Antiparkinsonian Agents Research Articles

Dopamine D2L receptor density influences the recruitment of β-arrestin2 and Gi1 induced by antiparkinsonian drugs

IntroductionBrain imaging studies have highlighted that the density of dopamine D2 receptors markedly fluctuates across the stages of Parkinson's disease and in response to pharmacological treatment. Moreover, receptor density constitutes a molecular determinant for the signaling profile of D2 receptor ligands. We therefore hypothesized that variations in receptor expression could influence D2 receptor response to antiparkinsonian drugs, most notably with respect to the recruitment bias between Gi1 and β-arrestin2. MethodsThe recruitment bias of dopamine, pramipexole, ropinirole, and rotigotine was examined using a nanoluciferase-based biosensor for probing the interactions of the D2L receptor with either Gi1 or β-arrestin2. The characterization of the functional selectivity of these D2 receptor agonists was performed at two distinct D2L receptor densities by taking advantage of a cell model carrying an inducible system that enables the overexpression of the D2L receptor when exposed to doxycycline. ResultsA high receptor density oriented the balanced signaling profile of dopamine towards a preferential recruitment of Gi1. It also moderated the marked Gi1 and β-arrestin2 biases of pramipexole and rotigotine, respectively. At variance, the Gi1 bias of ropinirole appeared as not being influenced by D2L receptor density. ConclusionsTaken together, these observations highlight receptor density as a key driver of the signaling transducer recruitment triggered by antiparkinsonian agents. Moreover, given the putative beneficial properties of β-arrestin2 in promoting locomotion, this study provides molecular insights that position the arrestin-biased ligand rotigotine as a putatively more beneficial D2 receptor agonist for the treatment of early and late Parkinson's disease.

Individual Pharmacotherapy Management (IPM) - I: a group-matched retrospective controlled clinical study on prevention of complicating delirium in the elderly trauma patients and identification of associated factors

BackgroundDelirium is one of the most frequent complications in hospitalized elderly patients with additional costs such as prolongation of hospital stays and institutionalization, with risk of reduced functional recovery, long-term cognitive impairment, and increased morbidity and mortality. We analyzed the effect of individual pharmacotherapy management (IPM) in the University Hospital Halle in geriatric trauma patients on complicating delirium and aimed to identify associated factors.MethodsIn a retrospective controlled clinical study of 404 hospitalized trauma patients ≥70 years we compared the IPM intervention group (IG) with a control group (CG) before IPM implementation. Delirium was recorded from the hospital discharge letter. The medication review and data records included baseline data, all medications, diagnoses, electrocardiogram (ECG), laboratory and vital parameters during hospitalization. The IPM internist and the senior trauma physician guaranteed personnel and structural continuity in the implementation of the interdisciplinary patient rounds.ResultsThere was a highly matched congruence between CG and IG in terms of age, gender, residency, BMI, most diagnoses, and injury patterns to compare the two groups. The total number of medications per patient was 11.1 ± 4.9 (CG) versus 10.4 ± 3.6 (IG). Our targeted IPM focus on 6 frontline aspects with reduction of antipsychotics, anticholinergic burden, benzodiazepines, serotonergic opioids, elimination of pharmacokinetic and pharmacodynamic drug interactions and overdosage reduced complicating delirium from 5% to almost zero at 0.5%. The association of IPM with a significant 10-fold reduction, OR = 0.09 [95% CI 0.01–0.7], in univariable regression, maintained of clinical relevance in multivariable regression OR = 0.1 [95% CI 0.01–1.1]. Factors most strongly associated with complicating delirium in univariable regression were cognitive dysfunction, nursing home residency, muscle relaxants, antiparkinsonian agents, xanthines, transient disorientation documented in the fall risk scale, antibiotic-requiring infections, antifungals, antipsychotics, and intensive care stay, the two latter maintaining significance in multivariable regression.ConclusionsIPM is associated with a highly effective prevention of complicating delirium in the elderly trauma patients. For patient safety it should be integrated as an essential preventative contribution. The associated factors help identify patients at risk.

Stakeholders' perspective on modalities to reduce anticholinergic burden

The cumulative effect of multiple drugs with anticholinergic properties that are commonly prescribed to the elderly, collectively known as anticholinergic burden (ACB), has long posed a concern for healthcare professionals. ACB has been associated with medications that include benzodiazepines, opioids, anticholinergic drugs, and other drugs with anticholinergic properties (e.g., antihistamines, tricyclic antidepressants, antispasmodics, antipsychotics, and antiparkinsonian agents). Greater ACB has been implicated in significantly increased risk of morbidity (falls, dementia, adverse cardiac events) and mortality, especially in the elderly.

