Evaluation of Betulinic Acid Effects on Pain, Anxiety, Catalepsy, and Oxidative Stress in Animal Model of Parkinson’s Disease.

BackgroundParkinson’s disease (PD) is known by motor impairments. Betulinic acid (BA) is a natural active compound with potent antioxidant activity. The present study addresses the question whether BA affects motor dysfunctions, pain, anxiety and molecular changes in the rat model of PD.MethodsRight medial forebrain bundle (MFB) was lesioned by injection of 6-OHDA in Male Wistar rats. BA (0.5, 5 & 10 mg/kg) and L-dopa (20 mg/kg) were administrated for 7 days. rigidity, anxiety, analgesia and memory, were assessed by bar test, open-field, elevated plus-maze (EPM), tail-flick and shuttle box. Additionally, the malondialdehyde (MDA), Superoxide dismutase (SOD), glutathione peroxidase (GPx) activity as well as Brain-derived neurotrophic factor (BDNF) and Interleukin 10 (IL10) levels in the brain tissue were measured.ResultsTreatment with BA significantly reversed the 6-OHDA-induced motor complication in the bar test, but it modified anxiety like behavior neither in open-field nor in EPM, it only decreased the time spent in open arms. Moreover no significant changes were found in the tail-flick between treatment and sham groups. On the other hand, the level of MDA & IL10 were decreased, and the activity of GPx, levels of SOD & BDNF in the rats brains were increased.ConclusionOur results showed that BA could affect as a potent natural free radical scavenger which removes brain tissue oxidants in PD. It can account a possible promise as a good therapeutic agent for motor and non-motor complications in PD.

P.042 Dopamine Dysregulation Syndrome in Parkinson’s Disease and its Management with Advanced Therapies

Background: Dopamine Dysregulation Syndrome (DDS) is an adverse non-motor complication of dopamine replacement therapy in Parkinson’s Disease. The current literature on DDS is limited, and it remains underdiagnosed and challenging to manage. Methods: We performed a retrospective chart review and classified patients according to risk factors that have been identified in the literature, UPDRS scores, intervention and outcome. Univariate analyses were performed to quantify these characteristics. Results: Prior psychiatric illness was identified in 70% of patients, impulse control disorder in 89% and substance abuse in 3.7%. Interventions included reduction of dopamine therapy (88.9%), deep brain stimulation (DBS) of the subthalamic nucleus (STN, 48.1%) or globus pallidus interna (GPi, 7.4%), and levodopa-carbidopa intestinal gel (LCIG) infusion (11.1%). Baseline UPDRS IV before treatment and MDS III after treatment were not significant between intervention groups (p=0.09 and p=0.13 respectively). Overall 88.9% patients improved at follow up, with medication only (75%), STN DBS (100%), GPi DBS (100%) and LCIG (33%). Relapse rate was 18.2%, in the STN group only. Conclusions: Our results suggest that GPi DBS, in concurrence with dopaminergic medication reduction, is the most effective intervention. STN DBS might be also beneficial although the associated medications reduction causes DDS relapse in a subgroup of patients.

Social Listening – Revealing Parkinson’s Disease over Day and Night

Background: Nocturnal symptoms in Parkinson’s disease and their related burdens on patients are often treated after management of daytime manifestations. In order to better understand the unmet needs of nocturnal symptoms management, we sought to analyze the characteristics of nocturnal symptoms and the burden of nocturnal-occurring motor and non-motor symptoms from patients’ perspectives.Methods: We used a contemporary Social Listening big-data technique to analyze large amounts of Parkinson’s disease symptoms in patient-doctor and patient-patient dialogues available from social media platforms in China. Frequency of nocturnal symptoms as a proportion of total dialogues per year and their relative negative sentiment were analyzed. As a contrast, overall symptoms (occurring at day or night) were also analyzed. Results: We found that share of voice for overall motor symptoms did not increase from 2016 to 2018 (79%, p = 0.5), but share of voice for non-motor symptoms was 69% in 2018, growing by 7% (p < 0.01), and motor complications was 9%, growing by 6% (p < 0.01), respectively. For nocturnal symptoms, 45% of the analyzed PD population reported nocturnal symptoms in 2018, growing by 6% from 2016 (p < 0.01). Share of voice for nocturnal-occurring motor symptoms was higher than non-motor symptoms. Non-motor symptoms evoked higher negative sentiment no matter whether they occurred during the day or night. For symptoms that can occur at either day or night, each nocturnal symptom was rated with a higher negative sentiment score than the same symptom during the day, regardless of the type of symptom (motor, non-motor, or motor complication).Conclusions: The growing share of voice and the greater negative sentiment of nocturnal symptoms from patients’ perspectives suggest that management of nocturnal symptoms is an unmet need of patients with Parkinson’s disease. A greater emphasis on detecting nocturnal symptoms and treating them with 24-hour care is encouraged.

