Action Of Levodopa Research Articles

DFT and QSAR study of Catechol-O-methyltransferase (COMT) as inhibitors for Parkinson’s disease treatment

Parkinson’s disease is characterized by a lack of the neurotransmitter or cell-signaling molecule dopamine. Levodopa is a well-known drug for Parkinson’s disease since it induces dopamine. Catechol-O-methyltransferase (COMT) are enzymes that break down levodopa, limiting the amount delivered to the brain. COMT inhibitors act by extending the duration of action of levodopa, thus improving the amount of time benefit from levodopa. There are several FDA-approved COMT inhibitors used, such as Entacapone and Tolcapone. Tolcapone can penetrate blood-brain barrier (BBB), but most of the drug stays in the plasma because its high protein bound, and it has severe side effects, while Entacapone cannot penetrate BBB, which reduces drug efficiency. This study aims to design higher-efficiency drug inhibitors by investigating the physical properties in terms of total energy, total dipole moment and HOMO/LUMO band gap at DFT: B3LYP level using the LAN2DZ basis set, in addition to quantitative structure activity relationship (QSAR) calculations to test the biological activity of these drug inhibitors for the treatment of Parkinson’s disease.

The use of L-dopa induces the resistance of Mauthner neurons to the neurotoxic action of beta-amyloid

BACKGROUND: Mauthner goldfish (Carassius auratus (L)) cells serve as model objects for studying brain pathologies at the level of identified neurons and their individual dendrites. L-dopa may be an agent that decelerates the destruction of neurons caused by the toxic effects of beta-amyloid.
 AIMS: To study the three-dimensional structure of Mauthner neurons in goldfish and the ultrastructure of their afferent synapses under the influence of L-dopa and the toxic 2535 fragment of beta-amyloid.
 MATERIAL AND METHODS: This study was performed on the Mauthner neurons of goldfish fry (n=12) by using light and electron microscopy. Serial sections 3 m thick were used to identify and integrally reconstruct the structure of Mauthner neurons; determine the volume of the soma and ventral and lateral dendrites; and study the structure of afferent synapses.
 RESULTS: The use of L-dopa stabilized the size of the soma and ventral dendrites. The reduction in the volume of lateral dendrites was accompanied either by an increase in the volume of their branches under the action of beta-amyloid followed by that of L-dopa or by an increase in the volume of medial dendrites under the action of L-dopa followed by that of beta-amyloid. Although pathological changes in the ultrastructure of neurons and afferent synapses were not found, signs of early amyloidosis were detected.
 CONCLUSION: The use of L-dopa decelerates the degeneration of Mauthner neurons. The resistance of whole neurons to the neurotoxic action of beta-amyloid has been suggested to be due to the mechanism of structural homeostasis aiming at the compensatory restoration of the morphological organization of neurons.

Can we add whey protein supplementation in patients with Parkinson’s disease without interfering with levodopa response?

Objective The main endpoint of the study was to evaluate if a daily intake of whey protein-based dietary supplement causes a worse response to levodopa in people with Parkinson’s Disease (PWPD) Background In PWPD, the competition between large neutral aminoacids and levodopa at intestinal absorption level may interfere with dopaminergic therapy’s (DRT) effect; therefore, protein redistribution dietary regimen has been suggested. Many dietary supplementations are available to help people in balancing the protein intake and overcoming muscle mass loss. However, most of the products contain protein and could potentially affect levodopa action in PWPD. Methods We performed a randomised single blind monocentric study on PWPD admitted in the rehabilitative unit for a 4-week multidisciplined intensive aerobic rehabilitation treatment. All patients received a standard protein redistribution dietary regimen plus a whey protein-based oral formula (N = 26) or Magnesium (N = 25) twice daily for 28 days. Neurological assessment and physical evaluation were conducted before (T0) and after (T1) rehabilitative treatment; DRT was recorded T0 and T1 as well. The delta of changes within groups in neurological (UPDRS III) and physical (TUG, 6 MW) evaluation scales was compared between groups. Results Groups were comparable at baseline in clinical and demographic data; at T1, both groups showed a decrease in UPDRS III, TUG and 6 MWT and no differences between deltas were found. DRT remained stable in both groups. Conclusions Our results show that whey protein supplementation does not interfere with DRT’s efficacy and can be used in PWPD who need a protein supplementation without restrictions in intake hours.

