Discovery of small-molecule compounds and natural products against Parkinson's disease: Pathological mechanism and structural modification

Testing of a hypothesis for osmotic opening of the blood-brain barrier.

It remains unclear which adjunctive drug for Parkinson’s disease (PD) in combination with levodopa is more effective, tolerable, and safe. We aimed to compare the efficacy, tolerability, and safety among anti-PD drugs from several classes in patients with fluctuating PD who received levodopa through network meta-analysis (NMA). Twelve anti-PD drugs belonging to 4 different drug classes (dopamine agonists, monoamine oxidase type B inhibitors, catechol-O-methyl transferase inhibitors, and an adenosine A2A receptor antagonist) were selected. We systematically searched PubMed, Embase, and the Cochrane Library for eligible randomized controlled trials (RCTs) comparing placebo with anti-PD drug or among anti-PD drugs in patients with PD who experienced motor fluctuations or wearing-off and received levodopa. We included 54 RCTs in the analysis. The NMA was performed under a frequentist framework using a random-effects model. The efficacy outcome was change in daily off-time, and the tolerability outcome was discontinuation due to all causes. Safety outcomes included discontinuation due to adverse events (AEs) and the incidence of AEs, dyskinesia, hallucination, and orthostatic hypotension. According to the surface under the cumulative ranking curve (SUCRA) in the NMA, ropinirole transdermal patch (SUCRA, 0.861) ranked the highest in efficacy, followed by pramipexole (0.762), ropinirole extended release (ER) (0.750), and safinamide (0.691). In terms of tolerability, ropinirole (0.954) ranked the highest, followed by pramipexole (0.857), safinamide (0.717), and ropinirole ER (0.708). Each anti-PD drug had different SUCRA ranking profiles for the safety outcomes. These findings suggest that ropinirole, pramipexole, and safinamide are well-balanced anti-PD drugs that satisfy both efficacy and tolerability outcomes.

Non-motor symptoms (NMS) are important factors when selecting treatments for patients with advanced Parkinson's disease (PD). We sought to elucidate the prescribing practices for advanced PD patients with NMS in Japanese clinical practice. We examined the prescription rates and doses of anti-PD drugs, and the use of non-steroidal anti-inflammatory drugs (NSAIDs) in post hoc analyses of a 52-week observational study of 996 PD patients with wearing-off on levodopa-containing therapy and ≥1 NMS. Dopamine agonists were the most frequently prescribed drugs combined with levodopa-containing drugs, followed by entacapone, zonisamide, istradefylline, selegiline, and amantadine. The daily dose of levodopa-containing drugs, rotigotine, entacapone, istradefylline, and droxidopa, and the levodopa-equivalent dose increased during the observation period. In a subgroup analysis of patients stratified by NMS status (improved/unchanged/deteriorated), the deteriorated group had higher prescription rates of entacapone and istradefylline, whereas the improved group had higher prescription rates of NSAIDs and zonisamide at Week 52. Prescriptions varied by geographical region for anti-PD drugs and by NMS status for NSAIDs. There were significant changes in the prescriptions and dosing of selected anti-PD drugs, especially newer drugs. Anti-PD drug and NSAID prescriptions also varied by changes in NMS status and geographic region.

We investigated treatment persistence and adherence for levodopa adjunct medications and their relationship with demographic factors in Japanese patients with Parkinson's disease (PD). This longitudinal retrospective study used a Japanese health insurance claims database for levodopa adjunct medications in patients newly prescribed anti-PD drugs other than levodopa between December 2020 and November 2021. Patients with a PD diagnosis were included in this study, and 17 anti-PD drug cohorts were formed. The primary outcomes were treatment persistence and adherence over 1 year. Multivariate analysis was conducted to evaluate demographic factors associated with treatment persistence/adherence. In total, 7,605 patients were included in this analysis, with a mean age of 77.2 years, and 43.6% were male. The 1-year treatment persistence rate was 44.8%. Median persistent treatment duration over 1 year was 270.0 days. Persistence rates ranged from 28.6 to 59.5% across the drug cohorts, and were highest for zonisamide (59.5%) followed by safinamide (55.8%). The proportion of patients with proportion of days covered ≥80% (good treatment adherence) was 96.9% in the all-drugs cohort and ≥ 90% in each drug-specific cohort. In the multivariate analysis, the factor most strongly associated with non-persistence was the number of concomitant anti-PD drugs (risk ratio [RR] 0.85 per 1 unit increase), with the exception of inpatient prescriptions (RR 0.75). More than half of the new anti-PD drugs added to levodopa were discontinued within 1 year, and adherence to treatment, as assessed by filling records, was extremely high in patients with PD, including the elderly population.

