Levodopa Administration Research Articles

Modulation of l-DOPA's antiparkinsonian and dyskinetic effects by α2-noradrenergic receptors within the locus coeruleus

Long-term l-DOPA use for Parkinson's disease (PD) is frequently complicated by the emergence of a debilitating motor side effect known as l-DOPA-induced dyskinesia (LID). Accumulating evidence has implicated the norepinephrine (NE) system in the pathogenesis of LID. Here we used the unilateral 6-hydroxydopamine rat model of PD to determine the role of the α2-adrenoceptors (α2R) in l-DOPA's therapeutic and detrimental motor-inducing effects. First, we characterized the effects of systemic α2R stimulation with clonidine, or blockade with atipamezole, on LID using the rodent abnormal involuntary movements scale, and l-DOPA's therapeutic effects using the forepaw adjusting steps test and locomotor activity chambers. The anatomical locus of action of α2R in LID was investigated by directly infusing clonidine or atipamezole into the locus coeruleus prior to systemic l-DOPA administration. Results showed systemic clonidine treatment reduced LID and locomotor activity but did not interfere with l-DOPA's antiparkinsonian benefits. Conversely, systemic atipamezole pretreatment prolonged LID and locomotor activity but did not modulate l-DOPA's antiparkinsonian benefits. Intra-LC infusions of clonidine and atipamezole mirrored systemic effects where clonidine reduced, and atipamezole increased, LID. Collectively, these results demonstrate that α2R play an important modulatory role in l-DOPA-mediated behaviors and should be further investigated as a potential therapeutic target.

Deep-brain stimulation of human nucleus accumbens dynamically alters risky decision-making

s / Brain Stimulation 8 (2015) 378e394 390 Levodopa administration lengthened the leading time of PPN. It seems that the increase of dopamine levels may open another route, probable via basal ganglia, for the connection of the two nuclei and this lead to a longer duration for the cross talk to occur.

Chronic Salsolinol Administration Prevents the Behavioral and Neurochemical Effects of l-DOPA in Rats

1-Methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol) is a well-known endogenous compound that has been proposed as a factor involved in the pathogenesis of Parkinson’s disease. In the present study, we investigated the impact of acute and chronic salsolinol (100 mg.kg i.p.) administration on l-DOPA-induced locomotor hyperactivity and neurochemical changes (the dopamine level and its metabolism in rat brain structures). Moreover, using the in vivo microdialysis technique, we measured the effect of acute and chronic salsolinol injection on l-DOPA-induced dopamine release in the rat striatum. The behavioral data demonstrated that both acute and chronic salsolinol administration antagonized l-DOPA-mediated hyperactivity. An ex vivo neurochemical experiment indicated that chronic but not acute salsolinol administration partially inhibited the l-DOPA-induced increases in the concentration of dopamine and all of its metabolites in dopaminergic structures. Additionally, the in vivo dopamine release data obtained from the microdialysis experiments clearly indicated that the differences in the effect of salsolinol on the activities of l-DOPA depended on the mode of salsolinol treatment. Acute injection of salsolinol enhanced the l-DOPA-induced elevation of dopamine release (by ~1200 %; P < 0.01), whereas chronic administration of salsolinol completely blocked the l-DOPA-induced elevation of dopamine release in the rat striatum. These data demonstrated that chronic administration of salsolinol significantly impaired the response of dopaminergic neurons to l-DOPA administration. In conclusion, we propose that an elevated salsolinol level in parkinsonian patients may represent a serious risk factor of the clinical efficacy of l-DOPA therapy.

The NR2B antagonist, ifenprodil, corrects the l-DOPA-induced deficit of bilateral movement and reduces c-Fos expression in the subthalamic nucleus of hemiparkinsonian rats

The use of NR2B antagonists in Parkinsonism is still controversial. To examine their anti-parkinsonian effects, the NR2B antagonist, ifenprodil, and l-DOPA were administered together and separately in hemiparkinsonian rats (hemi-PD) that were subjected to a cylinder test. Recovery from hypoactivity was achieved by single administration of 3–7mg/kg of l-DOPA; however, improvement in the deficit of bilateral forelimb use was not observed. When administered alone, ifenprodil had no anti-parkinsonian effects; however, combined administration of ifenprodil and 7mg/kg of l-DOPA significantly reversed the deficit of bilateral forelimb use without adversely affecting the l-DOPA-induced improvement in motor activity. Next, in order to identify the brain area influenced by l-DOPA and ifenprodil, quantitative analysis of l-DOPA-induced c-Fos immunoreactivity was performed in various brain areas of hemi-PD following administration of l-DOPA with and without ifenprodil. Among brain areas with robust c-Fos expression within the motor loop circuit in dopamine-depleted hemispheres, co-administered ifenprodil markedly attenuated l-DOPA-induced c-Fos expression in only the subthalamic nucleus (STN), suggesting that the STN is the primary target for the anti-parkinsonian action of NR2B antagonists.

