Low Doses Of Levodopa Research Articles

A Silent Threat: Deep Vein Thrombosis in Early-Stage Parkinson's Disease.

The primary clinical manifestation of venous thrombosis is discomfort in the lower extremities. Some early Parkinson's disease (PD) patients feel discomfort in the lower limbs. Venous thrombosis can risk lives by causing pulmonary embolism. This study examines the incidence of DVT in early PD patients and its correlation with different clinical and lab features. A cross-sectional study was conducted on 117 patients with early-stage PD. Ultrasonography was employed to detect the presence of DVT. Factors such as age, gender, body mass index, lifestyle habits (smoking and drinking), medical history (hypertension, diabetes, atrial fibrillation, and tumor), and other lab tests linked to thrombosis were analyzed. In 117 patients, 11 (9.4%) had DVT, while 106 (90.6%) did not. There were no significant differences in gender, BMI, habits, medical history, or other thrombosis-related tests between both groups. However, DVT patients were older with higher d-dimer levels. They also showed an increased right substantia nigra ultrasound echo area, higher HY grades, higher UPDRS 3 scores, less improvement in UPDRS 3 scores and levodopa response. The primary risk factors for lower extremity venous thrombosis were found to be age, d-dimer levels, and low-dose levodopa. Therefore, for elderly patients with early-stage PD, it is crucial to conduct d-dimer and lower extremity vascular ultrasound tests. The prevention of venous thrombosis in the lower extremities of early PD patients is of utmost importance.

Levodopa-responsive dystonia, parkinsonism, and treatment-resistant schizoaffective disorder in Williams syndrome.

Williams syndrome (WS; chromosome 7q11.23 deletion) is a rare, multisystemic, neurodevelopmental disorder with variable penetrance and expressivity. Although movement and psychiatric disorders are known to occur in individuals with WS, parkinsonism, dystonia, and treatment-resistant schizoaffective disorder have not been formally described. We present two unrelated cases of adults with molecularly confirmed WS and typical histories of developmental delays, intellectual/learning disabilities, and treatment-responsive anxiety/mood disorder who developed similar noteworthy neuropsychiatric expressions. We reviewed detailed neuropsychiatric histories, laboratory investigations, neuroimaging, and treatment responses and compared data for the two cases. Both individuals developed treatment-resistant schizoaffective disorder in adulthood requiring multiple trials of antipsychotic treatments. While on clozapine, both patients developed parkinsonism and generalized dystonia with truncal involvement that responded to trials of low-dose levodopa without exacerbating underlying psychotic or affective symptoms. This report illustrates the novel occurrence of levodopa-responsive movement disorders and treatment-resistant schizoaffective disorder in individuals with WS, adding to the expanding neuropsychiatric phenotypes, and highlighting potential shared underlying mechanisms. The observed treatment response suggests that levodopa, in relatively low doses, may be safe and useful in ameliorating presumed antipsychotic-associated parkinsonism and tardive dystonia in WS.

Delayed levodopa-responsive parkinsonism following acute midbrain injury

Acute midbrain injury may cause both hyperkinetic movement disorders and parkinsonism. The temporal interval between the insult and the emergence of hyperkinetic disorders can last years. A delayed appearance of parkinsonism, on the other hand, was rarely described. We present three cases of male patients (50-, 58- and 28-year-old) who developed levodopa-responsive parkinsonism 20, 8 and two years, respectively, after acute brain insult involving the midbrain. Insults included subcortical intracerebral hemorrhage dissecting into the midbrain, embolic basilar occlusion and trauma. A fluorodopa scan, performed in two cases, revealed reduced striatal uptake. All individuals improved on low doses of levodopa and developed motor fluctuations shortly after levodopa was introduced. We conclude that delayed, levodopa-responsive parkinsonism following midbrain injury should be recognized in the relevant clinical setup. Possible mechanisms include age-related loss of dopaminergic neurons superimposed on acute injury and secondary neurodegeneration.

The Pathophysiology of Gilles de la Tourette Syndrome: Changes in Saccade Performance by Low-Dose L-Dopa and Dopamine Receptor Blockers.

