Levodopa Treatment Research Articles

The pyroptosis mediated biomarker pattern: an emerging diagnostic approach for Parkinson’s disease

BackgroundParkinson’s disease (PD) affects 1% of people over 60, and long-term levodopa treatment can cause side effects. Early diagnosis is of great significance in slowing down the pathological process of PD. Multiple pieces of evidence showed that non-coding RNAs (ncRNAs) could participate in the progression of PD pathology. Pyroptosis is known to be regulated by ncRNAs as a key pathological feature of PD. Therefore, evaluating ncRNAs and pyroptosis-related proteins in serum could be worthy biomarkers for early diagnosis of PD.MethodsNcRNAs and pyroptosis/inflammation mRNA levels were measured with reverse transcriptase quantitative polymerase chain reaction (RT-qPCR). Luciferase assays were performed to confirm GSDME as a target of miR-675-5p and HMGB1 as a target of miR-1247-5p. In the serum of healthy controls (n = 106) and PD patients (n = 104), RT-qPCR was utilized to assess miR-675-5p, miR-1247-5p, and two related ncRNAs (circSLC8A1and lncH19) levels. The enzyme-linked immunosorbent assay measured serum levels of pyroptosis-related proteins in controls (n = 54) and PD patients (n = 70).ResultsOur data demonstrated that miR-675-5p and miR-1247-5p significantly changed in PD neuron and animal models. Overexpressed miR-675-5p or downregulated miR-1247-5p could regulate pyroptosis and inflammation in PD neuron models. Using the random forest algorithm, we constructed a classifier based on PD neuron-pyroptosis pathology (four ncRNAs and six proteins) having better predictive power than single biomarkers (AUC = 92%). Additionally, we verified the performance of the classifier in early-stage PD patients (AUC ≥ 88%).ConclusionSerum pyroptosis-related ncRNAs and proteins could serve as reliable, inexpensive, and non-invasive diagnostic biomarkers for PD.LimitationsAll participants were from the same region. Additionally, longitudinal studies in the aged population are required to explore the practical application value of the classifier.

Prediction of dyskinesia in Parkinson’s disease patients using machine learning algorithms

Dyskinesias are non preventable abnormal involuntary movements that represent the main challenge of the long term treatment of Parkinson’s disease (PD) with the gold standard dopamine precursor levodopa. Applying machine learning techniques on the data extracted from the Parkinson’s Progression Marker Initiative (PPMI, Michael J. Fox Foundation), this study was aimed to identify PD patients who are at high risk of developing dyskinesias. Data regarding clinical, behavioral and neurological features from 697 PD patients were included in our study. Our results show that the Random Forest was the classifier with the best and most consistent performance, reaching an area under the receiver operating characteristic (ROC) curve of up to 91.8% with only seven features. Information regarding the severity of the symptoms, the semantic verbal fluency, and the levodopa treatment were the most important for the prediction, and were further used to create a Decision Tree, whose rules may guide the pharmacological management of PD symptoms. Our results contribute to the identification of PD patients who are prone to develop dyskinesia, and may be considered in future clinical trials aiming at developing new therapeutic approaches for PD.

Peripheral neuropathy in Parkinson’s disease: Association between levodopa treatment and vitamin deficiency

Peripheral neuropathy in Parkinson’s disease: Association between levodopa treatment and vitamin deficiency

Aberrations in temporal dynamics of cognitive processing induced by Parkinson’s disease and Levodopa