Molecular imaging of levodopa-induced dyskinesias.

Levodopa-induced dyskinesias (LIDs) occur in the majority of patients with Parkinson's disease (PD) following years of levodopa treatment. The pathophysiology underlying LIDs in PD is poorly understood, and current treatments generate only minor benefits for the patients. Studies with positron emission tomography (PET) molecular imaging have demonstrated that in advanced PD patients, levodopa administration induces sharp increases in striatal dopamine levels, which correlate with LIDs severity. Fluctuations in striatal dopamine levels could be the result of the attenuated buffering ability in the dopaminergically denervated striatum. Lines of evidence from PET studies indicate that serotonergic terminals could also be responsible for the development of LIDs in PD by aberrantly processing exogenous levodopa and by releasing dopamine in a dysregulated manner from the serotonergic terminals. Additionally, other downstream mechanisms involving glutamatergic, cannabinoid, opioid, cholinergic, adenosinergic, and noradrenergic systems may contribute in the development of LIDs. In this article, we review the findings from preclinical, clinical, and molecular imaging studies, which have contributed to our understanding the pathophysiology of LIDs in PD.

Beneficial antioxidant properties of betaine against oxidative stress mediated by levodopa/benserazide in the brain of rats.

The present study was designed to evaluate antioxidant effects of betaine in the brain following administration of levodopa and benserazide, which are routinely used in the treatment of Parkinson's disease. Sprague-Dawley male rats were divided into levodopa (LD), Betaine (Bet.), levodopa plus betaine (LD/Bet.), levodopa plus benserazide (LD/Ben.), levodopa plus betaine-benserazide (LD/Bet.-Ben.) and control groups. The experimental groups received LD 300mg/kg, Bet. 1.5% w/w of the total diet, Ben. 75mg/kg and distilled water to controls for 10 consecutive days, orally. The concentration of plasma total homocysteine significantly increased in LD/Ben.-treated rats when compared to the other groups. Brain glutathione peroxidase (GPx) activity and glutathione content both elevated with betaine treatment in LD/Bet. and LD/Bet.-Ben groups. Superoxide dismutase activity was also higher in controls and betaine-treated rats in comparison with LD and LD/Ben. groups. Likewise, catalase activity significantly increased in control and betaine groups when compared to LD- and LD/Ben.-treated rats. In contrast, brain lipid peroxidation significantly increased in response to LD and LD/Ben. Regarding metabolism of LD in peripheral tissues, serumic dopamine concentration significantly increased in LD-treated rats in comparison with LD/Ben. group. The present results show beneficial antioxidant and methyl donor properties of betaine versus oxidative stress and hyperhomocysteinemia induced by levodopa and benserazide in an animal model.

Short prolactin profile for monitoring treatment in BH4 deficiency

Tetrahydrobiopterin (BH4) deficiency causes hyperphenylalaninemia and impaired synthesis of serotonin and dopamine, leading to brain degeneration and early death if left untreated. Replacement therapy with neurotransmitters precursors is the cornerstone of treatment, relying on 5-hydroxytryptophan and l-dopa administration. Effective restoration of dopaminergic activity is thickened, like in Parkinson's disease, by the pulsatile pharmacokinetic profile of l-dopa. Monitoring of l-dopa therapy in BH4 deficiency is generally based upon clinical observation and periodical measurement of homovanillic acid (HVA) concentration in the cerebrospinal fluid (CSF). According to the finding that dopamine is the natural inhibitor of prolactin (PRL) incretion, we introduced the use of peripheral PRL measurement as an index of dopaminergic homeostasis, so avoiding the need of repeated lumbar punctures in patients with BH4 deficiency. As a single PRL evaluation can be misleading, due to the dependency of PRL fluctuations on l-dopa administration schedule, here we show that a short PRL profile is suitable for monitoring these patients. Together with the assessment of patients' clinical symptoms, this standardized tool will ensure an objective non-invasive reference to the management of dopaminergic replacement therapy in BH4 deficiency, even in patients treated with dopamine agonists.