To elucidate the pathophysiology of Gilles de la Tourette syndrome (GTS), which is associated with prior use of dopamine receptor antagonists (blockers) and treatment by L-Dopa, through saccade performance. In 226 male GTS patients (5-14 years), we followed vocal and motor tics and obsessive-compulsive disorder (OCD) after discontinuing blockers at the first visit starting with low-dose L-Dopa. We recorded visual- (VGS) and memory-guided saccades (MGS) in 110 patients and 26 normal participants. At the first visit, prior blocker users exhibited more severe vocal tics and OCD, but not motor tics, which persisted during follow-up. Patients treated with L-Dopa showed greater improvement of motor tics, but not vocal tics and OCD. Patients with and without blocker use showed similarly impaired MGS performance, while patients with blocker use showed more prominently impaired inhibitory control of saccades, associated with vocal tics and OCD. Impaired MGS performance suggested a mild hypodopaminergic state causing reduced direct pathway activity in the (oculo-)motor loops of the basal ganglia-thalamocortical circuit. Blocker use may aggravate vocal tics and OCD due to disinhibition within the associative and limbic loops. The findings provide a rationale for discouraging blocker use and using low-dose L-Dopa in GTS.

D2 dopamine receptors and the striatopallidal pathway modulate L-DOPA-induced dyskinesia in the mouse

L-DOPA-induced dyskinesia (LID) remains a major complication of Parkinson's disease management for which better therapies are necessary. The contribution of the striatonigral direct pathway to LID is widely acknowledged but whether the striatopallidal pathway is involved remains debated. Selective optogenetic stimulation of striatonigral axon terminals induces dyskinesia in mice rendered hemiparkinsonian with the toxin 6-hydroxydopamine (6-OHDA). Here we show that optogenetically-induced dyskinesia is increased by the D2-type dopamine receptor agonist quinpirole. Although the quinpirole effect may be mediated by D2 receptor stimulation in striatopallidal neurons, alternative mechanisms may be responsible as well. To selectively modulate the striatopallidal pathway, we selectively expressed channelrhodopsin-2 (ChR2) in D2 receptor expressing neurons by crossing D2-Cre and ChR2-flox mice. The animals were rendered hemiparkinsonian and implanted with an optic fiber at the ipsilateral external globus pallidus (GPe). Stimulation of ChR2 at striatopallidal axon terminals reduced LID and also general motility during the off L-DOPA state, without modifying the pro-motor effect of low doses of L-DOPA producing mild or no dyskinesia. Overall, the present study shows that D2-type dopamine receptors and the striatopallidal pathway modulate dyskinesia and suggest that targeting striatopallidal axon terminals at the GPe may have therapeutic potential in the management of LID.

A Case of Autosomal Recessive Dopa Responsive Dystonia (DRD) with GCH1 Gene Mutation

Timely diagnosis of Segway’s disease is very important and neurologists should always consider it in the differential diagnosis of dystonia. Because the symptoms of this disease can be resolved with low doses of Levodopa and the patient can lead a normal life in the community. Another important issue is genetic counselling for these patients before marriage or pregnancy, the mode of inheritance and the risk of their children should be investigated and estimated. Here we present a case of Segawa patient who was challenging in genetic counselling.

Levodopa Is Associated with Reduced Development of Neovascular Age-Related Macular Degeneration