Garcinol blocks motor behavioural deficits by providing dopaminergic neuroprotection in MPTP mouse model of Parkinson's disease: involvement of anti-inflammatory response.

Although the etiology of Parkinson's disease (PD) is poorly understood, studies in animal models revealed loss of dopamine and the dopaminergic neurons harbouring the neurotransmitter to be the principal cause behind this neuro-motor disorder. Neuroinflammation with glial cell activation is suggested to play a significant role in dopaminergic neurodegeneration. Several biomolecules have been reported to confer dopaminergic neuroprotection in different animal models of PD, owing to their anti-inflammatory potentials. Garcinol is a tri-isoprenylated benzophenone isolated from Garcinia sp. and accumulating evidences suggest that this molecule could provide neuroprotection by modulating oxidative stress and inflammation. However, direct evidence of dopaminergic neuroprotection by garcinol in the pre-clinical model of PD is not yet reported. The present study aims to investigate whether administration of garcinol in the MPTP mouse model of PD may ameliorate the cardinal motor behavioural deficits and prevent the loss of dopaminergic neurons. As expected, garcinol blocked the parkinsonian motor behavioural deficits which include akinesia, catalepsy, and rearing anomalies in the mice model. Most importantly, the degeneration of dopaminergic cell bodies in the substantia nigra region was significantly prevented by garcinol. Furthermore, garcinol reduced the inflammatory marker, glial fibrillary acidic protein, in the substantia nigra region. Since glial hyperactivation-mediated inflammation is inevitably associated with the loss of dopaminergic neurons, our study suggests the anti-inflammatory role of garcinol in facilitating dopaminergic neuroprotection in PD mice. Hence, in the light of the present study, it is suggested that garcinol is an effective anti-parkinsonian agent to block motor behavioural deficits and dopaminergic neurodegeneration in PD.

1,5-Benzodiazepin-2(3H)-ones: In Vitro Evaluation as Antiparkinsonian Agents.

A new series of twenty-three 1,5-benzodiazepin-2(3H)-ones were synthesized and evaluated in the 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS), ferric reducing antioxidant power (FRAP), and 2,2-diphenyl-1-picrylhydrazyl (DPPH) assays as a new chemotype with antioxidant and good drug-like properties. All of the derivatives showed low cytotoxicity in comparison to curcumin against the human neuroblastoma SH-SY5Y and the human hepatoma HepG2 cell lines. Experimental solubility in bio-relevant media showed a good relationship with melting points in this series. Five compounds with the best antioxidant properties showed neuroprotectant activity against H2O2-induced oxidative stress in the SH-SY5Y cell line. From them, derivatives 4-phenyl-1H-1,5-benzodiazepin-2(3H)-one (18) and 4-(3,4,5-trimethoxyphenyl)-1H-1,5-benzodiazepin-2(3H)-one (20) yielded good neuroprotection activity in the same neuronal cell line under 6-OHD and MPP+ insults as in vitro models of mitochondrial dysfunction and oxidative stress in Parkinson’s disease (PD). Both compounds also demonstrated a significant reduction of intracellular Reactive Oxygen Species (ROS) and superoxide levels, in parallel with a good improvement of the Mitochondrial Membrane Potential (ΔΨm). Compared with curcumin, compound 18 better reduced lipid peroxidation levels, malondialdehyde (MDA), in SH-SY5Y cells under oxidative stress pressure and recovered intracellular glutathione synthetase (GSH) levels. Apoptosis and caspase-3 levels of SH-SY5Y under H2O2 pressure were also reduced after treatment with 18. Neuroprotection in neuron-like differentiated SH-SY5Y cells was also achieved with 18. In summary, this family of 1,5-benzodiazepin-2-ones with an interesting antioxidant and drug-like profile, with low cytotoxic and good neuroprotectant activity, constitutes a new promising chemical class with high potential for the development of new therapeutic agents against PD.