Nitrosative and cognitive effects of chronic l-DOPA administration in rats with intra-nigral 6-OHDA lesion

Besides motor disturbances, other symptoms found in the early stage of Parkinson’s disease (PD) are deficits in both learning and memory. The nigro-striatal–cortical pathway is affected in this pathology, with this neuronal circuit involved in cognitive processes such as spatial working memory (SWM). However, cognitive dysfunction appears even when the patients are receiving l-DOPA treatment. There is evidence that the dopamine metabolism formed by l-DOPA generates free radicals such as nitric oxide, which may cause damage through the nitrosative stress (NS). The aim of this study was to evaluate both the effects of chronic l-DOPA administration on SWM and the production of NS in rats using an intra-nigral lesion caused by 6-hydroxydopamine (6-OHDA). Post-lesion, the animals were administered orally with l-DOPA/Carbidopa (100-mg/kg) for 20days. An SWM task in a Morris water maze was conducted post-treatment. Nitrite levels and immunoreactivity of 3-Nitrotyrosine (3-NT), Inducible Nitric Oxide Synthase (iNOS), Glial Fibrillary Acidic Protein (GFAP), and Tyrosine Hydroxylase (TH) were evaluated in the substantia nigra pars compacta, the dorsal striatum and the medial prefrontal cortex. Our results show that chronic l-DOPA administration in rats with intra-nigral 6-OHDA-lesion caused significant increases in SWM deficit, nitrite levels and the immunoreactivity of 3-NT, iNOS and GFAP in the nigro-striatal–cortical pathway. These facts suggest that as l-DOPA can induce NS in rats with dopaminergic intra-nigral lesion, it could play a key role in the impairment of the SWM, and thus can be considered as a toxic mechanism that induces cognitive deficit in PD patients.

Levodopa reverses cytokine-induced reductions in striatal dopamine release.

Background:Studies using neuroimaging and in vivo microdialysis in humans and nonhuman primates indicate that inflammatory cytokines such as interferon-alpha reduce dopamine release in the ventral striatum in association with depressive symptoms including anhedonia and psychomotor slowing.Methods:Herein, we examined whether reduced striatal dopamine release in rhesus monkeys chronically treated with interferon-alpha can be restored by administration of the dopamine precursor levodopa via reverse in vivo microdialysis.Results:Levodopa completely reversed interferon-alpha–induced reductions in striatal dopamine release. No changes were found in the 3,4-dihydroxyphenylacetic acid to dopamine ratio, which increases when unpackaged dopamine is metabolized via monoamine oxidase.Conclusions:These findings suggest that inflammatory cytokines reduce the availability of dopamine precursors without affecting end-product synthesis or vesicular packaging and/or release and provide the foundation for future studies investigating therapeutic strategies that facilitate availability of dopamine precursors to improve depressive symptoms in patient populations with increased inflammation.

Limitations of the use of the MP-RAGE to identify neural changes in the brain: recent cigarette smoking alters gray matter indices in the striatum.

Limitations of the use of the MP-RAGE to identify neural changes in the brain: recent cigarette smoking alters gray matter indices in the striatum.

Pharmacological profile of opicapone, a third-generation nitrocatechol catechol-O-methyl transferase inhibitor, in the rat.

Catechol-O-methyltransferase (COMT) is an important target in the levodopa treatment of Parkinson's disease; however, the inhibitors available have problems, and not all patients benefit from their efficacy. Opicapone was developed to overcome those limitations. In this study, opicapone's pharmacological properties were evaluated as well as its potential cytotoxic effects. The pharmacodynamic effects of opicapone were explored by evaluating rat COMT activity and levodopa pharmacokinetics, in the periphery through microdialysis and in whole brain. The potential cytotoxicity risk of opicapone was explored in human hepatocytes by assessing cellular ATP content and mitochondrial membrane potential. Opicapone inhibited rat peripheral COMT with ED50 values below 1.4 mg⋅kg(-1) up to 6 h post-administration. The effect was sustained over the first 8 h and by 24 h COMT had not returned to control values. A single administration of opicapone resulted in increased and sustained plasma levodopa levels with a concomitant reduction in 3-O-methyldopa from 2 h up to 24 h post-administration, while tolcapone produced significant effects only at 2 h post-administration. The effects of opicapone on brain catecholamines after levodopa administration were sustained up to 24 h post-administration. Opicapone was also the least potent compound in decreasing both the mitochondrial membrane potential and the ATP content in human primary hepatocytes after a 24 h incubation period. Opicapone has a prolonged inhibitory effect on peripheral COMT, which extends the bioavailability of levodopa, without inducing toxicity. Thus, it exhibits some improved properties compared to the currently available COMT inhibitors.

