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)

(-)-Deprenyl (selegiline) is an irreversible inhibitor of monoamine oxidase (MAO) B, which was discovered in 1962 and become the "golden standard" of MAO research. Like the other MAO-B inhibitors, it was synthesized as an antidepressant, but in a selective MAO-B inhibitory dose it does not act in depression. It is used in the treatment of Parkinson's disease. (-)-Deprenyl potentiates the effect of dopamine, it has antioxidant activity and prevents the toxicity of the dopaminergic (6-OH-dopamine; 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP)), the noradrenergic (DSP-4) and cholinergic (AF64A) neurotoxins after pre-treatment. When (-)-deprenyl was administered with levodopa in a long-term treatment of Parkinsonian patients, it induces adverse events (nausea, dizziness, confusion, hallucination, insomnia and cardiovascular changes), which could be due to dopamine potentiation in dopaminergic systems (limbic system), other than the nigrostriatal pathway. (-)-Deprenyl in much lower concentrations needed to induce MAO-B inhibition (10(-9) to 10(-13) M) potently inhibits MPTP or serum withdrawal induced apoptosis in tissue cultures of neuro-ectodermal origin (PC12, M1, M2058). The (+)-enantiomer of deprenyl lacks of this property. The anti-apoptotic activity of (-)-deprenyl can be prevented by inhibiting the metabolism of the drug with SKF-525A pre-treatment, which suggests that some of the presently unknown metabolites could be responsible for the anti-apoptotic activity. In high concentration (10(-3) M), (-)-deprenyl and its metabolites induce apoptosis in tissue cultures without serum withdrawal (biphasic action). Our findings support the view that 100, or even 1000 times lower dose of (-)-deprenyl can be offered in human therapy to protect, or slow down neuronal degeneration, than it is presently used. With low dose of the drug the dopaminergic adverse events could be avoided, while anti-apoptotic activity might be preserved.
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PMID:(-)-Deprenyl, a selective MAO-B inhibitor, with apoptotic and anti-apoptotic properties. 1469 98

Noradrenaline has been shown to control dopamine turnover and release in rat brain. Noradrenergic lesion with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) decreases dopamine release in the striatum and enhances catalepsy in experimental models of Parkinson's disease. However, in due course, sprouting of remaining noradrenergic axons, to compensate for the decreased noradrenaline is said to occur in specific brain regions. Though this is to some extent understood, the longstanding effects of noradrenergic lesion on dopaminergic neurons of the basal ganglia and in Parkinsonian behavior is not known. Here the question is addressed, whether locus coeruleus lesion with DSP-4 in rats alters dopamine concentration of the basal ganglia and influences Parkinsonian behavior in a long term (6 months). Parkinsonian behavior was assessed by catalepsy and activity cage after challenging with subthreshold dose of haloperidol (0.2 mg/kg), on 7, 30, 90, 120 and 180 days after DSP-4 lesion. The concentrations of noradrenaline and dopamine and its metabolites were estimated by HPLC. 6 months after DSP-4 lesion, increased concentration of noradrenaline was found in prefrontal cortex and hippocampus. Other regions remain unaffected. The concentration of dopamine remained unchanged. However, dopamine turnover appeared to be increased in prefrontal cortex and reduced in striatum and nucleus accumbens. Catalepsy and hypoactivity were observed in DSP-4 lesioned animals after haloperidol challenge on 7th, 30th and 60th day. Though dopamine turnover was reduced after 6 months in the striatum, haloperidol-induced catalepsy was not observed after 60 days. These results indicate a gradual functional recovery, perhaps hyperinnervation of noradrenergic neurons after DSP-4 treatment and the reversal of its effects on dopaminergic neurons and on Parkinsonian symptoms.
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PMID:Functional recovery of locus coeruleus noradrenergic neurons after DSP-4 lesion: effects on dopamine levels and neuroleptic induced-parkinsonian symptoms in rats. 1471 12

