments; sniffing, locomotion, grooming and rearing occurrence were not affected by the administration of NMDA antagonists. The results suggest that the competitive antagonists which facilitated dopaminergic function without causing motor impairment could be useful supplements in the treatment of Parkinson's disease.
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PMID:The competitive NMDA antagonists CGP 43487 and APV potentiate dopaminergic function. 761 24

The glutamatergic cortico-striatal and subthalamo-entopeduncular pathways are both overactive in parkinsonism. Previous behavioural investigations have shown that intra-entopeduncular injection of either NMDA-site or glycine-site antagonists results in alleviation of parkinsonian symptoms, although injection of the former is associated with the appearance of anaesthetic-like side effects. These behavioural differences may be mediated by action on different NMDA receptor subtypes. Recent neurochemical and molecular pharmacological studies have indicated the existence of NMDA receptor subtypes which display differential modulation by glycine. In the present study, three potential modes of NMDA antagonism were differentiated in vitro by effects on [3H]-glycine binding to striatal sections. Specific [3H]-glycine binding was totally displaced by the glycine partial agonist (R)-HA-966; the NMDA-site antagonist D-CPP had no effect; and the NMDA-site antagonist D-AP5 displaced [3H]-glycine binding in a subpopulation of glycine sites. The anti-parkinsonian effects of (R)-HA-966, D-CPP and D-AP5 were assessed by intra-striatal injection in reserpine-treated rats and 6-OHDA-lesioned rats. Injection of (R)-HA-966 and D-CPP resulted in alleviation of parkinsonian akinesia, although the latter elicited anaesthetic-like side effects; D-AP5 was ineffective as an anti-parkinsonian agent. (R)-HA-966 was also effective as an anti-parkinsonian agent when administered systemically in the reserpine-treated rat. These data suggest that different classes of NMDA antagonist mediate different behavioural responses within the parkinsonian striatum. The behavioural response produced may depend on the exact nature of the conformational change induced by the antagonist and the location of the subtype most sensitive to that class of compound. Selection of a specific mode of NMDA receptor antagonism or targeting of striatal NMDA receptor subtypes may form the basis of a novel therapeutic approach to Parkinson's disease.
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PMID:Neurochemical and behavioural investigations of the NMDA receptor-associated glycine site in the rat striatum: functional implications for treatment of parkinsonian symptoms. 767 50

The pathogenesis of nerve cell death in neurodegenerative diseases is unknown. An attractive hypothesis is that an impairment of energy metabolism may underlie slow excitotoxic neuronal death. Several studies have demonstrated mitochondrial or oxidative defects in neurodegenerative diseases. Impaired energy metabolism results in decreases in high-energy phosphate stores and a deteriorating membrane potential. Under these conditions, the voltage-sensitive Mg2+ block of NMDA receptors is relieved, allowing the receptors to be persistently activated by endogenous concentrations of glutamate. In this way, metabolic defects may lead to neuronal death by a slow 'excitotoxic' mechanism. Recent studies indicate that such a mechanism occurs in vivo, and it may play a role in animal models of Huntington's disease and Parkinson's disease. If a similar mechanism occurs in neurodegenerative diseases in humans it may be possible to use either excitatory amino acid antagonists or agents to improve neuronal bioenergetics as therapeutic treatments for these disorders.
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PMID:Do defects in mitochondrial energy metabolism underlie the pathology of neurodegenerative diseases? 751 25