To determine whether levodopa (L-DOPA) is associated with a reduced likelihood of developing neovascular age-related macular degeneration (AMD). Three studies were performed: retrospective analyses in the Vestrum Health Retina Database (#1-2) and case-control analysis in the Merative MarketScan Research Databases (#3). Eyes with neovascular AMD and 2 years of follow-up (#1). Eyes with non-neovascular AMD and 1 to 5 years of follow-up (#2). Patients aged ≥ 55 years with newly diagnosed neovascular AMD matched to controls without neovascular AMD (#3). Eyes were divided into 2 groups (#1-2): exposed to L-DOPA before or on the date of neovascular (#1) or nonneovascular (#2) AMD diagnosis, and eyes not exposed to L-DOPA. We extracted AMD risk factors, number of intravitreal injections (#1), and conversion rate to neovascular AMD (#2). We calculated the percentage of newly diagnosed neovascular AMD cases and matched controls exposed to any L-DOPA and determined the cumulative 2-year dose in grams by tertiles (< 100 mg, approximately 100-300 mg, and approximately > 300 mg per day, #3). Number of intravitreal injections (#1) and detection of new-onset neovascular AMD (#2-3) after adjusting for AMD risk factors. In the Vestrum database, eyes with neovascular AMD that were exposed to L-DOPA underwent 1 fewer intravitreal injection over 2 years (N= 84 088 control vs. 530 L-DOPA eyes, P= 0.006). In eyes with nonneovascular AMD (N= 42 081-203 155 control vs. 314-1525 L-DOPA eyes), L-DOPA exposure was associated with a reduced risk of conversion to neovascular AMD by 21% at year 2 (P= 0.029), 35% at years 3 to 4 (P < 0.001), and 28% at year 5 (P= 0.024). In the MarketScan databases (N= 86 900 per group), cumulative 2-year doses of L-DOPA between approximately 100 to 300 mg per day and approximately > 300 mg were associated with decreased odds of developing neovascular AMD by 15% (odds ratio [OR], 0.85; 95% confidence interval [CI], 0.75-0.97) and 23% (OR, 0.77; 95% CI, 0.67-0.87), respectively. Levodopa use was associated with reduced detection of new-onset neovascular AMD. A prospective, randomized clinical trial should be considered to investigate whether low-dose L-DOPA reduces neovascular AMD conversion. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Downregulation of striatal CaV1.3 inhibits the escalation of levodopa-induced dyskinesia in male and female parkinsonian rats of advanced age

In the past 25 years, the prevalence of Parkinson's disease (PD) has nearly doubled. Age remains the primary risk factor for PD and as the global aging population increases this trend is predicted to continue. Even when treated with levodopa, the gold standard dopamine (DA) replacement therapy, individuals with PD frequently develop therapeutic side effects. Levodopa-induced dyskinesia (LID), a common side effect of long-term levodopa use, represents a significant unmet clinical need in the treatment of PD. Previously, in young adult (3-month-old) male parkinsonian rats, we demonstrated that the silencing of CaV1.3 (Cacan1d) L-type voltage-gated calcium channels via striatal delivery of rAAV-CaV1.3-shRNA provides uniform protection against the induction of LID, and significant reduction of established severe LID. With the goal of more closely replicating a clinical demographic, the current study examined the effects of CaV1.3-targeted gene therapy on LID escalation in male and female parkinsonian rats of advanced age (18-month-old at study completion). We tested the hypothesis that silencing aberrant CaV1.3 channel activity in the parkinsonian striatum would prevent moderate to severe dyskinesia with levodopa dose escalation. To test this hypothesis, 15-month-old male and female F344 rats were rendered unilaterally parkinsonian and primed with low-dose (3–4 mg/kg) levodopa. Following the establishment of stable, mild dyskinesias, rats received an intrastriatal injection of either the Cacna1d-specific rAAV-CaV1.3-shRNA vector (CAV-shRNA), or the scramble control rAAV-SCR-shRNA vector (SCR-shRNA). Daily (M-Fr) low-dose levodopa was maintained for 4 weeks during the vector transduction and gene silencing window followed by escalation to 6 mg/kg, then to 12 mg/kg levodopa. SCR-shRNA-shRNA rats showed stable LID expression with low-dose levodopa and the predicted escalation of LID severity with increased levodopa doses. Conversely, complex behavioral responses were observed in aged rats receiving CAV-shRNA, with approximately half of the male and female subjects—therapeutic ‘Responders’—demonstrating protection against LID escalation, while the remaining half—therapeutic ‘Non-Responders’—showed LID escalation similar to SCR-shRNA rats. Post-mortem histological analyses revealed individual variability in the detection of Cacna1d regulation in the DA-depleted striatum of aged rats. However, taken together, male and female therapeutic ‘Responder’ rats receiving CAV-shRNA had significantly less striatal Cacna1d in their vector-injected striatum relative to contralateral striatum than those with SCR-shRNA. The current data suggest that mRNA-level silencing of striatal CaV1.3 channels maintains potency in a clinically relevant in vivo scenario by preventing dose-dependent dyskinesia escalation in rats of advanced age. As compared to the uniform response previously reported in young male rats, there was notable variability between individual aged rats, particularly females, in the current study. Future investigations are needed to derive the sex-specific and age-related mechanisms which underlie variable responses to gene therapy and to elucidate factors which determine the therapeutic efficacy of treatment for PD.