Effect of Tramadol on Corticosteroid Receptor Function in patients with Major Depression

IntroductionIt is important to study the corticosteroid receptors hypothesis of Depression.ObjectivesThe goal of current study was - to test the influence of the opioid, adrenergic and benzodiazepine drugs on the immunosuppressive levels of leukocyte pyruvat dehydrogenase activity (LPDG) during the DST in patients with Major Depression and Anxiety Disorder.MethodsPatients. 40 male/ mean age, 33,1+3,2 years/ and 20 premenopausal female /35,1+1,6 years/ patients with Primary Major Depressive Episode were studied. All patients were diagnosed by a psychologist and fulfilled DSM- IV criteria for Major Depressive Episode. The DST was conducted to 60 patients with Primary Depressive Episode and 30 healthy subjectsResultsIn the cases of Primary Major Depressive Episode in separation with an Anxiety Disorder after TRAMADOL and DIASEPAM administration activity of LPDG increased more than 25%. Tramadol of a 50 mg dose and Diasepam of a 10 mg dose had a higher immunosuppressive effect than L-DOPA (0,5 g) on alteration of LPDG activity (more than 5 mmol/l/hour, p <0,05/.ConclusionsTRAMADOL immunosuppresssive action was higher than L-DOPA and DIASEPAM on LPDG activity in patients with an Anxiety Disorder and Major Depression. Diasepam immunosuppressive action did not correlate with positive dynamics of LPDG levels of DST in patients with Anxiety Disorder (after the 4-5 th week of Diasepam treatment). From other side, mechanism of L-DOPA action on corticosteroid receptors stimulated LPDG-activity (L-DOPA therapeutic effective dose-3 g). It means that opiate, adrenergic and benzodiazepine receptors are interactiing with each other and influencing on the corticosteroid receptors in different ways during immunosuppression.DisclosureNo significant relationships.

Fine-tuning role of L-DOPA and its receptor GPR143 for dopamine D2 receptor in the striatal indirect pathway

Levodopa (L-DOPA) therapy is the gold standard for the treatment with Parkinson's disease. The pharmacological actions of L-DOPA have been believed to be mediated through its conversion to dopamine. On the contrary, we propose that L-DOPA is a neurotransmitter. We identified G-protein coupled receptor (GPCR) GPR143, a gene product of ocular albinism-1, as a receptor for L-DOPA. In the course of our phenotypic analysis of Gpr143 gene-deficient (Gpr143-/y) mice, we found that behavioral response to quinpirole, a dopamine D2 receptor (D2R) agonist, was attenuated in Gpr143-/y mice when compared to wild type (WT) mice. This phenotype was also observed in the striatal indirect pathway specific Gpr143 gene-deficient (A2A-cre;Gpr143flox/y) mice. To investigate the physiological role of GPR143, we performed anxiety behavior using zero maze test. The anxiety behavior was attenuated in Gpr143-/y and A2A-cre;Gpr143flox/y mice when compared to corresponding control animals, as was reported in the striatal indirect pathway specific D2R deficient mice. These results suggest that L-DOPA-GPR143 fine-tunes the dopamine D2R in the striatal indirect pathway.

Striatal ΔFosB gene suppression inhibits the development of abnormal involuntary movements induced by L-Dopa in rats.