The Efek Neuroprotektif Kafein terhadap Fungsi Motorik pada Penyakit Parkinson

Abstract Background: Coffee is one of the most consumed drinks in the world and has become a routine part of everyday life. Coffee is known to be a stimulant because of its high caffeine content. Parkinson's disease is the second most common neurodegenerative disorder characterized by the clinical presentation of motor and non-motor disorders. Neuroinflammation plays a major role in the pathogenesis of Parkinson's disease which is regulated by reactive microglia and causes neurodegeneration of dopaminergic neurons. Consumption of caffeine can exert anti-inflammatory effects on nerves in a variety of pathological conditions. Method: The method used is a literature study from various national and international journals. This method is used with the aim of summarizing a current topic in order to increase an understanding. The literature study restates previously published material and reports new facts or analyzes from relevant literature studies and then compares the results in the article. Results: Caffeine can act as a neuroprotective against the development of Parkinson's disease by keeping the blood-brain barrier intact so that the function of the central nervous system remains stable. Caffeine can improve motor function in Parkinson's disease patients by modulating adenosine A2AR receptors at different doses. Caffeine as an adjuvant drug in the treatment of Parkinson's disease is given together with Trihexyphenidyl (THP) which is an anti-Parkinson's agent that has been used clinically to treat Parkinson's disease. Conclusion: Caffeine is a neuroprotective agent that is widely available and can be used in the treatment of Parkinson's disease with current therapies. However, the correct dosage and safety of caffeine are of particular concern, especially when given at high doses for a period of time and concurrently with other Parkinson's drugs.

Antiparkinsonian activity of new N-methyl-D-aspartate receptor ligands in the arecoline hyperkinesis test

Introduction. Parkinson’s disease (PD) is one of the most common neurodegenerative diseases in the population of older patients. Even though long-term combination therapy helps to cope with the main manifestations of PD. It inevitably leads to the appearance of such side effects as drowsiness, hallucinations, dyskinesia, and many others. [12]. Therefore, the search for effective antiparkinsonian drugs devoid of the above-mentioned adverse reactions remains an urgent task of modern neuropharmacology.The explored substances are derivatives of imidazole-4,5-dicarboxylic acid. These compounds belong to a fundamentally new class of N-methyl-D-aspartate ligands (NMDA) that are not channel blockers. Their pharmacological effect is realized due to interaction with the NMDA receptor recognition site, which, along with high efficiency, allows us to assume their higher safety, compared to previously existing channel blockers from the NMDA ligand group.Objective. Studing of the antiparkinsonian activity of new ligands of the glutamate NMDA-receptor complex-1,2-substituted imidazole-4,5-dicarboxylic acids on an experimental model of arecoline hyperkinesis.Materials and methods. Imidazole-dicarboxylic acid derivatives (IEM2258, IEM2248, IEM2247, and IEM1574) were injected into the lateral ventricles of the mouse brain 10 minutes before arecoline in a volume of 5 µl at doses of 0.1-0.5 µmol, then the latent period, intensity, and duration of tremor were recorded. Amantadine was used as a comparison drug.Results. Preliminary administration of the studied examined substances led to a significant decrease in the intensity and duration of arecoline tremor. The highest inhibitory activity with respect to the intensity and duration of the experimental tremor was demonstrated with the introduction of the compound IEM-2247 (at a dose of 0.1-0.5 mmol, the duration of the latent period of the tremor was 1.7-2.3 times longer than the control one, respectively, the duration of the tremor decreased by 1.5 - 2.5 times).Conclusions. The dose-dependent antiparkinsonian activity of imidazole-dicarboxylic acid derivatives is shown, indicating the prospects for the development of these substances and the further search for effective and safe antiparkinsonian agents among the compounds of this class.

Therapeutic Potential of Citrus sinensis Peels Against Rotenone Induced Parkinsonism in Rats