A proposal to prevent omissions and delays of antiparkinsonian drug administration in hospitals.

A prospective study carried out in the Netherlands showed that the most important risk factor for motor function deterioration in Parkinson's disease (PD) during hospital admission was medication error, including both incorrect timing of levodopa administration and prescription of contraindicated antidopaminergic drugs.1 Indeed, one of the reported reasons for omitting or delaying levodopa administration has been medication unavailability on time where needed, that is, in medical wards where the patient is admitted. Skelly et al in a recent study carried out in Derby Hospital (National Parkinson Foundation Centre of Excellence for Parkinson’s Disease) report that even in a ward specially designed to treat patients with PD, with an enhanced stock of anti-PD medications, 2.5% of all doses were not administered because the drug was not available on time.2 It is likely this problem is compounded in other nonspecialized wards and especially in smaller hospitals. To counteract this problem, Parkinson's United Kingdom “Get it on time campaign,”3 among others, has suggested that all commercially available antiparkinsonian drugs should be available in all hospital wards and on time. Given the data described previously, this seems unfeasible, especially in small hospitals where having available all the anti-PD drugs would certainly result in the expiration of many of these drugs before they are used. We think a possible solution can be found in Skelly et al’s reflections: “The available stock was not used as flexibly as we had hoped: e.g. doses of modified release medications were omitted rather than a temporary switch to available standard release drugs.”2 (p. 1246) We agree and propose a therapeutic interchange protocol (Figure 1) where the unavailable PD drug is first converted to the equivalent levodopa dose according to published dose equivalency.4 Then an immediate release levodopa dose could be administered until the original drug is available. Immediate release levodopa is cheap. Thus, having it in each hospital ward is a realistic approach. Figure 1. An example of applying the proposed protocol to prevent Parkinson’s disease (PD) drug omissions. It has to be kept in mind that dose equivalencies proposed by Tomlinson et al were developed to compare dose intensities of antiparkinsonian drugs in clinical trials rather than to use them in clinical practice and were catalogued by the authors as mere approximations. Paraphrasing Magdalinou et al5: “PD medications should be regarded as important as insulin is for diabetics.” (p. 540) Using short-acting insulin instead of the patient’s chronic insulin treatment is now routine clinical practice in hospitals. Although there may be some limitations to this approach, we think changing to an equivalent dose of immediate release levodopa could help to prevent PD drug omissions and delays.

Overexpression of blood microRNAs 103a, 30b, and 29a in L-dopa-treated patients with PD.

The aims of the present study were to profile the expression of several candidate microRNAs (miRNAs) in blood from L-dopa-treated and drug-naive patients with Parkinson disease (PD) vs unaffected controls and to interpret the miRNA expression data in a biological context. We analyzed RNAs from peripheral blood of 36 L-dopa-treated, 10 drug-naive patients with PD and unaffected controls matched 1:1 by sex and age. We evaluated expression by reverse transcription-quantitative real-time PCR, and we analyzed data using a 2-tailed paired t test. To detect miRNA targets, several miRNA resources were combined to generate an overall score for each candidate gene using weighted rank aggregation. Significant overexpression of miR-103a-3p (p < 0.0001), miR-30b-5p (p = 0.002), and miR-29a-3p (p = 0.005) in treated patients with PD was observed, and promising candidate target genes for these were revealed by an integrated in silico analysis. We revealed 3 candidate biomarkers for PD. miRNAs 30b-5p and 29a-3p replicated a documented deregulation in PD albeit opposite to published data, while for miR-103a-3p, we demonstrated for the first time an overexpression in treated patients with PD. Expression studies in patients and/or in isolated peripheral blood mononuclear cells before and after L-dopa administration are necessary to define the involvement of L-dopa treatment in the observed overexpression. Our in silico analysis to prioritize targets of deregulated miRNAs identified candidate target genes, including genes related to neurodegeneration and PD. Despite the preliminary character of our study, the results provide a rationale for further clarifying the role of the identified miRNAs in the pathogenesis of PD and for validating their diagnostic potential.