L-Dopa-induced dyskinesia (LID) is associated with upregulation of striatal ΔFosB in animal models and patients with Parkinson’s disease (PD). A mechanistic role of ΔFosB is suspected because its transgenic overexpression leads to early appearance of LID in rodents and primates. The present study in rodents is aimed at exploring the therapeutic potential of striatal ΔFosB gene suppression to control LID in patients with PD. To determine the effect of reducing striatal ΔFosB expression, we used RNAi gene knockdown in a rat model of PD and assessed abnormal involuntary movements (AIMs) in response to L-Dopa. Rats with dopamine depletion received striatal injections of rAAV-ΔFosB shRNA or a control virus before exposure to chronic L-Dopa treatment. Development of AIMs during the entire L-Dopa treatment period was markedly inhibited by ΔFosB gene knockdown and its associated molecular changes. The antiparkinsonian action of L-Dopa was unchanged by ΔFosB gene knockdown. These results suggest a major role for ΔFosB in the development of LID, and support exploring strategies to reduce striatal ΔFosB levels in patients with PD.

Combined 5-HT2A and mGlu2 modulation for the treatment of dyskinesia and psychosis in Parkinson's disease

Antagonising the serotonin 2A (5-HT2A) receptor is an efficacious way to alleviate dyskinesia and psychosis in Parkinson's disease (PD). However, previous research indicates that there might be a limit to the effects conferred by this approach. 5-HT2A receptors were shown to form hetero-dimers with metabotropic glutamate 2 (mGlu2) receptors, in which 5-HT2A blockade and mGlu2 activation elicit equivalent effects at the downstream signalling level. We have previously shown that mGlu2 activation reduces both dyskinesia and psychosis-like behaviours (PLBs) induced by L-3,4-dihydroxyphenylalanine (l-DOPA), in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primate. Here, we hypothesised that concurrent 5-HT2A antagonism and mGlu2 activation would provide greater anti-dyskinetic and anti-psychotic benefits than either approach alone. We conducted 3 series of experiments in the MPTP-lesioned marmoset. In the first series of experiments, the mGlu2 positive allosteric modulator LY-487,379 and the 5-HT2A antagonist EMD-281,014, either alone or in combination, were added to l-DOPA. In the second series of experiments, the mGlu2/3 orthosteric agonist LY-354,740 and EMD-281,014, either alone or in combination, were added to l-DOPA. In the last series of experiments, we investigated whether mGlu2 blockade would diminish the effects of antagonising 5-HT2A receptors. To this end, the mGlu2/3 orthosteric antagonist LY-341,495 and EMD-281,014, either alone or in combination, were added to l-DOPA. We found that the anti-dyskinetic effect of the combination LY-487,379/EMD-281,014 was greater than the ones conferred by LY-487,379 (by 35%, P < 0.05) and EMD-281,014 (by 38%, P < 0.01). The anti-dyskinetic and anti-psychotic effects of the combination LY-354,740/EMD-281,014 were also greater than the ones conferred by LY-354,740 (by 57% for dyskinesia and 54% for PLBs, both P < 0.001) and EMD-281,014 (by 61% for dyskinesia and 53% for PLBs, both P < 0.001). The anti-parkinsonian action of l-DOPA was maintained with all treatments. Lastly, the addition of LY-341,495 abolished the therapeutic effects of EMD-281,014 on dyskinesia and PLBs. Our results suggest that mGlu2 activation may enhance the anti-dyskinetic and anti-psychotic effects of 5-HT2A blockade and could provide relief to PD patients with dyskinesia and psychotic symptoms beyond what can be achieved with current therapies.