The motor symptoms of Parkinson's disease (PD) have been shown to significantly improve by Levodopa. However, despite the widespread adoption of Levodopa as a standard pharmaceutical drug for the treatment of PD, cognitive impairments linked to PD do not show visible improvement with Levodopa treatment. Furthermore, the neuronal and network mechanisms behind the PD-induced cognitive impairments are not clearly understood. In this work, we aim to explain these cognitive impairments, as well as the ones exacerbated by Levodopa, through examining the differential dynamic patterns of the phase-amplitude coupling (PAC) during cognitive functions. EEG data recorded in an auditory oddball task performed by a cohort consisting of controls and a group of PD patients during both on and off periods of Levodopa treatment were analyzed to derive the temporal dynamics of the PAC across the brain. We observed distinguishing patterns in the PAC dynamics, as an indicator of information binding, which can explain the slower cognitive processing associated with PD in the form of a latency in the PAC peak time. Thus, considering the high-level connections between the hippocampus, the posterior and prefrontal cortices established through the dorsal and ventral striatum acting as a modulatory system, we posit that the primary issue with cognitive impairments of PD, as well as Levodopa’s cognitive deficit side effects, can be attributed to the changes in temporal dynamics of dopamine release influencing the modulatory function of the striatum.

How does the method of formulation a drug affect its efficacy and safety, based on the comparison of modified and conventional release amantadine in the treatment of levodopa induced dyskinesia in patients with Parkinson's disease?

Background The choice of the appropriate method of drug production is determined mainly by the characteristics of the medicinal substances and excipients, the type of disease in which the drug is to be used and the expectations of patients. The appropriate method of drug production may be key importance for achieving clinically significant treatment effects. For this reason, an attempt has been made to evaluate modified and conventional release forms of amantadine for the treatment of levodopa-induced dyskinesias in patients with Parkinosn's disease. Methods The effect of two different forms of amantadine on the treatment of levodopa - induced dyskinesias in patients with Parkinson's disease was assessed through a systematic review of clinical trials following the PICOS regimen. The clinical efficacy of the treatment of levodopa-induced dyskinesias in patients with Parkinson's disease was assessed by a measure of the appropriate scale and the effect on the ON and OFF times. Results Although no studies were found directly comparing the use of amantadine ER with amantadine IR in this disease, in the studies of amantadine ER, the UDysRS score showed a significantly greater improvement in the treatment of dyskinesia in the study group compared to placebo. The amantadine IR studies did not show any significant effect on the treatment effects. Conclusions The choice of the method of producing a drug has a significant impact on the effects of treatment.

Effects of rasagiline combined with levodopa and benserazide hydrochloride on motor function and homocysteine and IGF-1 levels in elderly patients with Parkinson’s disease

BackgroundDuring the course of their illness, people with Parkinson’s disease may see changes in their insulin-like growth factor (IGF-1) and serum homocysteine (Hcy) indices. In this study, patients with intermediate to severe Parkinson’s disease were examined for how Resagiline and levodopa and benserazide hydrochloride affected their motor performance, serum levels of homocysteine (Hcy), and insulin-like growth factor (IGF-1).MethodsFrom June 2020 to December 2021, a total of 100+ cases of Parkinson’s patients over 60 years old in the middle and late stages of Parkinson’s were seen in the outpatient and inpatient departments of the Third People’s Hospital of Chengdu City and had a detailed observation record, and according to the inclusion criteria, the patients who met the criteria were randomly grouped into a clinical observation group and a control group. The subjects in the control group received only levodopa and benserazide hydrochloride treatment, while the observation group was treated with Resagiline in combination with the clinical control group. The total treatment observation period was 1 year for both groups, and the motor function and serum Hcy and IGF-1 indexes of both groups were compared after the end of treatment.ResultsWe randomly and evenly grouped 64 patients who met the requirements of the inclusion criteria into a clinical observation group and a control group, each with 32 patients, from among 168 patients over 60 years of age with detailed observation records in the middle and late stages of Parkinson’s. After the 1-year observation period, we found that the total effective rate after treatment in the clinical observation group (93.75%) and significantly higher than that in the control group (68.75%) (P < 0.05); after 1 year of treatment, the UPDRS score decreased in both groups, and the observation group was significantly lower than the control group (P < 0.05); after treatment, serum Hcy decreased and IGF-1 increased in both groups, and the observation group was higher than the control group mean values (P < 0.05).ConclusionsIn patients with Parkinson’s disease who are in the middle and late stages of the disease, the administration of Resagiline combined with levodopa and benserazide hydrochloride can significantly lower the body’s serum Hcy level, significantly raise IGF-1 levels, and significantly improve motor function in patients with Parkinson’s disease. It can also have significant therapeutic effects.