A Focused Update on Tardive Dyskinesia

Tardive dyskinesia (TD) is a delayed and potentially irreversible motor complication following chronic exposure to centrally acting dopamine receptor antagonists, mainly of the class of antipsychotics drugs. New generations of antipsychotic drugs reduced its mean prevalence to 20%, but it continues to mar the drug experience and social integration in a significant fraction of patients. The underlying molecular cascade remains elusive, explaining in part why TD management is so often difficult. Protocol variations between experimental laboratories and inter-species differences in the biological response to antipsychotic drugs have added layers of complexity. The traditional dopamine D2 receptor supersensitivity hypothesis was revisited in an experimental nonhuman primate model. Findings in the striatum revealed a strong upregulation of D3, not D2, receptors specific to dyskinetic animals, and indirect evidence suggestive of a link between overactivation of glycogen synthase kinase-3β signaling and TD. New effective vesicular monoamine transporter type 2 inhibitors alleviating TD have been approved in the USA. They were integrated to an emerging stepwise treatment algorithm for troublesome TD, which also includes consideration for changes in the current antipsychotic drug regimen and recognition of potentially aggravating factors such as anticholinergic co-medications. These advances may benefit TD.

Receptor Ligands as Helping Hands to L-DOPA in the Treatment of Parkinson’s Disease

Levodopa (LD) is the most effective drug in the treatment of Parkinson’s disease (PD). However, although it represents the “gold standard” of PD therapy, LD can cause side effects, including gastrointestinal and cardiovascular symptoms as well as transient elevated liver enzyme levels. Moreover, LD therapy leads to LD-induced dyskinesia (LID), a disabling motor complication that represents a major challenge for the clinical neurologist. Due to the many limitations associated with LD therapeutic use, other dopaminergic and non-dopaminergic drugs are being developed to optimize the treatment response. This review focuses on recent investigations about non-dopaminergic central nervous system (CNS) receptor ligands that have been identified to have therapeutic potential for the treatment of motor and non-motor symptoms of PD. In a different way, such agents may contribute to extending LD response and/or ameliorate LD-induced side effects.

LRRK2 G2019S Mutation: Prevalence and Clinical Features in Moroccans with Parkinson’s Disease

Background. The LRRK2 G2019S mutation is the most common genetic determinant of Parkinson’s disease (PD) identified to date. This mutation, reported in both familial and sporadic PD, occurs at elevated frequencies in Maghreb population. In the present study, we examined the prevalence of the G2019S mutation in the Moroccan population and we compared the motor and nonmotor phenotype of G2019S carriers to patients with idiopathic Parkinson’s disease. Methods. 100 PD patients were assessed for motor and nonmotor symptoms, current medication, and motor complication including motor fluctuations and dyskinesia. The LRRK2 G2019S mutation was investigated by direct sequencing in patients and ethnically matched controls, all of Moroccan origin. Results. Among the 100 PD Moroccan patients, 41 (41%) were carriers of the G2019S mutation. The mutation frequency was higher among probands with autosomal dominant inheritance (76%) than among sporadic ones (28%). Interestingly, G2019S mutation was also found in 5% of control individuals. Clinically, patients carrying the G2019S mutation have more dystonia (OR = 4.6, p = 0.042) and more sleep disorders (OR = 2.4, p = 0.045) than noncarriers. Conclusions. The LRRK2 G2019S prevalence in Morocco is the highest in the world reported to date. Some clinical features in G2019S carriers such as dystonia and sleep disturbances are worth noting.

Possible Treatment Concepts for the Levodopa-Related Hyperhomocysteinemia

The saga of harmful levodopa (LD) in the treatment of Parkinson's disease (PD) resulted from outcomes of animal—and cell culture studies and the clinical observation of motor complication related to the short half life of LD. Further aspects of LD long term application, the LD associated homocysteine increase and its emerging consequences on progression, and onset of neuropsychiatric symptoms and of vascular disease are only partially considered. Therapeutic approaches for this LD-mediated neurotoxic homocysteine increase are vitamin supplementation or LD application with an inhibitor of catechol-O-methyltransferase (COMT). However, forcing central dopamine metabolism further down the methylation path by central blocking of COMT and MAO-B may reduce oxidative stress and homocysteine levels. But it may also increase N-methylation of tetrahydroisoquinolines to neurotoxic N-methylated tetrahydroisoquinolines. These compounds were observed in cerebrospinal fluid and plasma of long term LD-treated PD patients. Therefore LD application with peripheral COMT inhibition may be safer.