Recent advances in discovery and development of natural products as source for anti-Parkinson's disease lead compounds

Objective: Levodopa up-titration is the primary therapeutic strategy as the Parkinson’s disease (PD) progresses. However, the effects of levodopa up-titration on blood pressure (BP) are inconclusive. This study aimed to investigate the effect of acute levodopa up-titration simulated by levodopa challenge test (LCT) on BP in patients with early stage PD.Methods: We monitored BP in 52 patients with early stage PD using a standardized standing test. BP was assessed in supine position after 10 min of rest and at 1 and 3 min after standing up. BP was measured in the “off-state” and the best “on-state” during LCT in the morning at hospital. In another day, “off-state” and the best “on-state” BP was measured before and after anti-PD drug uptake in the morning at home. Demographic and clinical features of the patients were evaluated and analyzed.Results: In the LCT, the prevalence of OH in the “off-state” and the best “on-state” was 11.5 and 13.5%, respectively. Additionally, the OH in the best “on-state” was associated with OH in the “off-state” and monoamine oxidase B inhibitor use. Although 38 (73.1%) patients experienced levodopa-induced hypotension during the LCT, no risk factors were identified. While BP reductions were observed after taking anti-PD drugs at home, no further reduction was seen during acute levodopa up-titration simulated by the LCT.Conclusion: Our results demonstrate that acute levodopa up-titration does not exacerbate BP reduction induced by anti-PD drugs at home. BP monitoring is critical for the management of patients with PD.

Jay Nutt: a boatman's calling

Bioanalysis was of no importance to drug discovery for 65 years. Today, it seems almost impossible that a drug could be discovered, developed and marketed without extensive bioanalysis. This brief editorial looks back at drug discovery practices and tries to provide a logical sequence of thinking and events that led to today. The author's belief is that the ingenuity and skills of bioanalytical scientists will be tested to the utmost in the present and future phase. Although simplistic, the author has divided drug discovery into three phases: PD, PK and PK/PD. The PD phase of drug discovery

We found that zonisamide (ZNS) has beneficial effects on Parkinson's disease (PD). ZNS is originally synthesized in Japan and has been used for over 10 years to treat intractable epilepsy. We administered 300 mg of ZNS to a patient with PD who incidentally had convulsive attacks. The attacks disappeared and, surprisingly, the parkinsonian symptoms improved dramatically. An open trial of ZNS (given in addition to their anti-PD drugs) in advanced PD patients clearly showed the lessening of symptoms, especially wearing-off. Although the effects gradually decreased after 1.5 years, more than 30% improvement of UPDRS total score was maintained up to 3 years. Nation-wide double-blind controlled study confirmed that the small dose (50mg/day) of ZNS improved all the cardinal symptoms of PD. As for its mechanism, we showed that ZNS increases dopamine contents in the striatum by activating dopamine synthesis and the level of mRNA of tyrosine hydroxylase (TH) prior to that of TH protein. ZNS moderately inhibits monoamine oxydase (MAO) B. It has no effects on dopamine receptors, dopamine transporter or dopamine release. ZNS has no direct effects on glutamate receptors, adenosine receptors, or serotonergic system, which have been suggested to be effective points of anti-PD drug other than dopamine system. Therefore, it is suggested that the activation of dopamine synthesis and the moderate level of MAOB inhibition are main mechanisms of ZNS effects on PD. ZNS has significant effects on T-type Ca(++) channels and oxidative stress. They may also affect the beneficial action of ZNS on PD.

The prevalence of Parkinson's disease in British Columbia, Canada, estimated by using drug tracer methodology

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Background: Deep brain stimulation (DBS) of the subthalamic nucleus is an effective treatment option for patients with Parkinson’s disease (PD). The risk factors associated with the occurrence of psychiatric symptoms have not been completely elucidated. Methods: We conducted a naturalistic observational study on patients with PD who would be subjected to DBS. Clinical data, including motor functions, cognitive functions, mental status, and daily dosage of anti-PD drugs were monitored. A psychiatrist evaluated their psychiatric symptoms at the initial assessment, three months, and one year after DBS. Results: We evaluated 44 participants with PD, of which 32 were subjected to DBS. Thirteen participants were diagnosed with mental disorders at the initial assessment. Twenty-six patients were reassessed at three months after surgery, and 19 participants were reassessed at one year. At three months, the motor function of the participants was significantly improved, and the mean anti-PD drug dose was significantly decreased. Sixteen participants were experiencing some psychiatric symptoms, of which 12 were considered as worsened due to DBS, whereas 6 participants experienced improved mental state. At one year, 6 participants were suffering from some psychiatric symptoms caused by DBS, whereas improvement was observed in 6 participants. An exploratory analysis revealed that participants without dopamine dysregulation syndrome (DDS) at the screening were likely to improve their psychiatric symptoms. Conclusion: Although DBS caused some psychiatric complications, mental status was improved in some patients in a longitudinal course. DDS is possible to predict poor outcome in psychiatric complication after DBS in PD patients.