A 12-month prospective real-life study of opicapone efficacy and tolerability in Emirati and non-White subjects with Parkinson’s disease based in United Arab Emirates

Parkinson’s disease (PD) is the second most common neurodegenerative disorder, and the condition is complicated by the emergence of wearing off/motor fluctuations with levodopa treatment after a variable period. COMT inhibitors when used as adjunct therapy to levodopa tend to smoothen out these wearing off fluctuations by enhancing delivery of levodopa and increasing its bioavailability to the brain. The study was conducted to investigate the motor and nonmotor effect, safety and tolerability of the third generation once-daily COMT inhibitor (opicapone), as add-on, adjuvant therapy to levodopa and at 6 and 12 months follow-up in a real-life cohort of consecutive Emirati and non-White PD patients. A real-life observational analysis using tolerability parameters as used previously by Rizos et al. and Shulman et al. based on clinical database of cases rat Kings College Hospital Dubai Parkinson care database. This was a prospective, single-arm follow-up clinical evaluation study that evaluated the effectiveness of opicapone 50 mg once-daily regime in 50 patients diagnosed with idiopathic neurodegenerative disorder. All patients were assessed with scales used in clinical pathway and include motor Unified Parkinson’s Disease Rating Scale (UPDRS), nonmotor symptom scale (NMSS), quality of life (PDQ8) Parkinson’s fatigue scale (PFS16) and King’s Parkinson’s Pain Scale (KIPS). Out of 50 patients treated with opicapone (72% male, mean age 66.9 years (SD 9.9, range 41–82 years) and mean duration of disease 5.7 years (SD 2.5 range (2–11), there was significant statistical improvements shown in motor function-UPDRS part 3: baseline 40.64 ± 2.7, at 6 months 32.12 ± 3.14 and after 12 months 33.72 ± 3.76. Nonmotor burden NMSS: 107.00 ± 21.86, at 6 months 100.78 ± 17.28 and 12 months 96.88 ± 16.11. Reduction in dyskinesias (UPDRS part 4): baseline 8.78 ± 1.07, at 6 months 7.4 ± 0.81 and 12 months 6.82 ± 0.75. Opicapone provides beneficial motor and nonmotor effects in Emirati and other non-White Parkinson’s patients, resident in UAE, proving its efficacy across different racial groups as COMT activity may vary between races.

Levodopa-induced dyskinesia: interplay between the N-methyl-D-aspartic acid receptor and neuroinflammation.

Parkinson's disease (PD) is a common neurodegenerative disorder of middle-aged and elderly people, clinically characterized by resting tremor, myotonia, reduced movement, and impaired postural balance. Clinically, patients with PD are often administered levodopa (L-DOPA) to improve their symptoms. However, after years of L-DOPA treatment, most patients experience complications of varying severity, including the "on-off phenomenon", decreased efficacy, and levodopa-induced dyskinesia (LID). The development of LID can seriously affect the quality of life of patients, but its pathogenesis is unclear and effective treatments are lacking. Glutamic acid (Glu)-mediated changes in synaptic plasticity play a major role in LID. The N-methyl-D-aspartic acid receptor (NMDAR), an ionotropic glutamate receptor, is closely associated with synaptic plasticity, and neuroinflammation can modulate NMDAR activation or expression; in addition, neuroinflammation may be involved in the development of LID. However, it is not clear whether NMDA receptors are co-regulated with neuroinflammation during LID formation. Here we review how neuroinflammation mediates the development of LID through the regulation of NMDA receptors, and assess whether common anti-inflammatory drugs and NMDA receptor antagonists may be able to mitigate the development of LID through the regulation of central neuroinflammation, thereby providing a new theoretical basis for finding new therapeutic targets for LID.