A quantitative systems pharmacology model for simulating OFF-Time in augmentation trials for Parkinson's disease: application to preladenant.

The clinical impact of therapeutic interventions in Parkinson's disease is often measured as a reduction in OFF-time when the beneficial effects of the standard-of-care L-DOPA formulations wanes off. We investigated the pharmacodynamic interactions of augmentation therapy to standard-of-care using a quantitative systems pharmacology (QSP) model of the basal ganglia motor circuit, essentially a computer model of neuronal firing in the different subregions with anatomically informed connectivity, cell-specific expression of 17 different G-protein coupled receptors and corresponding coupling to voltage-gated ion channel effector proteins based on experimentally observed intracellular signaling. The calculated beta/gamma (b/g) power spectrum of the local field potentials in the subthalamic nucleus was previously calibrated on the clinically relevant Unified Parkinson's Disease Rating Scale (UPDRS). When combining this QSP model with PK modeling of different formulations of L-DOPA, we calculated the b/g fluctuations over a 16h awake period and used a weighted distance from a specific threshold to determine the cumulative liability of OFF-Time. Prediction of OFF-time with clinical observations of different L-DOPA formulations showed a significant correlation. Simulations show that augmentation with the adenosine A2A antagonist preladenant reduces OFF-time with 6min for carbidopa/levodopa 950mg 5-times daily to 37min for 100mg L-DOPA - 3 or 5 times daily. Exploring delays between preladenant and L-DOPA intake did not improve the outcome. Hypothetical A2A antagonists with an ideal PK and pharmacology profile can achieve OFF-Time reductions ranging from 9.5min with DuoDopa to 55min with low dose L-DOPA formulations. Combination of the QSP model with PK modeling can predict the anticipated OFF-Time reduction of novel A2A antagonists with standard of care. With the large number of GPCR in the model, this combination can support both the design of clinical trials with new therapeutic agents and the optimization of combination therapy in clinical practice.

The clinical significance of disease diagnosis in the treatment of dopa-responsive dystonia with low-dose levodopa

article: The clinical significance of disease diagnosis in the treatment of dopa-responsive dystonia with low-dose levodopa - Gazzetta Medica Italiana - Archivio per le Scienze Mediche 2022 April;181(4):291-2 - Minerva Medica - Journals

Current Therapies and Drug Development Pipeline in Lewy Body Dementia: An Update.

The term Lewy body dementia refers to either of two related diagnoses: dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). Clinical management of Lewy body dementia is challenging. The current treatment options focus on relieving symptoms; no disease-modifying therapies are available. There are currently no US Food and Drug Administration (FDA) approved drugs for the treatment of DLB, and there are only a few for PDD. Cholinesterase inhibitors are shown to be beneficial in improving cognitive symptoms in Lewy body dementia. Rivastigmine was approved by the FDA to treat PDD. Donepezil was approved in Japan as a treatment for DLB. Levodopa may provide modest benefit in treating motor symptoms and zonisamide in adjunct to low-dose levodopa helps with parkinsonism. Treatment of autonomic symptoms are based on symptomatic treatment with off-label agents. Our main objective in this article is to present an overview of the current pharmacological options available to treat the clinical features of DLB and PDD. When evaluating the existing management options for Lewy body dementia, it is difficult to fully separate PDD from DLB. However, we have attempted to identify whether the cited studies include patients with PDD and/or DLB. Moreover, we have provided an overview of the current drug pipeline in Lewy body dementia. All currently active trials are in phase I or II and most are focused on disease modification rather than symptomatic treatment. Phase II trial results for neflamapimod show promising results. Due to heterogeneity of symptoms and underlying pathophysiology, there is a need for new biomarker strategies and improved definitions of outcome measures for Lewy body dementia drug trials.