In Parkinson's disease, besides the dopaminergic neurodegeneration, locus coeruleus noradrenergic neurons degenerate as well. Noradrenergic neurons have potential anti-parkinsonian, neuromodulatory and neuroprotective properties. Presently, an animal model with dopaminergic lesion has been used as a standard model of Parkinson's disease. The behavioral effects of dopaminergic agents in a Parkinson's animal model with additional noradrenergic lesions has not been studied so far. Here, the behavioral effects of dopaminergic agents L-DOPA (15 mg/kg) and D-amphetamine (4 mg/kg) in two different pathophysiological conditions have been explored; One group involving only dopaminergic deficiency with 6-hydroxydopamine (6-OHDA) and the other group with both dopaminergic and noradrenergic deficiency with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4). DSP-4 specifically depleted noradrenaline from locus coeruleus terminal fields. 6-OHDA lesion depleted dopamine and its metabolites DOPAC, HVA and 3-MT in the regions of basal ganglia and it was potentiated by additional locus coeruleus denervation. Dopaminergic lesion produced catalepsy and hypoactivity. Hypoactivity in openfield was potentiated by additional noradrenergic denervation of locus coeruleus neurons. L-DOPA produced effective anticataleptic activity in group with both dopaminergic and noradrenergic lesions and D-amphetamine was found to be more effective in group only with dopaminergic lesions, indicating increased dopaminergic neurodegeneration after noradrenergic lesions. L-DOPA produced hyperactivity in dual neurodegenerated group indicating its differential activity in an animal model with noradrenergic and dopaminergic lesions. These findings indicate the neuroprotective and symptomatic role of noradrenergic neurons. It implicates the importance of noradrenergic pathophysiology in Parkinson's disease and its treatment and need for a more relevant animal model.
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PMID:Behavioral and neurochemical effects of noradrenergic depletions with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine in 6-hydroxydopamine-induced rat model of Parkinson's disease. 1508 35

Mutations in the parkin gene cause autosomal recessive familial Parkinson's disease (PD). Parkin-deficient mouse models fail to recapitulate nigrostriatal dopaminergic neurodegeneration as seen in PD, but produce deficits in dopaminergic neurotransmission and noradrenergic-dependent behavior. Since sporadic PD is thought to be caused by a combination of genetic susceptibilities and environmental factors, we hypothesized that neurotoxic insults from catecholaminergic toxins would render parkin knockout mice more vulnerable to neurodegeneration. Accordingly, we investigated the susceptibility of catecholaminergic neurons in parkin knockout mice to the potent dopaminergic and noradrenergic neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) respectively. We report that nigrostriatal dopaminergic neurons in parkin knockout mice do not show increased susceptibility to the parkinsonian neurotoxin, MPTP, in acute, subacute and chronic dose regimens of the neurotoxin. Additionally, parkin knockout mice do not show increased vulnerability to the noradrenergic neurotoxin, DSP-4, regarding levels of norepinephrine in cortex, brain stem and spinal cord. These findings suggest that absence of parkin in mice does not increase susceptibility to the loss of catecholaminergic neurons upon exposure to both dopaminergic and noradrenergic neurotoxins.
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PMID:MPTP and DSP-4 susceptibility of substantia nigra and locus coeruleus catecholaminergic neurons in mice is independent of parkin activity. 1733 77

Besides dopaminergic deficiency, other neurotransmitter systems such as noradrenergic nuclei are affected in Parkinson's disease. Locus coeruleus degeneration might influence the response to dopamine replacement and the presence of long-term complications such as dyskinesias. In this scenario of noradrenergic and dopaminergic neurodegeneration, behavioural effects induced by dopaminergic-interacting drugs are incompletely known. We investigated whether noradrenergic lesion modulates the levodopa (l-DOPA) response and modifies the response to adenosine antagonists and its interaction with l-DOPA. We examined the motor behaviour induced by: 1) subthreshold doses of l-DOPA (2mg/kg, i.p.), 2) the adenosine-receptor antagonist caffeine (10mg/kg), and 3) the combination of l-DOPA (2mg/kg) and caffeine (10mg/kg). Each study was done in two experimental conditions: a) rats with unilateral 6-OHDA lesion and b) rats with a lesion of the nigrostriatal pathway (6-OHDA) combined with selective denervation of locus coeruleus-noradrenergic terminal fields by N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4). While only 28% of the 6-OHDA-lesioned animals presented circling behaviour after l-DOPA challenge, all (100%) double-denervated animals rotated after the same l-DOPA dose (p<0.05). No statistical differences in the percentage of rotating animals were observed between single- and double-denervated rats after caffeine challenge. Combined l-DOPA-caffeine challenge produced rotational behaviour in all (100%) single- and double-denervated rats. No differences in total turns were observed between single- and double-denervated animals in each treatment condition. These findings suggest that additional noradrenergic denervation selectively decreases the motor threshold to l-DOPA treatment without modifying the magnitude or the pattern of the motor response to adenosinergic antagonism.
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PMID:Modulation of the motor response to dopaminergic drugs in a parkinsonian model of combined dopaminergic and noradrenergic degeneration. 1788 1