Investigating Paracetamol's Role as a Potential Treatment for Parkinson's Disease: Ab Initio Analysis of Dopamine, l-DOPA, Paracetamol, and NAPQI Interactions with Enzymes Involved in Dopamine Metabolism.

Recently, it was found that paracetamol can extend the therapeutic window of l-DOPA treatment for Parkinson's disease [Golding (2019) BJPharm, 4(2), Article 619]. It has been posited that the effect could be due to paracetamol and its metabolite, NAPQI, inhibiting pain signals in the spinal column. In this work, we examine the possibility that the therapeutic effect of the paracetamol for the Parkinson's disease patient may be due to an inhibition of the enzymes that metabolize dopamine and/or l-DOPA, thus effectively extending the lifetime of the l-DOPA treatment. In this work, we use the M062X/6-311+G* level of theory to calculate the electronic binding energies (including explicit desolvation) of several ligands (paracetamol, NAPQI, dopamine, and l-DOPA) with a series of enzymes important to the production and metabolism of dopamine and compare them to calculated binding energy values for the natural substrates for those enzymes in order to predict possible inhibition. Benchmark interaction energies for a subset of the systems studied are calculated using the more accurate second-order Møller-Plesset perturbation (MP2) method in order to calibrate the accuracy of the M062X method. If we assume that the interaction energies calculated here can serve as a proxy for in vivo inhibition, then we can predict that paracetamol and NAPQI should not inhibit the natural production of dopamine and may in fact inhibit the metabolism of l-DOPA and dopamine, thus extending the length of l-DOPA treatments.

Effects of curcumin to counteract levodopa-induced toxicity in zebrafish

ABSTRACT Parkinson’s disease (PD) is a neurodegenerative disorder characterized by motor dysfunction due to the death of dopaminergic neurons in the substantia nigra pars compacta. Currently, treatment of PD has focused on increasing dopamine levels, using a dopamine precursor, levodopa (L-DOPA) or stimulation of dopaminergic receptors. Prolonged use of L-DOPA is associated with the occurrence of motor complications and dyskinesia, attributed to neurotoxic effects of this drug. The aim of this study was to investigate the effects of curcumin (CUR), a lipophilic polyphenol, to counteract L-DOPA induced toxicity. Zebrafish larvae were pre-treated with CUR (0.05 µM) or vehicle dimethyl sulfoxide (DMSO) for 24 hr and subsequently exposed to L-DOPA (1 mM) or vehicle. Immediately and 24 hr after L-DOPA exposure, spontaneous swimming and dark/light behavioral tests were performed. In addition, levels of reactive oxygen species (ROS) and lipid peroxidation products were determined at the end of treatment. CUR significantly improved the motor impairment induced by 24 hr L-DOPA treatment, and reduced levels of ROS and lipoperoxidation products in zebrafish larvae. In conclusion, our results suggest that CUR acts as a neuroprotector against toxicity initiated by L-DOPA. Evidence suggests the observed effects of CUR are associated with its antioxidant properties.

Levodopa-induced orthostatic hypotension in parkinsonism: A red flag of autonomic failure.

Levodopa (LD) is the main treatment for parkinsonism, but its use may be limited by a potential hypotensive effect. We evaluated the cardiovascular effect of LD performing head-up tilt test (HUTT) before and 60 min after 100/25 mg LD/dopa-decarboxylase inhibitor (pre-LD vs. post-LD HUTT) in 164 patients with parkinsonism on chronic LD treatment. Features predictive of LD-induced orthostatic hypotension (OH) were assessed by logistic regression analysis. Basal supine blood pressure (BP) and heart rate (HR) decreased after LD. During post-LD HUTT, BP drop and HR increase were significantly greater than at pre-LD HUTT. Thirty-eight percent of patients had OH at post-LD HUTT compared to 22% of patients presenting OH at pre-LD HUTT (p < 0.001). Risk factors for LD-induced/worsened OH were pre-LD OH (odds ratio [OR] = 36, 95% confidence interval [CI] = 10-131), absence of overshoot at Valsalva maneuver (OR = 9, 95% CI = 4-20), and pathological Valsalva ratio (OR = 6, 95% CI = 2-15). LD administration caused/worsened hypotension in both supine and orthostatic conditions. Patients with cardiovascular autonomic failure had a higher risk of developing LD-induced OH. In clinical practice, LD-induced OH could represent a red flag for cardiovascular autonomic failure.