Background:Parkinson’s disease (PD) is one of the most common neurodegenerative disorders spread worldwide in elderly people.Methods:The Citrus peels methanolic extract (100 mg/kg body weight) was evaluated as an antiparkinsonism agent in rats through estimation of oxidative stress markers, neurotransmitter levels, energetic indices, DNA fragmentation pattern, inflammatory mediators, adenosine A2A receptor gene expression and the histopathological analysis of the brain. In addition, its effect was compared with ZM241385; an adenosine A2A receptor antagonist, as well as the classical drug; (L-dopa).Results:The methanolic extract of C. sinensis peels constituted 17.59 ± 1.92 mg GAE/g and 4.88 ± 0.43 mg CE/g of total phenolic and flavonoid content, respectively. The polyphenolic composition was qualified and quantified using HPLC/DAD and UPLC/ESI-MS analysis. HPLC/DAD analysis led to identify 8 phenolic acids and 4 flavonoids. UPLC/MS analysis led to identify 20 polyphenolic compounds, including 9 polymethoxylated flavoniods, 7 flavonoidal glycosides and 4 phenolic derivatives. Nobiletin and tangeretin were found as abundant polymethoxylated flavones while, hesperidin and 1-caffeoyl-β-D-glucose were found as abundant glycosyl flavone and phenolic derivatives, respectively. Rotenone induced rats showed a significant decrease in neurotransmitter levels, energetic and antioxidant parameters, while a significant increase in total protein, inflammatory mediators, adenosine A2A receptor gene expression, DNA and lipid peroxidation levels was recorded. Treatments with plant extract, L-dopa and ZM241385 restored these selected parameters to variable extents with a more potent effect of ZM241385 than L-dopa. Rotenone induced rats were left free without treatment; not recorded a noticeable improvement level.Conclusion:Citrus sinensis peels was rich with bioactive valuable-added products. This may lead to the development of new nutraceutical and pharmaceutical agents as well as functional food products used as anti-oxidative, anti-inflammatory and anti-parkinsonian agent.

Laxative Agents in Nursing Homes: An Example of Prescribing Cascade

ObjectivesLaxatives are among the most prescribed medications to nursing home (NH) patients, and we evaluated the hypothesis that laxative agents could be prescribed as a result of a prescribing cascade. The aims of the study are (1) to investigate the use of laxative drugs in a large sample of Italian NHs and (2) to assess the relationship between medications that can induce constipation and laxative use. DesignRetrospective cross-sectional multicenter study. Setting and ParticipantsIndividuals living in long-term care NHs. MethodsStudy conducted in a sample of Italian long-term care NHs distributed throughout the country. Information on drug prescriptions, diseases and sociodemographic characteristics collected 4 times during 2018 and 2019. ResultsAmong the 2602 patients recruited from 27 NHs (mean age ± standard deviation: 88.4 ± 8.5; women: 1994, 76.6%), 1248 were receiving laxatives (48%). Parkinson disease, cerebrovascular disease, and hemiplegia were associated with laxative prescription, and diabetes was associated with a decrease. Benzodiazepines, anti-Parkinson dopaminergic agents, and antidepressants (tricyclic antidepressants and mirtazapine) were associated with laxative treatment in univariate and adjusted models. Tricyclic antidepressants users were 3 times more likely to be taking laxatives than nonusers (odds ratio 2.98, 95% confidence interval 1.31-6.77, P = .0093). A larger number of drugs that can induce constipation was associated with laxative use (P = .0003). In all, 2002 individuals had at least 2 different prescription times: from the first to the last visit laxative use rose from 46.1% to 49.9%. Time of stay was also associated with laxative use (P = .016). Conclusions and ImplicationsLaxatives are among the most prescribed medications in Italian NHs. Medications that can induce constipation, such as antidepressants, anti-Parkinson dopaminergic agents, and benzodiazepines, are often used together with laxatives, and combinations of these drugs further increase the use of laxatives. Optimizing the prescription of psychotropic drugs could help reduce the “prescribing cascade” with laxatives. The length of stay in NHs is often proportional to laxative use and chronic treatment is very common.

New therapeutic agents marketed in 2020: Part 2

New therapeutic agents marketed in 2020: Part 2

Characterization of the binding affinity between some anti-Parkinson agents and Mn2+, Fe3+ and Zn2+ metal ions: A DFT insight

In the current work, density functional theory calculations were carried out to evaluate the potential ability of apomorphine, dopamine, hinokitiol and deferiprone chelating agents to coordinate Mn2+, Fe3+ and Zn2+ metal ions with a 1:1 ratio in water solution. The binding energy values reveal that Zn2+/chelating agent complexes are more stable compared to Mn2+/chelating agent and Fe3+/chelating agent complexes. In order to evaluate the parameters that describe the affinity between the metal ions and chelating agents, the metal ion/chelating agent interactions were analyzed by CDA, NBO, QTAIM, FMO analyses. Interestingly, it was found that the FeO interactions in all complexes and MnO interactions in [Mn-DFP]+ complex are mainly electrostatic, whereas other interactions have a covalent character. Moreover, TD-DFT studies showed n → π* and π → π* transitions in the absorption spectra of the complexes.