Parkinson's disease (PD) is characterized not only by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) but also by a degeneration of locus coeruleus (LC) noradrenergic neurons. It has been suggested that deficient LC noradrenergic mechanisms might play a critical role in symptomatology and in the progression of PD. However, the effect of LC depletion on levodopa-induced motor complications, such as the motor fluctuations, is still unknown. Male Sprague-Dawley rats received 50 mg/kg intraperitoneal (i.p.) of [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine] (DSP-4) or saline 7 days before the day of 6-hydroxydopamine (6-OHDA, 8 microg) administration in the medial forebrain bundle. Four weeks later, animals were treated with levodopa (25 mg/kg with benserazide, twice at day, i.p.) for 22 days. Rotational behavior was measured on days 1 and 22 of levodopa administration. Tyrosine hydroxylase (TH) immunohistochemistry was performed to evaluate the neurodegeneration in the SNc and LC. Striatal dopamine transporter (DAT) immunohistochemistry was performed to evaluate DA depletion. As expected, levodopa administration decreased the duration of the motor response in the vehicle-pretreated group (P < 0.01). A potentiation of levodopa-induced shortening in the duration of motor response was not achieved after LC depletion since no significant differences were observed in the duration of rotational behavior between these two groups on day 22. In addition, LC depletion did not potentiate either the total number of rotations or the maximal peak of rotation induced by levodopa treatment. These results suggest that LC depletion might not be involved in the pathophysiology of levodopa-induced motor fluctuations.
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PMID:Effect of locus coeruleus denervation on levodopa-induced motor fluctuations in hemiparkinsonian rats. 1852 30

A decrease in noradrenergic activity in Parkinson's disease might play a critical role in long-term motor complications associated with chronic dopaminergic replacement. Using the rat model of parkinsonism with an additional noradrenergic degeneration induced by the N-(-2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) toxin we evaluated whether the circling motor activity and dose-failure episodes induced by levodopa (L-DOPA) differ between single (6-OHDA) and double (6-OHDA + DSP-4) denervated animals challenged with a single daily dose of L-DOPA. While single-lesioned animals showed a sensitization-desensitization turning response with a significant increase on day 15 and a decrease on day 22, in double-lesioned animals, the turning activity was maximal from day 1 and did not decay on day 22. Double-lesioned rats exhibited significantly higher number of turns on days 15 and 22 and a significantly lower percentage of dose-failure episodes during treatment. Noradrenergic denervation appears to be associated with prolonged long-term dopaminergic sensitization. This type of response appears to be comparable to that in the clinical setting with intermittent L-DOPA administration where no desensitization occurs once the abnormal response is established.
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PMID:Noradrenergic modulation of the motor response induced by long-term levodopa administration in Parkinsonian rats. 1946 17

Parkinson's disease is a motor and cognitive disorder characterised by a progressive loss of the substantia nigra pars compacta (SNc) dopaminergic neurons as well as of the locus coeruleus (LC) noradrenergic neurons. It has been suggested that LC neurodegeneration might influence levodopa-induced motor disturbances and cognitive performance. We investigated the influence of dopaminergic and noradrenergic lesions on levodopa-induced dyskinesias and on working memory in rats. Two groups of animals were used: (1) rats with a dopaminergic lesion induced by a unilateral administration of the neurotoxin 6-hydroxydopamine (6-OHDA), and (2) rats with a combined lesion of the dopaminergic and noradrenergic systems induced by 6-OHDA and N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), respectively. Dyskinesias were evaluated on days 1, 8, 15 and 22 of chronic levodopa treatment (6 mg/kg, twice at day, i.p.). Working memory was evaluated by a radial-arm maze (1) before lesions, (2) before levodopa administration and (3) after 22 days of levodopa treatment. Total, axial, limb and orofacial dyskinesias not differed significantly between both groups. Working memory tasks worsened in both lesioned groups reaching significance in terms of time of performance (P < 0.05). The number of repeated entries in the same arm (errors) was only significant in the double-lesioned group (P < 0.05). This behaviour was not different from the one observed after chronic levodopa treatment. These results suggest that levodopa-induced dyskinesias in the 6-OHDA-lesioned rats were not affected by the additional noradrenergic lesion, whereas this last condition was sufficient to worse the cognitive performance deficit produced by the dopaminergic lesion.
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PMID:Effect of the additional noradrenergic neurodegeneration to 6-OHDA-lesioned rats in levodopa-induced dyskinesias and in cognitive disturbances. 1971 Sep 96