The presence, release and actions of L-DOPA

The presence, release and actions of L-DOPA

Когнитивные флуктуации на фоне терапии у пациентов с болезнью Паркинсона

The aim of the research is the assessment of cognitive status dynamics during levodopa pharmacotherapy. Material and methods. A new approach was created to assess cognitive status in patients with PD. It allows diagnosing cognitive fluctuations at an early stage at the highest quality level as well as to correct the disorders rationally and timely. The patients were randomized into two groups. In group 1 (n = 25), the assessment of cognitive status was carried out at the “peak” dose of levodopa and in 6 months at the state of levodopa dose “outcome”. In group 2 (n = 25), respectively, on the contrary, the initial assessment of cognitive status was carried out at the “outcome” of levodopa dose and in 6 months later at the “peak”. The study groups were comparable in terms of such parameters as: age, gender, average duration and stage of disease. On average, all the participants by the study time were at 2.5 stage of the disease according to Hoehn and Yahr scale; and the average length of the disease was 5 years. Results. Th e following statistically signifi cant results were obtained: in the fi rst group (peak–outcome) the average values on MMSE scale at the “peak” were 27 points; at the “outcome” they were – 25; MOCA values were 25 and 22 points, respectively; on FAB scale the values were – 16 and 14.5 points, SCOPA-Cog values were 33 and 28 points. In the second group (outcome – peak), the average values on MMSE scale at the “outcome” were 27, at the “peak” – 28, on MOCA scale – 23 and 25.5, respectively, on FAB scale – 16 and 17.5, SCOPA–Cog – 30 and 33. Conclusion. The present study confi rms that cognitive status of patient associated with antiparkinsonian therapy changes depending on the peak of levodopa and its outcome. At the peak of levodopa action, patients show signifi cantly better results on scaling, and at the end of the day, they demonstrate more significant cognitive impairments. A new two-stage method for assessing CF allows diagnosing cognitive impairments at a better level. Such method is necessary for timely initiation of therapy and rational correction of antiparkinsonian treatment.

Selective blockade of the 5-HT3 receptor acutely alleviates dyskinesia and psychosis in the parkinsonian marmoset

In Parkinson's disease (PD), management of L-3,4-dihydroxyphenylalanine (l-DOPA)-related complications, such as l-DOPA induced dyskinesia and psychosis, remains inadequate, which poses a significant burden on the quality of life of patients. We have shown, in the hemi-parkinsonian rat model of PD, that the selective serotonin type 3 (5-HT3) receptor antagonists ondansetron and granisetron decreased the severity of established dyskinesia, and ondansetron even attenuated the development of dyskinesia. Here, we seek to confirm these favourable data on dyskinesia and to explore the effect of ondansetron on the severity of psychosis-like behaviours (PLBs) in the gold standard model of PD, the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned non-human primate. We first determined the pharmacokinetic profile of ondansetron in the marmoset. Subsequently, six MPTP-lesioned marmosets were administered l-DOPA chronically until they exhibited stable and reproducible dyskinesia and PLBs upon each administration of l-DOPA. On behavioural assessment days, ondansetron (0.01, 0.1 and 1 mg/kg) or vehicle was administered in conjunction with l-DOPA, and the severity of dyskinesia, PLBs and parkinsonism was evaluated. Ondansetron 0.1 mg/kg alleviated global dyskinesia severity by 73% (P < 0.0001) and decreased duration of on-time with disabling dyskinesia by 88% (P = 0.0491). Ondansetron 0.1 mg/kg reduced the severity of global PLBs by 80% (P < 0.0001) and suppressed on-time with disabling PLBs (P = 0.0213). Ondansetron enhanced the anti-parkinsonian action of l-DOPA, reducing global parkinsonism by 53% compared to l-DOPA (P = 0.0004). These results suggest that selective blockade of the 5-HT3 receptor with ondansetron may be an effective approach to alleviate l-DOPA-related complications.

Фармакокинетика леводопы и персонифицированная терапия болезни Паркинсона

The article provides a review of the pharmacokinetics of levodopa and personalized therapy for Parkinson’s disease. We analyzed the methods used to prolong the action of levodopa using peripheral inhibitors of DOPA decarboxylase, catechol-O-methyltransferase inhibitors, and monoamine oxidase type B inhibitors. The influence of levodopa metabolites with their own biological activity in the possible progression of the disease is emphasized. The role of determining the concentration of levodopa in blood plasma is discussed, as well as the concept of «continuous dopamine stimulation» for the prevention and treatment of side effects of long-term levodopa therapy, such as drug dyskinesias, motor and non-motor fluctuations. The article also provides an overview of the modern forms of levodopa that are currently being investigated.