Repurposing of Omarigliptin as a Neuroprotective Agent Based on Docking with A2A Adenosine and AChE Receptors, Brain GLP-1 Response and Its Brain/Plasma Concentration Ratio after 28 Days Multiple Doses in Rats Using LC-MS/MS.

The authors in the current work suggested the potential repurposing of omarigliptin (OMR) for neurodegenerative diseases based on three new findings that support the preliminary finding of crossing BBB after a single dose study in the literature. The first finding is the positive results of the docking study with the crystal structures of A2A adenosine (A2AAR) and acetylcholine esterase (AChE) receptors. A2AAR is a member of non-dopaminergic GPCR superfamily receptor proteins and has essential role in regulation of glutamate and dopamine release in Parkinson’s disease while AChE plays a major role in Alzheimer’s disease as the primary enzyme responsible for the hydrolytic metabolism of the neurotransmitter acetylcholine into choline and acetate. Docking showed that OMR perfectly fits into A2AAR binding pocket forming a distinctive hydrogen bond with Threonine 256. Besides other non-polar interactions inside the pocket suggesting the future of the marketed anti-diabetic drug (that cross BBB) as a potential antiparkinsonian agent while OMR showed perfect fit inside AChE receptor binding site smoothly because of its optimum length and the two fluorine atoms that enables quite lean fitting. Moreover, a computational comparative study of OMR docking, other 12 DPP-4 inhibitors and 11 SGLT-2 inhibitors was carried out. Secondly, glucagon-like peptide-1 (GLP-1) concentration in rats’ brain tissue was determined by the authors using sandwich GLP-1 ELISA kit bio-analysis to ensure the effect of OMR after the multiple doses’ study. Brain GLP-1 concentration was elevated by 1.9-fold following oral multiple doses of OMR (5 mg/kg/day, p.o. for 28 days) as compared to the control group. The third finding is the enhanced BBB crossing of OMR after 28 days of multiple doses that had been studied using LC-MS/MS method with enhanced liquid–liquid extraction. A modified LC-MS/MS method was established for bioassay of OMR in rats’ plasma (10–3100 ng/mL) and rats’ brain tissue (15–2900 ng/mL) using liquid–liquid extraction. Alogliptin (ALP) was chosen as an internal standard (IS) due to its LogP value of 1.1, which is very close to the LogP of OMR. Extraction of OMR from samples of both rats’ plasma and rats’ brain tissue was effectively achieved with ethyl acetate as the extracting solvent after adding 1N sodium carbonate to enhance the drug migration, while choosing acetonitrile to be the diluent solvent for the IS to effectively decrease any emulsion between the layers in the stated method of extraction. Validation results were all pleasing including good stability studies with bias of value below 20%. Concentration of OMR in rats’ plasma were determined after 2 h of the latest dose from 28 days multiple doses, p.o, 5 mg/kg/day. It was found to be 1295.66 ± 684.63 ng/mL estimated from the bio-analysis regression equation. OMR passed through the BBB following oral administration and exhibited concentration of 543.56 ± 344.15 ng/g in brain tissue, taking in consideration the dilution factor of 10. The brain/plasma concentration ratio of 0.42 (543.56/1295.66) was used to illustrate the penetration power through the BBB after the multiple doses for 28 days. Results showed that OMR passed through the BBB more effectively in the multiple dose study as compared to the previously published single dose study by the authors. Thus, the present study suggests potential repositioning of OMR as antiparkinsonian agent that will be of interest for researchers interested in neurodegenerative diseases.

Evaluation of the combined activity of benzimidazole arylhydrazones as new anti-Parkinsonian agents: monoamine oxidase-B inhibition, neuroprotection and oxidative stress modulation.