MK-801, a non-competitive antagonist of NMDA receptors, is known to exhibit a beneficial action in many animal models of Parkinson's disease. The aim of this study was to examine the influence of MK-801 on the reserpine-induced muscle rigidity. The rigidity was estimated by a direct mechanomyographic method. This method consists in successive bending and straightening of a rat's hind foot in the ankle joint and measuring the resistance of the foot to passive movements. Reserpine in doses of 5-10 mg/kg ip, given alone or in combination with alpha-methyl-p-tyrosine (alpha MT, 250 mg/kg ip), induced rigidity. The strongest muscle rigidity was induced by 10 mg/kg of reserpine 1 hour after administration. MK-801 (0.32-1.28 mg/kg sc) injected 70 min after reserpine (10 mg/kg ip) decreased the rigidity induced by the latter compound. Similarly, MK-801 (1.28 mg/kg sc), administered 27 h 40' after joint treatment with reserpine (10 mg/kg ip) and alpha MT (250 mg/kg ip), strongly inhibited the reserpine-induced muscle rigidity. The obtained results show that the glutamatergic hyperactivity plays a significant role in the reserpine-induced rigidity. As the reserpine-induced motor disturbances are commonly accepted to be an animal model of parkinsonian symptoms, it may be assumed that the NMDA receptor blocking component may contribute substantially to the therapeutic action of antiparkinsonian drugs.
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PMID:Antiparkinsonian action of MK-801 on the reserpine-induced rigidity: a mechanomyographic analysis. 771 Jun 66

Some treatments used for Parkinson's disease attenuate locomotor depression in rats treated with reserpine and alpha-methyl-p-tyrosine. In the present study memantine (2.5, 5.0 mg/kg), amantadine (10, 20 mg/kg) (both uncompetitive NMDA antagonists), and L-deprenyl (1.0, 5.0 mg/kg; MAO-B inhibitor) were tested for possible synergistic interactions with the dopamine agonists: bromocriptine (2.5, 5.0 mg/kg) and L-dopa (50, 100 mg/kg, +benserazide, 100 mg/kg). At higher doses, memantine (10 mg/kg), amantadine (40 mg/kg), bromocriptine (5 and 10 mg/kg) and L-dopa (100, 200 mg/kg) but not L-deprenyl (up to 10 mg/kg) produced a pronounced increase in locomotor activity when given alone. The combination of memantine, amantadine and L-deprenyl with bromocriptine did not result in synergism of action and, at best, an additive effect was seen. On the other hand the combination of these agents with L-dopa produced a pronounced synergistic effect. Hence, the clinical observation that coadministration of L-dopa with either memantine or amantadine results in enhancement of their action is also reflected in an animal model of Parkinson's disease. Such a combination therapy should allow the use of lower doses of both drugs which may reduce the occurrence of side effects and may also be predicted to have additional benefits related to the neuroprotective properties of memantine, amantadine, and L-deprenyl.
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PMID:Memantine, amantadine, and L-deprenyl potentiate the action of L-dopa in monoamine-depleted rats. 771 Jul 39

Systemic administration of the non-competitive antagonist of NMDA receptors MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine) potentiates the circling response induced by direct stimulation of the striatal dopaminergic receptors through intracerebral application of dopamine. Microinjection of dopamine (1, 5, 25 or 50 micrograms/1.0 microliters) induced a dose-dependent contralateral circling response, when injected directly into the lesioned side of unilaterally 6-hydroxydopamine-lesioned rats. Interestingly, intrastriatal application of dopamine (1, 5, 25 or 50 micrograms/1.0 microliters) followed by a systemic administration of MK-801 (100 micrograms/kg i.p.) produced a potentiated contralateral circling response in unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats. This motor effect is reversed compared to the marked ipsilateral circling response produced by MK-801 when given alone. Moreover, the potentiated responses persist 4-fold longer compared to the circling induced by dopamine alone. The results suggest that the potentiation by NMDA receptor antagonists of motor activity induced by dopaminergic agonists in animal models of Parkinson's disease cannot be ascribed simply to increased release of dopamine. Other mechanisms including increased sensitivity of dopamine D1 receptors or blockade or glutamatergic transmission in output structures must be considered.
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PMID:Systemic administration of the NMDA receptor antagonist MK-801 potentiates circling induced by intrastriatal microinjection of dopamine. 771 55


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