Striatal overexpression of β-arrestin2 counteracts L-dopa-induced dyskinesia in 6-hydroxydopamine lesioned Parkinson's disease rats

Prolonged administration of Levodopa (L-dopa) therapy can generate L-dopa–induced dyskinesia (LID). Accumulating evidence indicates that hyper-activation of the dopamine D1 receptor (D1R) and the cAMP signaling cascade in the medium spiny neurons (MSNs) of the striatum are involved in LID. Previous studies have shown that striatal β-arrestin2 overexpression significantly reduces LID severity and have indicated that β-arrestin2 may play a causal role in the dyskinesia sensitization process. L-dopa-induced changes in the expression of signaling molecules and other proteins in the striatum were examined immunohistochemically and by western blot. A rAAV (recombinant adeno-associated virus) vector was used to overexpress and ablate β-arrestin2. We found that striatal overexpression of AAV-mediated β-arrestin2 produced less severe AIMs (abnormal involuntary movements) in response to L-dopa, whereas selective deletion of β-arrestin2 in the striatal neurons dramatically enhanced the severity of dyskinesia induced by L-dopa. Furthermore, no significant improvements in motor behavior (FFT: forelimb functional test) were seen with the inhibition or overexpression of β-arrestin2. Finally, overexpression of β-arrestin2 diminished L-dopa-induced D1R and phosphor-DARPP32/ERK levels. Viral deletion of β-arrestin2 markedly enhanced the key biochemical markers in the direct pathway. We found that increased availability of β-arrestin2 ameliorated dyskinesia severity with no influence on the anti-Parkinsonian action of L-dopa, suggesting a promising approach for controlling LID in Parkinson's disease. In addition, overexpression of β-Arrestin2 prevented the development of LID by inhibiting G protein-dependent D1R and phosphor-DARPP32/ERK signaling in dyskinetic rats.

Comparison of Actions between L-DOPA and Different Dopamine Agonists in Striatal DA-Depleted Microcircuits In Vitro: Pre-Clinical Insights

Parkinson's disease (PD) is a neurodegenerative illness presenting motor and non-motor symptoms due to the loss of dopaminergic terminals in basal ganglia, most importantly, the striatum. L-DOPA relieves many motor signs. Unfortunately, in the long term, L-DOPA use causes motor disabilities by itself and does not act in comorbid conditions such as depression. These deficiencies have led to search for drugs such as dopamine (DA) receptor agonists (DA-agonists) that allow the reduction of L-DOPA dose. Previously, we have identified the attributes of non-stimulated (resting) and cortical stimulated (active) striatal microcircuits following the activity of dozens of neurons simultaneously using calcium imaging in brain slices. We also have characterized the changes that take place in DA-depleted microcircuits in vitro. In control conditions, there is low spontaneous activity. After cortical stimulation (CtxS) sequences and alternation of neuronal ensembles activity occur, including reverberations. In contrast, DA-deprived circuits exhibit high spontaneous activity at rest, and a highly recurrent ensemble curtails alternation. Interestingly, CtxS briefly relieves these Parkinsonian signs in DA-depleted tissue. Here we compare the actions of some DA-agonists used in PD therapeutics on the pathological dynamics of DA-depleted microcircuits at rest and with CtxS; taking L-DOPA as reference. D2-class agonists better reduce the excessive spontaneous activity of DA-depleted microcircuits. All DA-agonists tend to maintain ensemble alternation seen in control circuits after CtxS. However, quantitative analyses suggest differences in their actions: in general, DA-agonists only approximate L-DOPA actions. Nonetheless no treatment, including L-DOPA, completely restores microcircuit dynamics to control conditions.