Neuroprotective drugs and selective monoamine oxidase inhibitors can slow down the progression and improve symptoms of Parkinson's disease (PD). Since there is an implication of oxidative stress in the pathophysiological mechanisms of the disease, the compounds possessing an ability to reduce the oxidative stress are prime candidates for neuroprotection. Thereby our current study is focused on the development of new multi-target PD drugs capable of inhibiting the activity of monoamine oxidase-B while exerting neuroprotective and antioxidant properties. A small series of benzimidazole derivatives containing hydroxy and methoxy arylhydrazone fragments has been synthesized and the neurotoxicity of the compounds has been evaluated in vitro on neuroblastoma SH-SY5Y cells and on isolated rat brain synaptosomes by measuring the cell viability and the levels of reduced glutathione and a good safety profile has been shown. The 2-hydroxy-4-methoxy substituted arylhydrazone 7 was the least toxic on neuronal SH-SY5Y cells and showed the lowest neurotoxicity in rat brain synaptosomes. The neuroprotective properties of the test compounds were further assessed using two models: H2O2-induced oxidative stress on SH-SY5Y cells and 6-hydroxydopamine-induced neurotoxicity in rat brain synaptosomes. Compound 7 showed more pronounced neuroprotective activity on SH-SY5Y cells, compared to the referent melatonin and rasagiline. It also preserved the synaptosomal viability and the reduced glutathione levels; the effects were stronger than those of rasagiline and comparable to melatonin. All the tested compounds were capable to inhibit human monoamine oxidase-B enzyme to a significant extent, however, compound 7 exerted the most prominent inhibitory activity, similar to selegiline and rasagiline. The carried out molecular docking studies revealed that the activity is related to the appropriate molecular structure enabling the ligand to enter deeper in the narrow and highly lipophylic active site pocket of the human monoamine oxidase-B and has a favoring interaction with the key amino acid residues Tyr326 and Cys172. Since much scientific evidence points out the implication of iron dyshomeostasis in PD, the compounds were tested to reduce the ferrous iron induced oxidative molecular damage on biologically important molecules in an in vitro lecithin containing model system. All the investigated compounds denoted protection effect, stronger than the one of the referent melatonin. In order to support the assignments of the significant neuroprotective and antioxidant pharmacological activities, the radical-scavenging mechanisms of the most promising compound 7 were evaluated using DFT methods. It was found that the most probable free radicals scavenging mechanism in nonpolar phase is the hydrogen atom transfer from the amide group of compound 7, while in polar medium the process is expected to occur by a proton transfer. The current study outlines a perspective leading structure, bearing the potential for a new anti-PD drug. All performed procedures were approved by the Institutional Animal Care Committee of the Medical University of Sofia (Bulgarian Agency for Food Safety with Permission № 190, approved on February 6, 2020).

Ligand and Structure-Based Hybrid Screening for Anti-Parkinson Agents and their Pharmacological Evaluation

The behavioral and biochemical antiparkinson effect of 7-hydroxyflavone (7-HF) was evaluated by using virtual screening with an e-pharmacophore and shape-based screening approach, and the compound was screened by using the Sigma Aldrich compound library. Screened hits were filtered based on Lipinski’s rule, absorption, distribution,metabolism,elimination, (software for evaluation) (ADME), and toxicity parameters. The best scoring hit, 7-hydroxy 2 phenyl-4H-chromen-4-one, i.e., 7-HF was selected based on shape similarity (> 0.7), g-score, and conserved interactions. Toxicity assessment of retrieved hits was carried out by Osiris and Lazar programs. This study aims to obtain some potential hits, against various antiparkinson category from reported literature and available online resources, and validate their potency by in vivo, in vitro methods. Reserpine 5 mg/kg produces Parkinson’s like condition by depleting presynaptic catecholamines, particularly dopamine through the process of degranulation of storage vesicles. 7-HF 25, 50, and 100 mg/kg was used as a test compound. Syndopa 275 mg/kg was used as a standard drug. The results demonstrate that treatment with 7-HF improved the total locomotor activity and muscular coordination in the rotarod test. In the open field test, enhanced rearing, grooming duration of mobility, and gripping strength in the chimney test, while a decrease in cataleptic scores in the bar test. 7-HF significantly increases catalase, superoxide dismutase, and reduces glutathione level, while reduced the Malondialdehyde (MDA) level. The total protein concentration was also increased in 7-HF treated groups. The behavioral and biochemical results obtained from this study disclosed a definite neuroprotective role of 7-HF in a dose-dependent manner. It is also clear that 7-HF showed potent and effective antiparkinson activity in a similar way as standard. Interestingly, in behavioral and biochemical studies, 7-HF showed approximately equivalent effects as compared to syndopa.

