Wearing‐off fluctuations in Parkinson's disease: Contribution of postsynaptic mechanisms

Bravi, Daniele; Mouradian, M. Maral; Roberts, John W.; Davis, Thomas L.; Sohn, Y.H.; Chase, T. N.

doi:10.1002/ana.410360108

Cited by 148 publications

(59 citation statements)

References 15 publications

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“…One hypothesis is that they are primarily caused by postsynaptic alterations in receptor density or sensitivity (Bravi et al, 1994;Verhagen Metman et al, 1997;Zigmond et al, 1990). However, some recent studies suggest that changes in presynaptic autoregulatory function may accompany disease progression and that these changes may contribute to the development of altered therapeutic response (Ekesbo et al, 1999;Tedroff et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Apomorphine-Induced Changes in Synaptic Dopamine Levels: Positron Emission Tomography Evidence for Presynaptic Inhibition

Fuente‐Fernández

Lim

Sossi

et al. 2001

J Cereb Blood Flow Metab

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Summary:The authors developed a novel positron emission tomography method to estimate changes in the synaptic level of dopamine ([DA]) induced by direct dopamine agonists (for example, apomorphine) in patients with Parkinson disease. The method is based on the typical asymmetry of the nigrostriatal lesion that often occurs in Parkinson disease. Using the between-side difference (ipsilateral (I) and contralateral (C) putamen to the more affected body side) of the inverse of the putamen [ 11 C]raclopride binding potential (BP), the authors obtainedat baseline (that is, before apomorphine administration) andafter apomorphine administration (assuming the concentration of apomorphine is equal in both putamina). The between-side difference in the estimated synaptic concentration of dopamine (diff [DA]) should remain constant unless apomorphine affects dopamine release differently between the two sides. The authors found that apomorphine given subcutaneously at doses of 0.03 and 0.06 mg/kg induced significant changes in their estimate of diff[DA] (P < 0.05). Such changes were more pronounced when only patients with a stable response to levodopa were considered (P < 0.01). These findings provide in vivo evidence that direct dopamine agonists can inhibit the release of endogenous dopamine. The authors propose that this effect is mainly mediated by the activation of presynaptic D 2 /D 3 dopamine receptors. Key Words: Dopamine release-Motor complications-Parkinson disease-Presynaptic inhibition-PET-Raclopride.The progression of Parkinson disease (PD) is invariably accompanied by changes in the therapeutic response to levodopa (Marsden and Parkes, 1976) and to dopamine agonists such as apomorphine (Verhagen Metman et al., 1997). In the case of apomorphine, such changes include a shortened response duration, a steeper doseresponse curve, and a narrower therapeutic window (Verhagen Metman et al., 1997).The physiologic alterations underlying these changes have been the subject of some studies. One hypothesis is that they are primarily caused by postsynaptic alterations in receptor density or sensitivity (Bravi et al., 1994;Verhagen Metman et al., 1997;Zigmond et al., 1990). However, some recent studies suggest that changes in presynaptic autoregulatory function may accompany disease progression and that these changes may contribute to the development of altered therapeutic response (Ekesbo et al., 1999;Tedroff et al., 1996). These studies were based on the idea that dopamine synthesis, storage, and release are "autoregulated" in such a way as to maintain the synaptic concentration of dopamine. There is substantial evidence for this autoregulation and for its mediation by dopamine receptors. For 1151instance, in studies of the nigrostriatal system in various species, dopamine agonists have been shown to negatively regulate tyrosine hydroxylase activity (Cho et al., 1997), aromatic amino acid decarboxylase activity (Hadjiconstantinou et al., 1993), electrical firing (Bunney et al., 1973), and cerebrospinal fluid dopamine levels...

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Section: Discussionmentioning

confidence: 99%

Apomorphine-Induced Changes in Synaptic Dopamine Levels: Positron Emission Tomography Evidence for Presynaptic Inhibition

Fuente‐Fernández

Lim

Sossi

et al. 2001

J Cereb Blood Flow Metab

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“…PD is a progressive disorder of the nervous system that is characterized by a deficiency of the neurotransmitter dopamine and degeneration of presynaptic dopaminergic terminals (Bravi et al, 1994). The disease manifests by tremor, muscular rigidity, and slow, imprecise movement, changes in speech and gait and mainly affects middle-aged and elderly people.…”

Section: Parkinson's Disease (Pd)mentioning

confidence: 99%

“…The main current therapy is levodopa. Patients, however, experience a progressive shortening of its antiparkinsonian action (wearing-off) as a function of presynaptic degeneration (Bravi et al, 1994). As MAO is responsible inter-alia for the degradation of dopamine and both subtypes of MAO recognize dopamine as substrate, MAO inhibitors have been investigated as an approach to lessening the wearing-off phenomena (Sternic et al, 1998;Shapira, 2011).…”

Section: Parkinson's Disease (Pd)mentioning

confidence: 99%

Monoamine Oxidase Inhibitors—Revisiting a Therapeutic Principle

Entzeroth¹,

Ratty²

2017

OJD

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Over more than 60 years, monoamine oxidase (MAO) inhibitors are available for therapy of central nervous diseases. Although they have shown to be efficacious specifically in the treatment of major depressive disorders and treatment-resistant depression, they became less a therapeutic choice for the physicians mostly due to severe side effects, such as liver failure and hypertensive crisis associated specifically with the first generation of inhibitors. Nevertheless, this class of drugs is still being used for treatment specifically as more selective and reversible inhibitors became available and will provide clinicians with additional treatment options. The current review revisits monoamine oxidase inhibitors and their potential in the treatment of human diseases, such as anxiety, depression, mood and personality disorders, and pain and introduces current ideas and developments.

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“…50 % of PD patients the first year of levodopa treatment and in 100 % of the patients within 5 years (78), is thought to be caused by the progressive loss of dopaminergic presynaptic terminals in the SN resulting in a reduced ability to buffer the shifts in levodopa concentration due to intermittent oral administration of levodopa (79,80). However, PD patients treated with apomorphine and other DA agonists, that are not stored in dopaminergic terminals, also suffer from wearing off (81). This indicates that postsynaptic mechanisms might be involved in the wearing off phenomenon (82,83).…”

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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Wearing‐off fluctuations in Parkinson's disease: Contribution of postsynaptic mechanisms

Cited by 148 publications

References 15 publications

Apomorphine-Induced Changes in Synaptic Dopamine Levels: Positron Emission Tomography Evidence for Presynaptic Inhibition

Apomorphine-Induced Changes in Synaptic Dopamine Levels: Positron Emission Tomography Evidence for Presynaptic Inhibition

Monoamine Oxidase Inhibitors—Revisiting a Therapeutic Principle

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

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