Dopa-responsive dystonia or Segawa disease in Ghana: a case report

Dystonias are rare in childhood and consist of variably sustained twisting deformation of a limb or parts of a trunk. Dystonias can be considered primary because of a genetic disorder or secondary due to a central nervous system injury like cerebral palsy or medications. The rare dopa-responsive dystonia is often mistaken for cerebral palsy, stroke, localized limb trauma or conversion disorder. The aim of this report is to increase the awareness of a rare but eminently treatable type of dystonia known as dopa–responsive dystonia or Segawa disease. In this report a young girl with dystonia who was severely disabled and could not attend school was misdiagnosed as cerebral palsy for two years. After treatment with low dose L-dopa within 48 hours, a dramatic and sustained response with restoration of foot dystonia and mobility was observed. Recognition of L-dopa dystonia facilitates proper treatment and significant improvement in quality of life

Commentary on a case report of Dopa-responsive dystonia or Segawa disease in Ghana

The case of Dopa-Responsive Dystonia or Segawa Disease reported in this issue brings to the fore the age-old tenets of medicine which is based on the taking of a detailed history, physical examination, and the request of relevant investigations to achieve a diagnosis. This is followed with an evidence-based treatment planning. This maxim remains important especially in resource poor environments where sometimes one must depend on the history and physical examination findings alone to make a diagnosis and commence treatment. The patient under review had had her condition progressively worsening for two years and had been managed as a case of cerebral palsy.The initial consideration of a possible dyskinetic cerebral palsy from bilirubin encephalopathy which the author indicated was common is understandable as this is one of the commonest causes of such presentation in the setting. However, having a more detailed history and having other differentials in mind such as childhood Dopa-Responsive Dystonia, as was the case presented, helped in identifying subtle differences in presentation that influenced the ultimate diagnosis. In this case, a later onset of symptoms (dystonia), with the symptoms being minimal after sleep and becoming more severe late afternoon having helped to clinch the diagnosis. Considering each patient one sees as eligible for a possible case report allows one to update his or her knowledge on the condition, identify peculiar features and directs the request of relevant investigations. The use of telemedicine is yet to be widespread in the developing world even though telecommunication infrastructure is improving in these regions. This case had the diagnosis essentially made by contacting a paediatric neurologist by telephone. Such specialist consultations need to be encouraged as there are very few specialists across the globe and less still in the developing economies.Governments and Medical Associations may have to lead in creating these platforms to assist in this direction to improve the overall access to specialist care and reviews in less endowed regions. In the case presented, the diagnosis of Dopa-Responsive Dystonia was confirmed after a demonstration of a marked and sustained response to low dose L-dopa without motor fluctuations or dyskinesias. We applaud the author for the diagnosis having been made by essentially a detailed history and physical examination and response to L-dopa. It was however indicated that there are recent developments that involve analysis of cerebrospinal fluid for neurotransmitters that demonstrate low concentrations of biopterin and neopterin with DNA sequencing demonstrating mutation of the GTP cyclohydrolase-1 gene in up to 80% of cases in gene studies. These diagnostic tests hinge on the finding of an autosomal dominant heterozygous mutation in the GTPcyclohydrolase-I gene that results in biopterin deficiency, a cofactor for tyrosine hydroxylase and dopamine deficiency and considered the most classic molecular pathophysiology of this condition [1]. These additional tests were not done bringing to the fore the limited access to investigative tools in some developing economies. While National Reference Laboratories are in existence in some countries, regional efforts could be made to set up reference laboratories that serve entire region to allow for pooling of infrequently performed laboratory tests for analysis. This will make such infrequently encountered medical conditions be accurately diagnosed and treated. Of concern is how to achieve an un-interrupted supply of L-Dopa as the child returns to the village. This should engage the attention of all involved in her treatment as they follow the patient up.To conclude, the suggestion by the author that the diagnosis of Dopa-Responsive Dystopia or Segawa disease must be considered in all cases of dystonia including cases of apparent dystonic cerebral palsy and especially where there is no history of birth asphyxia need being emphasized.

Spectral signatures of L-DOPA-induced dyskinesia depend on L-DOPA dose and are suppressed by ketamine