L-Dopa and Fluoxetine Upregulate Astroglial 5-HT2B Receptors and Ameliorate Depression in Parkinson’s Disease Mice

Here, we report the association between depressive behavior (anhedonia) and astroglial expression of 5-hydroxytryptamine receptor 2B (5-HT2B) in an animal model of Parkinson’s disease, induced by bilateral injection of 6-hydroxydopamine (6-OHDA) into the striatum. Expression of the 5-HT2B receptor at the mRNA and protein level was decreased in the brain tissue of 6-OHDA-treated animals with anhedonia. Expression of the 5-HT2B receptor was corrected by four weeks treatment with either l-3,4-dihydroxyphenylalanine (l-dopa) or fluoxetine. Simultaneously, treatment with l-dopa abolished 6-OHDA effects on both depressive behavior and motor activity. In contrast, fluoxetine corrected 6-OHDA-induced depression but did not affect 6-OHDA-induced motor deficiency. In addition, 6-OHDA downregulated gene expression of the 5-HT2B receptor in astrocytes in purified cell culture and this downregulation was corrected by both l-dopa and fluoxetine. Our findings suggest that 6-OHDA-induced depressive behavior may be related to the downregulation of gene expression of the 5-HT2B receptor but 6-OHDA-induced motor deficiency reflects, arguably, dopamine depletion. Previously, we demonstrated that fluoxetine regulates gene expression in astrocytes by 5-HT2B receptor-mediated transactivation of epidermal growth factor receptor (EGFR). However, the underlying mechanism of l-dopa action remains unclear. The present work indicates that the decrease of gene expression of the astroglial 5-HT2B receptor may contribute to development of depressive behavior in Parkinson’s disease.

A Selective Phosphodiesterase 10A Inhibitor Reduces L-Dopa-Induced Dyskinesias in Parkinsonian Monkeys.

Phosphodiesterase 10A is a member of the phosphodiesterase family whose brain expression is restricted to the striatum. Phosphodiesterase 10A regulates cyclic adenosine monophosphate and cyclic guanosine monophosphate, which mediate responses to dopamine receptor activation, and the levels of these cyclic nucleotides are decreased in experimental models of l-dopa-induced dyskinesia. The elevation of cyclic adenosine monophosphate/cyclic guanosine monophosphate levels by phosphodiesterase 10A inhibition may thus be targeted to reduce l-dopa-induced dyskinesia. The present study was aimed at determining the potential antidyskinetic effects of phosphodiesterase 10A inhibitors in a primate model of Parkinson's disease (PD). The experiments performed in this model were also intended to provide translational data for the design of future clinical trials. Five MPTP-treated macaques with advanced parkinsonism and reproducible l-dopa-induced dyskinesia were used. MR1916, a selective phosphodiesterase 10A inhibitor, at doses 0.0015 to 0.05 mg/kg, subcutaneously, or its vehicle (control test) was coadministered with l-dopa methyl ester acutely (predetermined optimal and suboptimal subcutaneous doses) and oral l-dopa chronically as daily treatment for 5 weeks. Standardized scales were used to assess motor disability and l-dopa-induced dyskinesia by blinded examiners. Pharmacokinetics was also examined. MR1916 consistently reduced l-dopa-induced dyskinesia in acute tests of l-dopa optimal and suboptimal doses. Significant effects were present with every MR1916 dose tested, but the most effective was 0.015 mg/kg. None of the MR1916 doses tested affected the antiparkinsonian action of l-dopa at the optimal dose. The anti-l-dopa-induced dyskinesia effect of MR1916 (0.015 mg/kg, subcutaneously) was sustained with chronic administration, indicating that tolerance did not develop over the 5-week treatment. No adverse effects were observed after MR1916 administration acutely or chronically. Results show that regulation of striatal cyclic nucleotides by phosphodiesterase 10A inhibition could be a useful therapeutic approach for l-dopa-induced dyskinesia, and therefore data support further studies of selective phosphodiesterase 10A inhibitors for PD therapy. © 2018 International Parkinson and Movement Disorder Society.