Design, evaluation and in vivo pharmacokinetic study of a cationic flexible liposomes for enhanced transdermal delivery of pramipexole

Pramipexole is a widely preferred antiparkinsonian agent because of its several advantages, one being the delayed onset of motor fluctuations and dyskinesia observed with other antiparkinsonian drugs. However, it may cause pulsatile stimulation of the dopamine receptors responsible for the majority of the side effects such as orthostatic hypotension, constipation, dizziness, drowsiness, dry mouth, etc. Thus, the objective of the present work was to develop flexible liposomes of pramipexole for enhanced transdermal drug delivery and consequently to reduce side effects. Structure of phospholipids, edge activator, and surfactants being major determinants of liposomes, phospholipids of varying hydrocarbon chain length and degree of substitution, and cationic and anionic surfactants (sodium hexadecyl sulfate or cetylpyridinium chloride) were used for formulating flexible liposomes. All the batches of flexible liposomes of pramipexole were prepared by the thin-film hydration method. Liposomes were characterized by TEM, % drug entrapment, vesicle size, and deformability index. Liposomes were incorporated into the gel base and formulated as a transdermal patch. Ex-vivo drug release studies demonstrated greater and faster drug releases from all the prepared cationic flexible liposomal (CFL) gel patches as compared to flexible and anionic flexible liposomal gel patches. Further, the flexible liposomes of shorter carbon chain length and monosubstitution provide rapid drug release, while the sustained release was observed through liposomes comprising of longer carbon chain length and increased substitution. Pharmacokinetic studies demonstrated that the designed transdermal patches were capable of delivering pramipexole at the desired concentration and overcome the skin barrier function efficiently. Hence, CFL transdermal patch prepared with phospholipids containing higher carbon content appears to be promising to deliver pramipexole by the transdermal route and can thus overcome the pulsatile stimulation of dopamine receptors and associated side effects.

S-adenosylmethionine administration inhibits levodopa-induced vascular endothelial growth factor-A expression.

Background: Studies have demonstrated that S-adenosylmethionine could effectively affect the clinical wearing-off phenomena of levodopa, an antiparkinsonian agent; however, the detailed mechanisms for this effect need to be further clarified.Results: S-adenosylmethionine and levodopa had opposite effects on the protein stability of vascular endothelial growth factor-A. The analysis of tube formation and cell viability also showed the nonconforming functions of S-adenosylmethionine and levodopa on cell angiogenesis and proliferation. Meanwhile, S-adenosylmethionine could significantly abolish the increased angiogenesis and cell viability induced by levodopa. S-adenosylmethionine resulted in G1/S phase arrest, with decreased cyclin dependent kinase 4/6 and increased p16, a specific cyclin dependent kinase inhibitor. Mechanically, the different effects of levodopa and S-adenosylmethionine were dependent on the phosphorylation and activation of extracellular signal-regulated kinase. S-adenosylmethionine could be fitted into the predicted docking pocket in the crystal structure of vascular endothelial growth factor-A, enhancing its acetylation level and reducing half-life.Conclusions: These observations suggested that methyl donor S-adenosylmethionine could act as a potential agent against vascular endothelial growth factor-A-related diseases induced by levodopa treatment.Methods: We performed in vitro cytological analyses to assess whether S-adenosylmethionine intake could influence levodopa-induced vascular endothelial growth factor-A expression in human umbilical vein endothelial cells.

Pyrimido[1,2-b]indazole derivatives: Selective inhibitors of human monoamine oxidase B with neuroprotective activity.

Structurally diverse heterotricyclic compounds are recognized as monoamine oxidase (MAO) inhibitors and thus represent an appealing scaffold in development and optimization of novel MAO inhibitors. Herein we explored the chemical space of pyrimido[1,2-b]indazoles as MAO inhibitors by preparing a small library of (hetero)aryl derivatives. An efficient synthetic strategy was developed starting from commercially available 1H-indazol-3-amines, which were converted to various 3-bromoheterotricyclic derivatives and further functionalized via Suzuki-Miyaura coupling reaction. Derivatives 4a-t selectively inhibited human MAO-B isoform in a reversible and competitive manner as confirmed by kinetic experiments and docking studies. Selected derivatives were not cytotoxic to neuroblastoma SH-SY5Y cells. Moreover, analogue 4i protected human neuroblastoma SH-SY5Y cells against 6-hydroxydopamine-induced cell death, which confirms the applicability of the pyrimido[1,2-b]indazoles as potential antiparkinsonian agents.

A New Series of 1,3-Dimethylxanthine Based Adenosine A2A Receptor Antagonists as a Non-Dopaminergic Treatment of Parkinson's Disease.