Exploring the levodopa-paradox of freezing of gait in dopaminergic medication-naïve Parkinson’s disease populations

The relationship between dopaminergic treatment and freezing of gait (FOG) in Parkinson’s disease (PD) is complex: levodopa is the most effective symptomatic treatment for FOG, but long-term pulsatile levodopa treatment has also been linked to an increase in the occurrence of FOG. This concept, however, continues to be debated. Here, we compared the occurrence of FOG between a levodopa-naive PD cohort and a levodopa-treated cohort. Forty-nine treatment-naive patients and 150 levodopa-treated patients were included. The time since first motor symptoms was at least 5 years. Disease severity was assessed using the MDS-UPDRS part III. Occurrence of FOG was assessed subjectively (new freezing-of-gait-questionnaire) and objectively (rapid turns test and Timed Up-and-Go test). The presence of FOG was compared between the levodopa-treated and levodopa-naive groups using a chi-square test of homogeneity. We also performed a binomial Firth logistic regression with disease duration, disease severity, country of inclusion, location of measurement, and executive function as covariates. Subjective FOG was more common in the levodopa-treated cohort (n = 41, 27%) compared to the levodopa-naive cohort (n = 2, 4%, p < 0.001). The association between FOG and levodopa treatment remained after adjustment for covariates (OR = 6.04, 95%Cl [1.60, 33.44], p = 0.006). Objectively verified FOG was more common in the levodopa-treated cohort (n = 21, 14%) compared to the levodopa-naive cohort (n = 1, 2%, p = 0.02). We found an association between long-term pulsatile levodopa treatment and an increased occurrence of FOG. Future studies should further explore the role of nonphysiological stimulation of dopamine receptors in generating FOG, as a basis for possible prevention studies.

The Cannabigerol Derivative VCE-003.2 Exerts Therapeutic Effects in 6-Hydroxydopamine-Lesioned Mice: Comparison with The Classic Dopaminergic Replacement Therapy.

(1) Background: A cannabigerol aminoquinone derivative, so-called VCE-003.2, has been found to behave as a neuroprotective agent (administered both i.p. and orally) in different experimental models of Parkinson's disease (PD) in mice. These effects were exerted through mechanisms that involved the activation of a regulatory site within the peroxisome proliferator-activated receptor-γ (PPAR-γ). (2) Methods: We are now interested in comparing such neuroprotective potential of VCE-003.2, orally administered, with the effect of the classic dopaminergic replacement therapy with L-DOPA/benserazide in similar conditions, using 6-hydroxydopamine-lesioned mice. (3) Results: The oral administration of VCE-003.2 during 14 days at the dose of 20 mg/kg improved, as expected, the neurological status (measured in motor tests) in these mice. This correlated with a preservation of TH-labelled neurons in the substantia nigra. By contrast, the treatment with L-DOPA/benserazide (during 7 days at 2 mg/kg) was significantly less active in these experimental conditions, in concordance with their profile as a mere symptom-alleviating agent. (4) Conclusions: Our results confirmed again the therapeutic profile of VCE-003.2 in experimental PD and revealed a different and more relevant effect, as a disease modifier, compared to the classic symptom-alleviating L-DOPA treatment. This reinforces the interest in VCE-003.2 for a future clinical development in this disease.