Gamma aminobutyric acid type A (GABAA) receptors are the major inhibitory neurotransmitter receptors in the Central Nervous System (CNS). Several clinically important drugs used to treat anxiety, insomnia and epilepsy act via an allosteric modulation of postsynaptic GABAA receptors. The currently used drugs are associated with serious side-effects, mainly due to a lack of receptor subtype selectivity. This raises the medical need for discovery of novel types of GABAA receptor modulators. We previously identified a series of allosteric GABAA receptor agonists with the aid of HPLC-based activity profiling, whereby activity was tracked with an electrophysiological assay in Xenopus oocytes expressing GABAA receptors of desired subunit composition. In an expansion of our investigations, aiming at acceleration of the activity profiling, an in-house assay was established using larval zebrafish locomotor activity model. In that, larval convulsions were provoked by the pro-convulsant GABAA receptor antagonist pentylenetetrazol (PTZ), and GABAA receptor agonistic extracts and compounds were identified through a decrease in larval locomotion. The assay was validated with the aid of known GABAergic compounds that had previously shown activity in the Xenopus oocyte assay. Assay validation was approached with respect to parameters relevant for the quality of results, including PTZ concentration, number of larvae, concentration of test samples, duration of incubation with test solutions and tracking of larval locomotion, as well as data visualization protocol. The validated protocol was subsequently translated into an HPLC-based activity profiling protocol using ethyl acetate extracts of Valeriana officinalis and Magnolia officinalis. The zebrafish larvae locomotor assay was later employed for activity profiling of South African medicinal plants traditionally used for the treatment of epilepsy and other neurological disorders. An initial screening of medicinal plants in Xenopus oocytes patch clamp assay revealed GABAergic activity of a dichloromethane extract from leaves of Searsia pyroides. The extract significantly lowered PTZ-provoked locomotion in zebrafish larvae when tested at 4 μg/mL. HPLC-based profiling followed by targeted isolation of phytochemicals in the active timewindow, revealed identification of three anacardic acid derivatives (1-3). Also, three structurally related compounds (4-6) were purified from inactive areas. After assessment of the isolated compounds with both Xenopus oocyte and larval zebrafish models, GABAA receptor modulation activity of the extract was successfully correlated with the phytochemicals in the active time-window. Additionally, in the zebrafish larval assay a series of GABAA receptor agonistic natural products, previously identified by the Xenopus oocyte assay, were tested. Lowering of locomotor activity was found for these compounds with exception of sanggenone C. Physicochemical and biochemical properties (PSA, cLogP, number of H-donor and acceptor sites, and number of rotatable bonds) of tested compounds were calculated in silico. A lack of permeability across the blood-brain-barrier (BBB) was concluded for sanggenone C, inferring its lack of activity in vivo, which also remarked the exclusivity of the zebrafish larvae assay for discovery of BBB permeable natural products. The last part of our research focused on the membrane permeability of kaempferol (KMF), a sedative flavonoid which targets GABAA receptors, and its major intestinal metabolite, 4-hydroxyphenylacetic acid (4-HPAA). In previous studies, KMF induced sedative effects in mice only after oral administration (i.o.) but not after intraperitoneal application (i.p.). However, 4- HPAA, the biotransformation product of KMF by intestinal microflora, induced behavioral changes after i.p. injection. To further explore the relation between KMF and 4-HPAA bioactivities and their route of administration, their ability to cross biological barriers has been examined. Intestinal barrier permeability studies were performed with Caco-2 cells, and bloodbrain barrier transport studies were done with an immortalized mono-culture human model and a primary triple-co-culture rat model. UHPLC–MS/MS quantification methods for bioanalysis of KMF and 4-HPAA in the corresponding transport media were developed and validated according to international guidelines. The fundamental validation parameters included accuracy, precision, specificity, selectivity, sensitivity, repeatability, reproducibility, short-term and long-term stabilities. Data obtained with all barrier models were indicative of high intestinal and BBB permeation of KMF, and no permeation for 4-HPAA when compared with the fluorescent barrier integrity markers. In all experiments efflux ratios were below two, indicating that no active transport processes were involved for both compounds. Within a calcein-AM uptake assay in porcine brain capillary endothelial cells, kaempferol and 4-HPAA were found neither Pglycoprotein substrates nor P-glycoprotein inhibitors. Our in vitro data supported the previous described in vivo CNS effects of KMF while the role of 4-HPAA needs to be further studied.

Treatment of Parkinson's disease in Zebrafish model with a berberine derivative capable of crossing blood brain barrier, targeting mitochondria, and convenient for bioimaging experiments

A novel adenosine A 1 and A 2A receptor antagonist ASP5854 ameliorates motor impairment in MPTP-treated marmosets: Comparison with existing anti-Parkinson's disease drugs