Adenosine receptors (AR) have emerged as competent and innovative nondopaminergic targets for the development of potential drug candidates and thus constitute an effective and safer treatment approach for Parkinson's disease (PD). Xanthine derivatives are considered as potential candidates for the treatment Parkinson's disease due to their potent A2A AR antagonistic properties. The objectives of the work are to study the impact of substituting N7-position of 8-m/pchloropropoxyphenylxanthine structure on in vitro binding affinity of compounds with various AR subtypes, in vivo antiparkinsonian activity and binding modes of newly synthesized xanthines with A2A AR in molecular docking studies. Several new 7-substituted 8-m/p-chloropropoxyphenylxanthine analogues have been prepared. Adenosine receptor binding assays were performed to study the binding interactions with various subtypes and perphenazine induced rat catatonia model was used for antiparkinsonian activity. Molecular docking studies were performed using Schrödinger molecular modeling interface. 8-para-substituted xanthine 9b bearing an N7-propyl substituent displayed the highest affinity towards A2A AR (Ki = 0.75 μM) with moderate selectivity versus other AR subtypes. 7-Propargyl analogue 9d produced significantly long-lasting antiparkinsonian effects and also produced potent and selective binding affinity towards A2A AR. In silico docking studies further highlighted the crucial structural components required to develop xanthine derived potential A2A AR ligands as antiparkinsonian agents. A new series of 7-substituted 8-m/p-chloropropoxyphenylxanthines having good affinity for A2A AR and potent antiparkinsonian activity has been developed.

A Doença de Parkinson e o Processo de Envelhecimento Motor: uma Revisão de Literatura

Introdução: A Doença de Parkinson (DP) é uma doença crônica degenerativa caracterizada por sintomas motores clássicos, podendo influenciar o desenvolvimento de algumas alterações posturais. Podendo comprometer o desenvolvimento de alguns sintomas não motores que, associados com os demais déficits funcionais, acabam influenciando negativamente na qualidade de vida (QV). Objetivo: Verificar a sintomatologia da doença de Parkinson os distúrbios motores, não motores e o comprometimento da doença. Métodos: O estudo consiste em uma revisão bibliográfica, realizada por meio de pesquisa no banco de dados Medline, Pubmed, Scielo e Google acadêmico. Foram selecionados estudos observacionais, coorte e ensaios clínicos randomizados e controlados, publicados no período entre 1967 e 2019, em inglês e português nos quais as palavras-chaves estivessem presentes no título ou resumo. Resultados: Foram identificados 77 artigos e após a leitura de resumos e resultados, foram excluídos 12 artigos por não abordarem o tema da pesquisa e por estarem fora do período proposto, restando 65 artigos que foram incluídos abordando o tema da pesquisa. Conclusão: Cabe salientar que existe um grande interesse na descoberta de novos agentes antiparkinsonianos que consigam bloquear ou mesmo reverter o processo de neurodegeneração na (DP).

Possible synergies between isatin, an endogenous MAO inhibitor, and antiparkinsonian agents on the dopamine release from striatum of freely moving rats.

Isatin is an endogenous indole that inhibits monoamine oxidase (MAO). When exogenously administered, it increases the striatal dopamine and acetylcholine levels and presents neuroprotective effects in the brain. Previous studies show that intrastriatal administration of isatin increased the in vivo dopamine release from striatum in a concentration-dependent form. In the present work, we investigated the effects of combined administration of isatin together with other substances actually used in antiparkinsonian pharmacotherapy on in vivo dopamine overflow. For this, we co-administered isatin with the MAO inhibitors selegiline and clorgyline, l-DOPA, the catechol-o-methyl-transferase (COMT) inhibitors tropolone and dinitrocatechol, with the dopaminergic agonist ropinirole, and with the psychostimulant caffeine, in order to evaluate possible synergies between these substances to increase the dopamine extracellular levels in freely moving rats. Intrastriatal administration of isatin (10 mM, 60 min) significantly increased dopamine release to 1164 ± 152%, compared to the baseline. Co-administration of isatin together with selegiline (1 mM) or clorgyline (1 mM) alone or in combinations showed a similar profile to increase in vivo dopamine release. Intrastriatal infusion of isatin together with antiparkinsonian drugs l-DOPA (25 μM), tropolone (1 mM), dinitrocatechol (100 μM), amantadine (5 mM) and caffeine (5 mM) significantly elevated extracellular dopamine levels more than any single drug, showing a good neurochemical synergy by improving the effect of isatin on the extracellular dopamine levels in the striatum. Infusion of isatin + ropinirole (5 mM) did not change the isatin-induced increase in dopamine overflow. These results could be useful to carry out further investigations with a possible clinical application.