Serotonergic neurons mediate the anxiolytic effect of l-DOPA: Neuronal correlates in the amygdala

Anxiety in Parkinson's disease is a comorbid non-motor symptom that alters the quality of life of patients. Its neuronal substrates and those of l-Dopa treatment are still poorly known. Using different combinations of monoaminergic system lesions in the rat, we addressed the contribution of these systems in the efficacy of l-DOPA on anxiety and on the neuronal activity of basolateral amygdala (BLA), a brain structure involved in anxiety. Anxiety, locomotor activity and motor performance were assessed using the elevated plus maze, the open field and the skinner box, respectively. The neuronal activity of BLA was electrophysiologically recorded and the loss of dopamine, noradrenaline and serotonin neurons was quantified by immunohistochemistry and stereology. Selective bilateral lesion of dopamine neurons, with or without the additional lesions of noradrenaline and/or serotonin neurons, induced anxiety disorder. l-Dopa significantly decreased anxiety in animals with bilateral lesion of dopamine neurons alone or combined with that of noradrenaline neurons. In these two groups, l-DOPA enhanced the firing rate of BLA neurons. However, in animals with combined lesions of dopamine and serotonin neurons or in animals with lesions of the three monoaminergic systems, l-Dopa was no longer able to decrease anxiety behavior or to change the electrophysiological parameters of BLA neurons. Our data provide the first evidence of the key and positive role of the serotonergic system in the combined efficacy of l-Dopa on anxiety and the paralleled BLA neuronal activity, suggesting that the enhancement of the activity of serotonin neurons may boost the anxiolytic action of l-DOPA.

L-DOPA inhibits excitatory synaptic transmission in the rat nucleus tractus solitarius through release of dopamine

The mode of action of L-DOPA on excitatory synaptic transmission in second-order neurons of the nucleus tractus solitarius (NTS) was studied using the rat brainstem slices. Superfusion of L-DOPA (10μM) reduced the frequency of miniature excitatory postsynaptic currents (mEPSCs) without any effect on the amplitude. A low concentration (1μM) was ineffective on the mEPSCs, and the highest concentration (100μM) exerted a stronger inhibitory effect. L-DOPA (10μM) decreased the amplitude of EPSCs (eEPSCs) evoked by electrical stimulation of the tractus solitarius and increased the paired-pulse ratio. The inhibitory effects of L-DOPA on mEPSCs and eEPSCs were similar to those of dopamine (100μM). The effects of L-DOPA were blocked by a competitive antagonist, L-DOPA methyl ester (100μM) and also by a D2 receptor antagonist, sulpiride (10μM), while those of dopamine were blocked by the latter but not by the former. In reserpine (5mg/kg, s.c.)-treated rats, the effects of L-DOPA on both mEPSCs and eEPSCs were completely abolished, but those of dopamine remained unchanged. The present results suggest a possibility that L-DOPA may induce the release of dopamine from the axon terminals in the NTS and the released dopamine suppresses the glutamatergic transmission through activation of the presynaptic D2 receptors.

Response of non-motor symptoms to levodopa in late-stage Parkinson's disease: Results of a levodopa challenge test

BackgroundNon-motor symptoms (NMS) are extremely common among late-stage Parkinson's disease (LSPD) patients. Levodopa (L-dopa) responsiveness seems to decrease with disease progression but its effect on NMS in LSPD still needs to be investigated. ObjectiveTo assess the response of blood pressure (BP), pain, fatigue and anxiety to L-dopa in LSPD patients. Methods20 LSPD patients, defined as Schwab and England ADL Scale <50 or Hoehn Yahr Stage >3 (MED ON) and 22 PD patients treated with subthalamic deep brain stimulation (advanced PD group) underwent an L-dopa challenge. BP and orthostatic hypotension (OH) assessment, a visual analogue scale (VAS) for pain and fatigue and the Strait Trait Anxiety (STAI) were evaluated before and after the L-dopa challenge. ResultsSystolic BP dropped significantly after L-dopa intake (p < 0.05) in LSPD patients, while there was no change in pain, fatigue or anxiety. L-dopa significantly improved (p < 0.05) pain and anxiety in the advanced PD group, whereas it had no effect on BP or fatigue. L-dopa-related adverse effects (AEs), namely OH and sleepiness, were more common among LSPD patients. 40% and 65% of LSPD patients were not able to fill out the VAS and the STAI, respectively, while measurement of orthostatic BP was not possible in four LSPD patients. ConclusionsThis exploratory study concludes that some non-motor variables in LSPD do not benefit from the acute action of L-dopa while it can still induce disabling AEs. There is a need for assessment tools of NMS adapted to these disabled LSPD patients.