L-DOPA-induced dyskinesias (LID) are debilitating motor symptoms of dopamine-replacement therapy for Parkinson's disease (PD) that emerge after years of L-DOPA treatment. While there is an abundance of research into the cellular and synaptic origins of LID, less is known about how LID impacts systems-level circuits and neural synchrony, how synchrony is affected by the dose and duration of L-DOPA exposure, or how potential novel treatments for LID, such as sub-anesthetic ketamine, alter this activity. Sub-anesthetic ketamine treatments have recently been shown to reduce LID, and ketamine is known to affect neural synchrony. To investigate these questions, we measured movement and local-field potential (LFP) activity from the motor cortex (M1) and the striatum of preclinical rodent models of PD and LID. In the first experiment, we investigated the effect of the LID priming procedures and L-DOPA dose on neural signatures of LID. Two common priming procedures were compared: a high-dose procedure that exposed unilateral 6-hydroxydopamine-lesioned rats to 12 mg/kg L-DOPA for 7 days, and a low-dose procedure that exposed rats to 7 mg/kg L-DOPA for 21 days. Consistent with reports from other groups, 12 mg/kg L-DOPA triggered LID and 80-Hz oscillations; however, these 80-Hz oscillations were not observed after 7 mg/kg administration despite clear evidence of LID, indicating that 80-Hz oscillations are not an exclusive signature of LID. We also found that weeks-long low-dose priming resulted in the emergence of non-oscillatory broadband gamma activity (> 30 Hz) in the striatum and theta-to-high-gamma cross-frequency coupling (CFC) in M1. In a second set of experiments, we investigated how ketamine exposure affects spectral signatures of low-dose L-DOPA priming. During each neural recording session, ketamine was delivered through 5 injections (20 mg/kg, i.p.) administered every 2 h. We found that ketamine exposure suppressed striatal broadband gamma associated with LID but enhanced M1 broadband activity. We also found that M1 theta-to-high-gamma CFC associated with the LID on-state was suppressed by ketamine. These results suggest that ketamine's therapeutic effects are region specific. Our findings also have clinical implications, as we are the first to report novel oscillatory signatures of the common low-dose LID priming procedure that more closely models dopamine replacement therapy in individuals with PD. We also identify neural correlates of the anti-dyskinetic activity of sub-anesthetic ketamine treatment.

Is safinamide useful as a levodopa sparing-therapy in Parkinson's disease patients?

Safinamide is a new drug approved for the treatment of Parkinson's disease (PD) with fluctuations as an adjunct to levodopa alone or in combination with other drugs.1 When fluctuations arise, several therapeutic options can be taken. Safinamide is a MAO-B inhibitor and glutamate modulator which may allow lower doses of levodopa and dopaminergic agonists to be used, minimizing side effects that emerge frequently with high doses of these drugs.2.3

Child Neurology: A young child with an undiagnosed case of dystonia responsive to l -dopa

Childhood-onset dystonias are a heterogeneously diverse group. There exists a specific set of dystonias that respond profoundly well to low doses of l-dopa (dopa-responsive dystonia [DRD]). Classical DRD is caused by deficiency of GTP cyclohydrolase 1 or tyrosine hydroxylase, but other conditions can cause dystonias that are partially responsive to dopamine. The idea of a diagnostic therapeutic trial with l-dopa for children who present with dystonia has been around for decades and is frequently advocated for; however, l-dopa trials are not without risk.

NYX-458 Improves Cognitive Performance in a Primate Parkinson's Disease Model.

NYX-458 is a N-methyl-d-aspartate receptor (NMDAR) modulator that enhances synaptic plasticity. Dopaminergic cell loss in Parkinson's disease (PD) leads to NMDAR dysregulation in the cortico-striato-pallidal-thalmo-cortical network and altered plasticity in brain regions important to cognitive function. We hypothesize that targeting the NMDAR may be an efficacious approach to treating cognitive impairment in PD. NYX-458 was evaluated in 2 nonhuman primate models of PD. The first, a chronic low-dose 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-administration model, was used to assess the effects of NYX-458 on cognitive domains impacted early in PD including attention, working memory, executive function, and visuospatial learning. The second, a high-dose MPTP-administration model, was used to assess potential for NYX-458 induced change in motor symptoms. NYX-458 was evaluated in the chronic low-dose MPTP model using the variable delayed response measure to assess attention and working memory and simple discrimination reversal to assess executive function. NYX-458 was also assessed in the high-dose MPTP model as a monotherapy and in combination with low-dose or high-dose levodopa to assess potential impact on motor symptoms. NYX-458 administration resulted in rapid and long-lasting improvement in cognitive function across the domains of attention, working memory, and executive function. Dose levels effective in improving cognitive performance had no effect on PD motor symptoms, the antiparkinsonian benefit of levodopa, or dyskinesia. NYX-458 provides benefit in specific domains known to be impaired in PD in a dopamine depletion model of PD-like cognitive impairment. These data support the continued evaluation of NYX-458 as a potential therapeutic for cognitive decline in PD. © 2020 International Parkinson and Movement Disorder Society.