L-DOPA induces iron accumulation in roots of Ipomoea aquatica and Arabidopsis thaliana in a pH-dependent manner

BackgroundIron deficiency is the leading cause of anemia worldwide, particularly in countries with predominant plant-based diets. Plants constitute the main source of dietary iron. Increasing their iron concentration could reduce the occurrence of anemia. The water spinach Ipomoea aquatica is consumed as a vegetable throughout Asia and tolerates high iron concentrations making it an attractive candidate for iron biofortification. L-DOPA is an allelopathic molecule secreted by some legumes. L-DOPA can trigger the expression of Fe deficiency-inducible genes, and could potentially be used as a biostimulant to increase Fe concentration.ResultsL-DOPA significantly affected root growth of water spinach, and triggered a massive accumulation of Fe in roots. Both effects were exacerbated when L-DOPA was dissolved in KOH, which is surprising given that L-DOPA is less stable at high pH. To check whether a higher pH could indeed increase the bioactivity of L-DOPA, we used Arabidopsis thaliana, which grows at lower pH than water spinach, and subjected the plants to L-DOPA treatments at pH 5.5 and pH 6.0, which are both within the optimal range for Arabidopsis nutrition. At pH 6.0, the root growth of Arabidopsis was more strongly inhibited than at pH 5.5. We found that at higher pH, L-DOPA oxidizes to form a melanin precipitate.ConclusionsWe concluded that the oxidation of L-DOPA that we observed upon solubilization in KOH, or in nutrient solutions at slightly higher pH produces melanin-related molecules that are more potent than L-DOPA itself to trigger the primary root growth inhibition, Fe uptake and root Fe accumulation in water spinach and Arabidopsis.

Oculometric measures as a tool for assessment of clinical symptoms and severity of Parkinson’s disease

Abnormalities of oculometric measures (OM) are widely described in people with Parkinson's disease (PD). However, knowledge of correlations between abnormal OM, disease severity and clinical assessment in PD patients is still lacking. To evaluate these correlations, PD patients (215 patients, mean age 69 ± 9.1 years, 79 females) with severe (H&Y > 3) and mild to moderate (H&Y ≤ 2) disease, and 215 age-matched healthy subjects were enrolled. All patients were evaluated using MDS-UPDRS and an oculometric test using computer vision and deep learning algorithms. Comparisons of OM between groups and correlations between OM and MDS-UPDRS scores were calculated. Saccadic latency (ms) was prolonged in patients with severe compared with mild to moderate disease (pro-saccades: 267 ± 69 vs. 238 ± 53, p = 0.0011; anti-saccades: 386 ± 119 vs. 352 ± 106, p = 0.0393) and in patients with mild to moderate disease versus healthy subjects (pro-saccades: 238 ± 53 vs. 220 ± 45, p = 0.0003; anti-saccades: 352 ± 106 vs. 289 ± 71, p < 0.0001). Error rate (%) was higher among patients with severe (64.06 ± 23.08) versus mild to moderate disease (49.84 ± 24.81, p = 0.0001), and versus healthy subjects (49.84 ± 24.81 vs. 28.31 ± 21.72, p = 0.00001). Response accuracy (%) was lower for patients with severe (75.66 ± 13.11) versus mild to moderate disease (79.66 ± 13.56, p = 0.0462), and versus healthy subjects (79.66 ± 13.56 vs. 90.27 ± 8.79, p < 0.0001). Pro- and anti-saccadic latency, error rate and accuracy were correlated with MDS-UPDRS scores (r = 0.32, 0.28, 0.36 and -0.30, respectively, p < 0.0001) and similar correlations were found with its axial subscore (R = 0.38, 0.29, 0.44, and -0.30, respectively, p < 0.0001). Several OM were different in patients under levodopa treatment. OM worsened as PD severity increases, and were correlated with MDS-UPDRS scores. Using OM can be implemented for PD patients’ assessment as a tool to follow disease progression.

Investigation of PRKN Mutations in Levodopa-Induced Dyskinesia in Parkinson's Disease Treatment.