Parkinson's disease (PD) is characterized by a degeneration of dopaminergic neurons and also by a degradation of noradrenergic neurons from the locus coeruleus and serotonergic neurons from the dorsal raphe. However, the effect of these depletions on the neuronal activity of basal ganglia nuclei is still unknown. By using extracellular single-unit recordings, we have addressed this question by testing the effects of selective depletions of noradrenaline (NA) (with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4)) and serotonin (5-HT) (with 4-chloro-l-phenylalanine (pCPA)) on the neuronal activity of globus pallidus (GP) and substantia nigra pars reticulata (SNr) neurons in the 6-hydroxydopamine (6-OHDA) rat model of PD and sham-lesioned rats. We showed that 6-OHDA-induced dopamine (DA) depletion resulted in an increased number of GP and SNr neurons discharging in a bursty and irregular manner, confirming previous studies. These pattern changes were region-dependently influenced by additional monoamine depletion. Although the number of irregular and bursty neurons in 6-OHDA rats tended to decrease in the GP after NA depletion, it did not change after pCPA treatment in both GP and SNr. Furthermore, a significant interaction between DA and 5-HT depletions was observed on the firing rate of SNr neurons. By themselves, NA depletion did not change GP or SNr neuronal activity, whereas 5-HT depletion decreased the firing rate and increased the proportion of bursty and irregular neurons in both brain regions, suggesting that 5-HT, but not NA, plays a major role in the modulation of both the firing rate and patterns of GP and SNr neurons. Finally, our data suggest that, in addition to the primary role of DA in the control of basal ganglia activity, NA and 5-HT depletion also contribute to the dysregulation of the basal ganglia in PD by changes to neuronal firing patterns.
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PMID:Effects of noradrenaline and serotonin depletions on the neuronal activity of globus pallidus and substantia nigra pars reticulata in experimental parkinsonism. 2213 5

Research on Parkinson's disease (PD) has mainly focused on the degeneration of the dopaminergic neurons of nigro-striatal pathway; however, post-mortem studies have demonstrated that other brain regions such as the locus coeruleus (LC) and raphe nuclei (RN) are significantly affected as well. Degeneration of these crucial neuronal cell bodies may be responsible for depressive behavior and cognitive decline present in the pre-motor stage of PD. We have thus set out to create a pre-motor rodent model of PD which mimics the early stages of the condition. N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), a selective noradrenergic neurotoxin, and parachloroampetamine (pCA), a selective serotonergic neurotoxin, were utilized concomitantly with bilateral 6-hydroxydopamine (6-OHDA) injections into the striatum to produce a pre-motor rodent model of PD with partial deficits in the dopaminergic, noradrenergic, and serotonergic systems. Our model exhibited a depressive/anhedonic condition as assessed using sucrose preference testing and the forced swim test. Our model also demonstrated deficits in object memory. These behavioral impairments were accompanied by a decline in both tissue and extracellular levels of all three neurotransmitters in both the frontal cortex and striatum. Immunohistochemistry also revealed a decrease in TH+ cells in the LC and substantia nigra. Exendin-4 (EX-4), a glucagon-like peptide-1 receptor (GLP-1R) agonist, promoted recovery of both the biochemical and behavioral dysfunction exhibited by our model. EX-4 was able to preserve the functional integrity of the dopaminergic, noradrenergic, and serotonergic systems. In conclusion, we have generated a novel animal model of PD that recapitulates certain pre-motor symptomology. These symptoms and causative physiology are ameliorated upon treatment with EX-4 and thus it could be used as a possible therapy for the non-motor symptoms prominent in the early stages of PD.
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PMID:Exendin-4 reverses biochemical and behavioral deficits in a pre-motor rodent model of Parkinson's disease with combined noradrenergic and serotonergic lesions. 2386 74


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