A simple and effective method for building inexpensive infrared equipment used to monitor animal locomotion

BackgroundInfrared (IR) technology is a flexible and effective way of measuring animal locomotion. However, the cost of most commercial IR equipment can limit their availability. We have designed an inexpensive and effective replacement for commercial IR sensors that can be attached to enclosures to monitor animal locomotion. New methodIR components were soldered to circuits connected to a single microcontroller. These IR components were housed inexpensively using plastic tubing and cork discs to further focus and extend detection of the IR beam. A standard personal computer recorded data from circuit boards connected to an inexpensive interface. This system may be used in a range of lighting conditions without requiring readjustment or recalibration. ResultsValidation of our equipment design was done with male Sprague Dawley rats treated with reserpine 22h prior to administration of saline or l-DOPA (125mg/kg). Data was collected in eight different measures: horizontal activity, immobile time, elevated activity, centre elevated activity, elevation time, elevation bout, and repeated and non-repeated movement while elevated. l-DOPA increased horizontal movement and all elevated activity excepting elevated movement and centre elevated movement, demonstrating selective drug effects. Comparison with existing methodsThe total cost of our complete IR system (US$517.45) was substantially less than the least expensive quote (US$19,666.90) obtained for a commercial IR system. ConclusionsWe have successfully designed and constructed a flexible and inexpensive IR system to monitor at least eight measures of rodent locomotion at a significantly lesser cost than quoted by commercial suppliers.

NR2B antagonist CP-101,606 inhibits NR2B phosphorylation at tyrosine-1472 and its interactions with Fyn in levodopa-induced dyskinesia rat model

The augmented tyrosine phosphorylation of NR2B subunit of N-methyl-d-aspartate receptors (NMDAR) dependent on Fyn kinase has been associated with levodopa (l-dopa)-induced dyskinesia (LID). CP-101,606, one selective NR2B subunit antagonist, can improve dyskinesia. Yet, the accurate action mechanism is less well understood. In the present study, the evidences were investigated. Valid 6-hydroxydopamine-lesioned parkinsonian rats were treated with l-dopa intraperitoneally for 22 days to induce LID rat model. On day 23, rats received either CP-101,606 (0.5mg/kg) or vehicle with each l-dopa dose. On the day of 1, 8, 15, 22, and 23 during l-dopa treatment, we determined abnormal involuntary movements (AIMs) in rats. The levels of NR2B phosphorylation at tyrosine-1472 (pNR2B-Tyr1472) and interactions of NR2B with Fyn in LID rat model were detected by immunoblotting and immunoprecipitation. Results showed that CP-101,606 attenuated l-dopa-induced AIMs. In agreement with behavioral analysis, CP-101,606 reduced the augmented pNR2B-Tyr1472 and its interactions with Fyn triggered during the l-dopa administration in the lesioned striatum of parkinsonian rats. Moreover, CP-101,606 also decreased the level of Ca2+/calmodulin-dependent protein kinase II at threonine-286 hyperphosphorylation (pCaMKII-Thr286), which was the downstream signaling amplification molecule of NMDAR overactivation and closely associated with LID. However, the protein level of NR2B and Fyn had no difference under the above conditions. These data indicate that the inhibition of the interactions of NR2B with Fyn and NR2B tyrosine phosphorylation may contribute to the CP-101,606-induced downregulation of NMDAR function and provide benefit for the therapy of LID.

The role of pallidal serotonergic function in Parkinson's disease dyskinesias: a positron emission tomography study

We have investigated the role of globus pallidus (GP) serotonergic terminals in the development of levodopa-induced dyskinesias (LIDs) in Parkinson's disease (PD). We studied 12 PD patients without LIDs, 12 PD patients with LIDs, and 12 healthy control subjects. We used 11C-DASB positron emission tomography (PET), a marker of serotonin transporter availability, and 11C-raclopride PET to measure changes in synaptic dopamine levels following levodopa administration. PD patients without LIDs showed a significant reduction of GP serotonin transporter binding compared with healthy controls although this was within the normal range in PD patients with LIDs. Levels of GP serotonin transporter binding correlated positively with severity of dyskinesias. 11C-raclopride PET detected a significant rise in GP synaptic dopamine levels of patients with LIDs after a levodopa challenge but not in patients with a stable response. Our findings indicate that LIDs in PD are associated with higher GP serotonergic function. This increased serotonin function may result in further dysregulation of thalamocortical signals and so promote the expression of dyskinesias.

CSF tau and tau/Aβ42 predict cognitive decline in Parkinson's disease.