Early onset peak-dose L-dopa induced dyskinesia in 55-year-old Ethiopian Parkinson’s disease patient

A case study of a 55-year-old newly diagnosed Parkinson’s disease patient naïve to L-dopa, who develop disabling early onset L-dopa induced dyskinesia (LID), which occurs immediately following L-dopa administration is presented. It is recommend to start with low dose L-dopa and to escalate slowly to avoid L-dopa included dyskinesia in dopamine naïve Parkinson’s disease patients.Keywords: Parkinson’s disease, L-dopa, peak-dose induced dyskinesia, 55-year-old male, Ethiopian

Genetic silencing of striatal CaV1.3 prevents and ameliorates levodopa dyskinesia.

BackgroundLevodopa‐induced dyskinesias are an often debilitating side effect of levodopa therapy in Parkinson's disease. Although up to 90% of individuals with PD develop this side effect, uniformly effective and well‐tolerated antidyskinetic treatment remains a significant unmet need. The pathognomonic loss of striatal dopamine in PD results in dysregulation and disinhibition of striatal CaV1.3 calcium channels, leading to synaptopathology that appears to be involved in levodopa‐induced dyskinesias. Although there are clinically available drugs that can inhibit CaV1.3 channels, they are not adequately potent and have only partial and transient impact on levodopa‐induced dyskinesias.MethodsTo provide unequivocal target validation, free of pharmacological limitations, we developed a CaV1.3 shRNA to provide high‐potency, target‐selective, mRNA‐level silencing of striatal CaV1.3 channels and examined its ability to impact levodopa‐induced dyskinesias in severely parkinsonian rats.ResultsWe demonstrate that vector‐mediated silencing of striatal CaV1.3 expression in severely parkinsonian rats prior to the introduction of levodopa can uniformly and completely prevent induction of levodopa‐induced dyskinesias, and this antidyskinetic benefit persists long term and with high‐dose levodopa. In addition, this approach is capable of ameliorating preexisting severe levodopa‐induced dyskinesias. Importantly, motoric responses to low‐dose levodopa remained intact in the presence of striatal CaV1.3 silencing, indicating preservation of levodopa benefit without dyskinesia liability.DiscussionThe current data provide some of the most profound antidyskinetic benefit reported to date and suggest that genetic silencing of striatal CaV1.3 channels has the potential to transform treatment of individuals with PD by allowing maintenance of motor benefit of levodopa in the absence of the debilitating levodopa‐induced dyskinesia side effect. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Baicalein enhances the effect of low dose Levodopa on the gait deficits and protects dopaminergic neurons in experimental Parkinsonism

Parkinson’s Disease (PD) is the second most common neurodegenerative disease with the clinical characteristics of gait deficits. The classical symptomatic treatment for PD is Levodopa (L-DOPA) which brings a plethora of side effects and dosage problems in a prolonged drug regimen. Baicalein is a flavonoid extracted from Scutellaria baicalensis Georgi with the properties of neuroprotection. In this study, we investigated the ameliorative effect of baicalein with low dose L-DOPA (25 mg/kg) on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced Parkinsonism. The gait variability was assessed by a computer-assisted gait analysis system Catwalk. The results showed that MPTP challenged mice had significant gait deficits on dynamic paw function and posture stability. L-DOPA reversed the MPTP induced gait deficits and the effect was positively dose-dependent. The combined treatment of baicalein and under threshold dose of L-DOPA significantly improved gait functions, compared with exclusive low dose L-DOPA treatment, and the effect was comparable with high dose L-DOPA treatment. The histological assessment demonstrated that the Tyrosine hydroxylase expression increased in all the baicalein stratified groups, which suggest baicalein might have the neuroprotective effect to retain the dopaminergic neurons or enhance the dopaminergic neuron regeneration after MPTP injection. This neuroprotection probably depended on altering the inflammatory response and resisting the apoptosis through the underlying mechanism investigation. Our study provides experimental evidence that the combination of L-DOPA and baicalein might be a potential treatment for Parkinson's disease. The synergistic interaction of baicalein and L-dopa treatment might reduce the side-effect of the normal to high dose L-DOPA used today.