Mitophagy is an important process that participates in mitochondrial quality control. Dysfunctions in this process can be caused by mutations in genes like PRKN and are associated with the development and progression of Parkinson's Disease (PD). The most used drug in the treatment of PD is levodopa (LD), but it can cause adverse effects, such as dyskinesia. Currently, few studies are searching for biomarkers for an effective use of lLD for this disease, especially regarding mitophagy genetics. Thus, this work investigates the association of 14 variants of the PRKN gene with LD in the treatment of PD. We recruited 70 patients with PD undergoing treatment with LD (39 without dyskinesia and 31 with dyskinesia). Genotyping was based on Sanger sequencing. Our results reinforce that age at onset of symptoms, duration of PD, and treatment and dosage of LD can influence the occurrence of dyskinesia but not the investigated PRKN variants. The perspective presented here of variants of mitophagy-related genes in the context of treatment with LD is still underexplored, although an association has been indicated in previous studies. We suggest that other variants in PRKN or in other mitophagy genes may participate in the development of levodopa-induced dyskinesia in PD treatment.

Calcineurin inhibition protects against dopamine toxicity and attenuates behavioral decline in a Parkinson’s disease model

BackgroundParkinson’s disease (PD), a highly prevalent neuro-motor disorder is caused due to progressive loss of dopaminergic (DAergic) neurons at substantia nigra region of brain. This leads to depleted dopamine (DA) content at striatum, thus affecting the fine tuning of basal ganglia. In patients, this imbalance is manifested by akinesia, catalepsy and tremor. PD associated behavioral dysfunctions are frequently mitigated by l-DOPA (LD) therapy, a precursor for DA synthesis. Due to progressive neurodegeneration, LD eventually loses applicability in PD. Although DA is cytotoxic, it is unclear whether LD therapy can accelerate PD progression or not. LD itself does not lead to neurodegeneration in vivo, but previous reports demonstrate that LD treatment mediated excess DA can potentiate neurotoxicity when PD associated genetic or epigenetic aberrations are involved. So, minimizing DA toxicity during the therapy is an absolute necessity to halt or slowdown PD progression. The two major contributing factors associated with DA toxicity are: degradation by Monoamine oxidase and DAquinone (DAQ) formation.ResultsHere, we report that apoptotic mitochondrial fragmentation via Calcineurin (CaN)-DRP1 axis is a common downstream event for both these initial cues, inhibiting which can protect cells from DA toxicity comprehensively. No protective effect is observed, in terms of cell survival when only PxIxIT domain of CaN is obstructed, demonstrating the importance to block DRP1-CaN axis specifically. Further, evaluation of the impact of DA exposure on PD progression in a mice model reveal that LD mediated behavioral recovery diminishes with time, mostly because of continued DAergic cell death and dendritic spine loss at striatum. CaN inhibition, alone or in combination with LD, offer long term behavioral protection. This protective effect is mediated specifically by hindering CaN-DRP1 axis, whereas inhibiting interaction between CaN and other substrates, including proteins involved in neuro-inflammation, remained ineffective when LD is co-administered.ConclusionsIn this study, we conclude that DA toxicity can be circumvented by CaN inhibition and it can mitigate PD related behavioral aberrations by protecting neuronal architecture at striatum. We propose that CaN inhibitors might extend the therapeutic efficacy of LD treatment.

Radiomics and Hybrid Models Based on Machine Learning to Predict Levodopa-Induced Dyskinesia of Parkinson's Disease in the First 6 Years of Levodopa Treatment.