A substantial proportion of patients with Parkinson's disease (PD) have concomitant cognitive dysfunction. Identification of biomarker profiles that predict which PD patients have a greater likelihood for progression of cognitive symptoms is pressingly needed for future treatment and prevention approaches. Subjects were drawn from the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) study, a large clinical trial that enrolled initially untreated PD patients. For the current study, Phase One encompassed trial baseline until just prior to levodopa administration (n = 403), and Phase Two spanned the initiation of levodopa treatment until the end of cognitive follow-up (n = 305). Correlations and linear mixed models were performed to determine cross-sectional and longitudinal associations between baseline amyloid β1-42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF) and measures of memory and executive function. Analyses also considered APOE genotype and tremor- vs. rigidity-dominant phenotype. No association was found between baseline CSF biomarkers and cognitive test performance during Phase One. However, once levodopa treatment was initiated, higher p-tau and p-tau/Aβ42 predicted subsequent decline on cognitive tasks involving both memory and executive functions. The interactions between biomarkers and cognition decline did not appear to be influenced by levodopa dosage, APOE genotype or motor phenotype. The current study has, for the first time, demonstrated the possible involvement of tau species, whose gene (MAPT) has been consistently linked to the risk of PD by genome-wide association studies, in the progression of cognitive symptoms in PD.

Growth hormone responses to provocative tests in children with short stature.

Growth hormone deficiency (GHD) is defined as a serum peak GH concentration <10 ng/mL with provocation as tested by a combination of at least two separate tests. The aim of this study was to compare two standard tests, insulin and levodopa (L-dopa), with a primary focus on specificity and accuracy. Clinical data were collected retrospectively from a review of 120 children who visited the pediatric endocrine clinic at Chonnam National University Hospital for the evaluation of short stature between January 2006 and April 2014. Subjects underwent GH provocation tests with insulin and L-dopa. Blood samples were obtained at 0, 15, 30, 45, 60, 90, and 120 min after administration, and GH levels were measured. In the insulin test, serial glucose levels were also checked, closely monitoring hypoglycemia. A total of 83 children (69.2%) were diagnosed with GHD and 37 children (30.8%) were diagnosed with idiopathic short stature (ISS). Peak GH levels were achieved an average of 45 min after the administration of insulin and L-dopa for both groups. The specificity and accuracy were 78.4% and 93.6% for the insulin test and 29.7% and 79.2% for L-dopa test, respectively. In the ISS group, the cumulative frequency of a GH cutoff value of >10 ng/mL at 120 min was 75.6% after insulin stimulation compared with 35.1% after L-dopa stimulation. Considering these results, we recommend performing the insulin test first to exclude ISS and then the L-dopa test for the diagnosis of GHD. This way, ISS patients are diagnosed after a single test, thus reducing hospital days and the burden of undergoing two serial tests.

Gene therapy in Parkinson's disease: targeting the endplasmic reticulum proteostasis network.

Parkinson's disease (PD) is the second most common neurodegenerative disease affecting 1% of the population over 60 years of age. The progressive degeneration of dopaminergic neurons at the substantia nigra pars compacta (SNpc) results in a severe and gradual depletion of dopamine content in the striatum, a phenomena that is responsible for the characteristic motor symptoms of this disease. There is no cure for PD and available treatments only aim to restore dopamine deficits. Administration of the dopamine precursor Levodopa (L-DOPA) is the main temporal palliative treatment that increases overall dopamine levels. However, its chronic use limits its effectiveness and generates a number of adverse effects such as debilitating dyskinesia.

Cortical plasticity in patients with Parkinson's disease a window for therapeutic non-invasive neuromodulation.

Several evidences in animal models have consistently an alteration of cortico-striatal plasticity, which is related to the degeneration of the substantia nigra. An alteration of plasticity have also been reported in humans by recording evoked field potentials in the substantia nigra pars reticulata of PD patients undergoing subthalamic nucleus (STN) stimulation where high-frequency (HF) in the OFF state did not induce a lasting change in field potential amplitude in the substantia nigra. In addition protocols of non-invasive brain stimulation, such as paired associative stimulation (PAS) and theta-burst stimulation (TBS), can be used to investigate cortical plasticity of the human primary motor cortex. Despite data reported in literature are apparently controversial with some studies showing a reduced or increased or even normal LTP and LTD like plasticity, recent evidences suggest the hypothesis that these different pat- terns of cortical plasticity likely depend on the stage of the disease and on the concomitant administration of L-DOPA. The current review will provide an up-to-date of these issues on cortical plasticity in PD discussing the clinical implications in rehabilitation. In addition in the last section we will review the state of art of non invasive neuro- modulation as adjuvant treatment in the advanced stage of the disease.