Chemogenetic stimulation of striatal projection neurons modulates responses to Parkinson's disease therapy.

Parkinson's disease (PD) patients experience loss of normal motor function (hypokinesia), but can develop uncontrollable movements known as dyskinesia upon treatment with L-DOPA. Poverty or excess of movement in PD has been attributed to overactivity of striatal projection neurons forming either the indirect (iSPNs) or the direct (dSPNs) pathway, respectively. Here, we investigated the two pathways' contribution to different motor features using SPN type-specific chemogenetic stimulation in rodent models of PD (PD mice) and L-DOPA-induced dyskinesia (LID mice). Using the activatory Gq-coupled human M3 muscarinic receptor (hM3Dq), we found that chemogenetic stimulation of dSPNs mimicked, while stimulation of iSPNs abolished the therapeutic action of L-DOPA in PD mice. In LID mice, hM3Dq stimulation of dSPNs exacerbated dyskinetic responses to L-DOPA, while stimulation of iSPNs inhibited these responses. In the absence of L-DOPA, only chemogenetic stimulation of dSPNs mediated through the Gs-coupled modified rat muscarinic M3 receptor (rM3Ds) induced appreciable dyskinesia in PD mice. Combining D2 receptor agonist treatment with rM3Ds-dSPN stimulation reproduced all symptoms of LID. These results demonstrate that dSPNs and iSPNs oppositely modulate both therapeutic and dyskinetic responses to dopamine replacement therapy in PD. We also show that chemogenetic stimulation of different signaling pathways in dSPNs leads to markedly different motor outcomes. Our findings have important implications for the design of effective antiparkinsonian and antidyskinetic drug therapies.

LONG-TERM DOPAMINERGIC THERAPY OF PARKINSON DISEASE

The use of dopaminergic tools, particularly levodopa and dopamine receptors agonists (DRA), for many years allowed to effectively control the major motor symptoms of Parkinson disease, supporting mobility and daily activity, and eventually increasing the survivability of patients. However, a few years after the start of the Levodopa intake the vast majority of patients have motor fluctuations and dyskinesias. The Levodopa action is ensured not only by the short-term but also by the so-called long-term effect of Levodopa, which is developing when the drug is taken regularly. The long-term response provides at least half of the total response to dopaminergic drugs, particularly, Levodopa. As the disease progresses, the long-term response tends to decrease, with a more precise «pulse» of a short-term reaction that does not affect its parameters. It is believed that this is related to the development of the phenomenon of «dose-end exhaustion» and then to «turn on-off». Thus, the task of delaying the occurrence of motor fluctuations must be to keep the long-term dopaminergic effect as long as possible. Dopaminergic receptors agonists (DRA) are capable of direct stimulating of dopamine receptors on striatal neurons, bypassing degeneration nigrostriatal cells, thus simulating operation of an endogenous mediator. Agonists of D2-receptors can induce long-term reactions. It is shown that in six weeks after the Ropinirol intake, the subsequent discontinuation of its application results in a slow rise in the motor symptoms during a week. The effectiveness of Ropinirol with the prolonged release at various stages of the PD is confirmed in several placebo-controlled studies. The role of a slow release dosage of Ropinirol in maintaining a long-term response requires special study.