Combined 5-HT1A and 5-HT1B receptor agonists for the treatment of L-DOPA-induced dyskinesia

Muñoz, Ana; Li, Qin; Gardoni, Fabrizio; Marcello, Elena; Qin, Chuan; Carlsson, Thomas; Kirik, Deniz; Luca, Monica Di; Björklund, Anders; Bézard, Erwan; Carta, Manolo

doi:10.1093/brain/awn235

Cited by 225 publications

(159 citation statements)

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“…In addition, treatment with a dopamine D 2 agonist or combination of L-Dopa with 5-HT 1A and 5-HT 1B agonists, which did not produce dyskinesias or reversed LIDs, also reversed the elevation of ΔFosB (Doucet et al, 1996;Munoz et al, 2008). These findings suggest that increased ΔFosB expression, in the striatonigral pathway (expressing SP/DYN neuropeptides), may be associated with the development of dyskinesia.…”

Section: Discussionmentioning

confidence: 75%

“…MPTP monkeys rendered parkinsonian displayed elevated amounts of ΔFosB-like proteins and chronic administration of L-Dopa or a selective D 1 agonist, which produced dyskinesias, induced a further elevation of ΔFosB-like immunoreactivity (Doucet et al, 1996;Munoz et al, 2008). In addition, treatment with a dopamine D 2 agonist or combination of L-Dopa with 5-HT 1A and 5-HT 1B agonists, which did not produce dyskinesias or reversed LIDs, also reversed the elevation of ΔFosB (Doucet et al, 1996;Munoz et al, 2008).…”

Section: Discussionmentioning

confidence: 93%

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Nur77 mRNA levels and L-Dopa-induced dyskinesias in MPTP monkeys treated with docosahexaenoic acid

Mahmoudi

Samadi

Gilbert

et al. 2009

Neurobiology of Disease

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We have previously shown that docosahexaenoic acid (DHA) significantly reduced L-Dopainduced dyskinesia (LID) in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys (Samadi et al., Ann. Neurol. 59:282-288, 2006). In the present study, we measured for the first time mRNA levels of Nur77, an orphan nuclear receptor that participates to adaptive and/or aberrant dopamine-related behaviors, and retinoid X receptor γ1 (RXRγ1), a putative brain receptor for DHA and transcriptional partner of Nur77, in MPTP monkeys treated with L-Dopa and DHA. The RXRγ1 mRNA is strongly expressed in monkey caudate nucleus and putamen, but no change in levels of RXRγ1 was observed following MPTP and L-Dopa treatments. On the other hand, denervation reduced Nur77 mRNA levels, whereas chronic L-Dopa treatment strongly induced Nur77 transcripts. These modulations are taking placed in substance P positive cells and are associated with both caudate-putamen matrix and striosome compartments. Interestingly, combination of L-Dopa with DHA further increases Nur77 mRNA levels in the anterior caudateputamen, and mainly in striosomes. This is accompanied by a significant inverse correlation between Nur77 mRNA levels and dyskinetic scores. Taken together, our results show that Nur77 expression is modulated following dopamine denervation and chronic L-Dopa therapy in a nonhuman primate model of Parkinson's disease, and suggest that strong modulation of Nur77 expression might be linked to a reduced risk to develop LIDs.

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Section: Discussionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 93%

Nur77 mRNA levels and L-Dopa-induced dyskinesias in MPTP monkeys treated with docosahexaenoic acid

Mahmoudi

Samadi

Gilbert

et al. 2009

Neurobiology of Disease

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“…However, in the absence of any autoregulatory control mechanisms, DA released from 5-HT terminals is likely to show excessive swings that may be particularly prone to induce dyskinesias. Therefore, it is likely that L-DOPA-derived DA, released as a "false transmitter" from 5-HT terminals, is the main trigger of the side-effect of dyskinesia (6,7).…”

Section: Introductionmentioning

confidence: 99%

Effect of Selective Serotonin Reuptake Inhibitors via 5-HT<SUB>1A</SUB> Receptors on L-DOPA-Induced Rotational Behavior in a Hemiparkinsonian Rat Model

et al. 2012

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Abstract. L-Dihydroxyphenylalanine (L-DOPA) is considered the gold standard for the treatment of Parkinson's disease (PD). However, long-term administration of L-DOPA can induce abnormal side effects. On the other hand, selective serotonin reuptake inhibitors (SSRIs) including fluoxetine have gained tremendous popularity in the treatment of depression in PD. SSRIs are thought to influence motor function in PD via pharmacological modification of interactions between serotonergic and dopaminergic networks, which are complex and not yet fully understand. In this study, intranigral injection of 6-hydroxydopamine (6-OHDA) in rats caused a significant loss of tyrosine hydroxylase immunoreactivity in the striatum and substantia nigra. However, tryptophan hydroxylase immunoreactivity of the striatum and raphe nucleus was unaffected by 6-OHDA. Immunohistochemical analysis reveal that the serotonergic system was unaffected by the injection of 6-OHDA. We demonstrated also that pre-treatment with fluoxetine significantly suppressed L-DOPA-induced rotational behavior. Additionally, fluoxetine suppressed L-DOPAinduced ERK1/2 and histone H3 phosphorylation. These effects of fluoxetine were abolished by pre-treatment with WAY 100135, a 5-HT 1A antagonist. These results suggest that fluoxetine may influence motor function in PD via pharmacological modification of interactions between serotonergic and dopaminergic neuronal networks.