Current research on the prediction of movement complications associated with levodopa therapy in Parkinson's disease (PD) is limited. levodopa-induced dyskinesia (LID) is a movement complication that seriously affects the life quality of PD patients. One-third of PD patients develop LID within 1 to 6 years of levodopa treatment. This study aimed to construct models based on radiomics and machine learning to predict early LID in PD. We extracted radiomics features from the T1-weighted MRI obtained in the baseline of 49 PD control and 54 PD with LID in the first 6 years of levodopa therapy. Six brain regions related to the onset of PD were segmented as regions of interest (ROIs). The least absolute shrinkage and selection operator (LASSO) was used for feature selection. Using the machine learning methods of support vector machine (SVM), random forest (RF), and AdaBoost, we constructed radiomics models and hybrid models. The hybrid models combined the radiomics features and the Unified Parkinson's Disease Rating Scale part III (UPDRS III) total score. The five-fold cross-validation was performed and repeated 20 times to validate the stability of the classifiers. We used sensitivity, specificity, accuracy, receiver operating characteristic (ROC) curves, and area under the ROC curve (AUC) for model validation. We selected 33 out of 6138 radiomics features. In the testing set of the radiomics model, the AUC values of the SVM, RF, and AdaBoost classifiers were 0.905, 0.808, and 0.778, respectively, and the accuracies were 0.839, 0.742, and 0.710. The hybrid models had better prediction performance. In the testing set, the AUC values of SVM, RF, and AdaBoost classifiers were 0.958, 0.861, and 0.832, respectively, and the accuracies were 0.903, 0.806, and 0.774. Our results indicate that T1-weighted MRI is valuable in predicting early LID in PD. This work demonstrates that the combination of radiomics features and clinical features has good potential and value for identifying early LID in PD.

BDNF/TrkB pathway activation in D1 receptor-expressing striatal projection neurons plays a protective role against L-DOPA-induced dyskinesia

L-DOPA-induced dyskinesia (LID) is a frequent adverse side effect of L-DOPA treatment in Parkinson's disease (PD). Understanding the mechanisms underlying the development of these motor disorders is needed to reduce or prevent them. We investigated the role of TrkB receptor in LID, in hemiparkinsonian mice treated by chronic L-DOPA administration. Repeated L-DOPA treatment for 10 days specifically increased full-length TrkB receptor mRNA and protein levels in the dopamine-depleted dorsal striatum (DS) compared to the contralateral non-lesioned DS or to the DS of sham-operated animals. Dopamine depletion alone or acute L-DOPA treatment did not significantly increase TrkB protein levels. In addition to increasing TrkB protein levels, chronic L-DOPA treatment activated the TrkB receptor as evidenced by its increased tyrosine phosphorylation. Using specific agonists for the D1 or D2 receptors, we found that TrkB increase is D1 receptor-dependent. To determine the consequences of these effects, the TrkB gene was selectively deleted in striatal neurons expressing the D1 receptor. Mice with TrkB floxed gene were injected with Cre-expressing adeno-associated viruses or crossed with Drd1-Cre transgenic mice. After unilateral lesion of dopamine neurons in these mice, we found an aggravation of axial LID compared to the control groups. In contrast, no change was found when TrkB deletion was induced in the indirect pathway D2 receptor-expressing neurons. Our study suggests that BDNF/TrkB signaling plays a protective role against the development of LID and that agonists specifically activating TrkB could reduce the severity of LID.

Behavioral effects of zonisamide on L-DOPA-induced dyskinesia in Parkinson's disease model mice.

Zonisamide (ZNS; 1,2-benzisoxazole-3-methanesulfonamide) was initially developed and is commonly used as an anticonvulsant drug. However, it has also shown its beneficial effects on Parkinson's disease (PD), a progressive neurodegenerative disorder caused by the loss of dopaminergic neurons in the midbrain. Recent clinical studies have suggested that ZNS can also have beneficial effects on L-DOPA-induced dyskinesia (LID), which is a major side effect of long-term L-DOPA treatments for PD. In the present study, we examined the behavioral effects of ZNS on LID in PD model mice. Acute ZNS treatment did not have any observable behavioral effects on LID. Contrastingly, chronic ZNS treatment with L-DOPA delayed the peak of LID and reduced the severity of LID before the peak but increased the duration of LID in a dose-dependent manner of ZNS compared to PD model mice treated with L-DOPA alone. Thus, ZNS appears to have both beneficial and adverse effects on LID.