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“…Serotonergic neurons are able to convert exogenous levodopa to DA and release it as a "false transmitter" giving symptom relief in PD patients (71)(72)(73)(74)(75) and may therefore play a role in the converting process of exogenous levodopa to DA. One theory is that the autoregulating function of the DA release is lacking in serotonergic neurons resulting in an un-controlled DA release after levodopa administration and thus causing LID (90)(91)(92). The serotonergic hyperinnervation and the dysregulated DA release in different areas of the brain could also be possible actors in the origination of some NMS in PD, for example impaired cognition, depression and anxiety (8,(93)(94)(95)(96)(97)(98)(99)(100).…”

Section: Discussionmentioning

confidence: 99%

“…Serotonergic neurons may therefore play a role in the converting process of exogenous levodopa to DA. One theory is that the autoregulating function of the DA release is lacking in serotonergic neurons resulting in an un-controlled DA release after levodopa administration resulting in pulsatile stimulation of the striatal postsynaptic dopaminergic receptors and thus causing LID (90)(91)(92). There are also several NMS in PD, for example impaired cognition, depression and anxiety (8,(93)(94)(95)(96)(97)(98) and the serotonergic hyperinnervation and the dysregulated DA release in different areas of the brain could be possible actors in the origination of some of them (93,99,100).…”

Section: Motor Complicationsmentioning

confidence: 99%

Levodopa pharmacokinetics -from stomach to brain : A study on patients with Parkinson’s disease

Nord¹

2017

Linköping University Medical Dissertations

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Parkinson’s disease (PD) is one of the most common neurodegenerative disorders and it is caused by a loss of dopamine (DA) producing neurons in the basal ganglia in the brain. The PD patient suffers from motor symptoms such as tremor, bradykinesia and rigidity and treatment with levodopa (LD), the precursor of DA, has positive effects on these symptoms. Several factors affect the availability of orally given LD. Gastric emptying (GE) is one factor and it has been shown to be delayed in PD patients resulting in impaired levodopa uptake. Different enzymes metabolize LD on its way from the gut to the brain resulting in less LD available in the brain and more side effects from the metabolites. By adding dopa decarboxylase inhibitors (carbidopa or benserazide) or COMT-inhibitors (e.g. entacapone) the bioavailability of LD increases significantly and more LD can pass the blood-brain-barrier and be converted to DA in the brain. It has been considered of importance to avoid high levodopa peaks in the brain because this seems to induce changes in postsynaptic dopaminergic neurons causing disabling motor complications in PD patients. More continuously given LD, e.g. duodenal or intravenous (IV) infusions, has been shown to improve these motor complications. Deep brain stimulation of the subthalamic nucleus (STN DBS) has also been proven to improve motor complications and to make it possible to reduce the LD dosage in PD patients. In this doctoral thesis the main purpose is to study the pharmacokinetics of LD in patients with PD and motor complications; in blood and subcutaneous tissue and study the effect of GE and PD stage on LD uptake and the effect of continuously given LD (CDS) on LD uptake and GE; in blood and cerebrospinal fluid (CSF) when adding the peripheral enzyme inhibitors entacapone and carbidopa to LD infusion IV; in brain during STN DBSand during oral or IV LD treatment. To conclude, LD uptake is more favorable in PD patients with less severe disease and GE is delayed in PD patients. No obvious relation between LD uptake and GE or between GE and PD stage is seen and CDS decreases the LD levels. Entacapone increases the maximal concentration of LD in blood and CSF. This is more evident with additional carbidopa and important to consider in avoiding high LD peaks in brain during PD treatment. LD in brain increases during both oral and IV LD treatment and the DA levels follows LD well indicating that PD patients still have capacity to metabolize LD to DA despite probable pronounced nigral degeneration. STN DBS seems to increase putaminal DA levels and together with IV LD treatment also increases LD in brain possibly explaining why it is possible to decrease LD medication after STN DBS surgery.Parkinsons sjukdom (PS) är en av de vanligaste s.k. neurodegenerativasjukdomarna och orsakas av förlust av dopamin(DA)producerande nervceller i hjärnan. Detta orsakar motoriska symptom såsom skakningar, stelhet och förlångsammade rörelser. Levodopa (LD) är ett ämne, som kan omvandlas till DA i hjärnan och ge symptomlindrin...

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Combined 5-HT1A and 5-HT1B receptor agonists for the treatment of L-DOPA-induced dyskinesia

Cited by 225 publications

References 56 publications

Nur77 mRNA levels and L-Dopa-induced dyskinesias in MPTP monkeys treated with docosahexaenoic acid

Nur77 mRNA levels and L-Dopa-induced dyskinesias in MPTP monkeys treated with docosahexaenoic acid

Effect of Selective Serotonin Reuptake Inhibitors via 5-HT<SUB>1A</SUB> Receptors on L-DOPA-Induced Rotational Behavior in a Hemiparkinsonian Rat Model

Levodopa pharmacokinetics -from stomach to brain : A study on patients with Parkinson’s disease

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