Antiparkinsonian Activity Research Articles

Bioactive Steroids Bearing Oxirane Ring.

This review explores the biological activity and structural diversity of steroids and related isoprenoid lipids, with a particular focus on compounds containing an oxirane ring. These natural compounds are derived from fungi, fungal endophytes, as well as extracts of plants, algae, and marine invertebrates. To evaluate their biological activity, an extensive examination of refereed literature sources was conducted, including in vivo and in vitro studies and the utilization of the QSAR method. Notable properties observed among these compounds include strong anti-inflammatory, antineoplastic, antiproliferative, anti-hypercholesterolemic, antiparkinsonian, diuretic, anti-eczematic, anti-psoriatic, and various other activities. Throughout this review, 3D graphs illustrating the activity of individual steroids are presented, accompanied by images of selected terrestrial or marine organisms. Furthermore, this review provides explanations for specific types of biological activity associated with these compounds. The data presented in this review are of scientific interest to the academic community and carry practical implications in the fields of pharmacology and medicine. By analyzing the biological activity and structural diversity of steroids and related isoprenoid lipids, this review offers valuable insights that contribute to both theoretical understanding and applied research. This review draws upon data from various authors to compile information on the biological activity of natural steroids containing an oxirane ring.

Effect of the mGlu4 positive allosteric modulator ADX-88178 on parkinsonism, psychosis-like behaviours and dyskinesia in the MPTP-lesioned marmoset.

Positive allosteric modulation of metabotropic glutamate type 4 (mGlu4) receptors is a promising strategy to alleviate parkinsonian disability and L-3,4-dihydroxyphenylalanine (L-DOPA) induced dyskinesia. ADX-88178 is a highly selective mGlu4 positive allosteric modulator (PAM) that previously enhanced the anti-parkinsonian action of L-DOPA in the 6-hydroxydopamine-lesioned rat model of Parkinson's disease (PD). We sought to explore the effects of ADX-88178 on psychosis-like behaviours (PLBs) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. We also aimed to determine the effect of ADX-88178 on parkinsonism and dyskinesia. Six MPTP-lesioned marmosets were administered L-DOPA chronically to induce stable PLBs and dyskinesias. They were then administered ADX-88178 (0.01, 0.1 and 1mg/kg) or vehicle, in combination with L-DOPA/benserazide (15/3.75mg/kg), both sub-cutaneously, in a randomised fashion. PLBs, parkinsonism and dyskinesia were then measured. ADX-88178 mildly worsened global PLBs at the dose of 1mg/kg (by 13%, P = 0.020). L-DOPA alone conferred 158min of on-time, while the duration of on-time was 212min (34% increase, P = 0.011), after adding ADX-88178 1mg/kg to L-DOPA. Accordingly, ADX-88178 1mg/kg reduced global parkinsonian disability, by 38% (P = 0.0096). ADX-88178 1mg/kg diminished peak dose dyskinesia by 34% (P = 0.015). Minimal effects were provided by lower doses. Whereas these results provide additional evidence of the anti-parkinsonian and anti-dyskinetic effects of mGlu4 positive allosteric modulation as an adjunct to L-DOPA, they also suggest that ADX-88178 may exacerbate dopaminergic psychosis. Further studies are needed to evaluate this possible adverse effect of mGlu4 PAMs on PD psychosis.

The 5-HT2A/2C inverse agonist nelotanserin alleviates L-DOPA-induced dyskinesia in the MPTP-lesioned marmoset.

Nelotanserin is a serotonin 2A and 2C (5-HT2A/2C) inverse agonist that was previously tested in the clinic for rapid-eye movement sleep behaviour disorder and psychosis in patients with Parkinson's disease (PD) dementia. Its effect on L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia has however not been investigated. As 5-HT2A antagonism/inverse agonism is a validated approach to alleviate dyskinesia, we undertook the current study to evaluate the anti-dyskinetic potential of nelotanserin in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. Parkinsonism was induced in six common marmosets (Callithrix jacchus, three females and three males) that were then chronically treated with L-DOPA to induce dyskinesia. On experimental days, they were administered L-DOPA in combination with vehicle or nelotanserin (0.1, 0.3 and 1mg/kg) subcutaneously, in a randomised fashion. Dyskinesia and parkinsonism were rated post hoc by a blinded observer. In comparison to vehicle, the addition of nelotanserin 0.3 and 1mg/kg to L-DOPA diminished peak dose dyskinesia by 47% (P < 0.05) and 69% (P < 0.001). Nelotanserin 0.3 and 1mg/kg also reduced the severity of global dyskinesia, by 40% (P < 0.01) and 55% (P < 0.001), when compared to vehicle. Nelotanserin 0.1mg/kg did not alleviate peak dose or global dyskinesia severity. Nelotanserin had no impact on the anti-parkinsonian action of L-DOPA. Our results highlight that nelotanserin may represent an efficacious anti-dyskinetic drug and provide incremental evidence of the potential benefit of 5-HT2A/2C antagonism/inverse agonism for drug-induced dyskinesia in PD.

Biological Activity and Structural Diversity of Steroids Containing Aromatic Rings, Phosphate Groups, or Halogen Atoms.

This review delves into the investigation of the biological activity and structural diversity of steroids and related isoprenoid lipids. The study encompasses various natural compounds, such as steroids with aromatic ring(s), steroid phosphate esters derived from marine invertebrates, and steroids incorporating halogen atoms (I, Br, or Cl). These compounds are either produced by fungi or fungal endophytes or found in extracts of plants, algae, or marine invertebrates. To assess the biological activity of these natural compounds, an extensive examination of referenced literature sources was conducted. The evaluation encompassed in vivo and in vitro studies, as well as the utilization of the QSAR method. Numerous compounds exhibited notable properties such as strong anti-inflammatory, anti-neoplastic, anti-proliferative, anti-hypercholesterolemic, anti-Parkinsonian, diuretic, anti-eczematic, anti-psoriatic, and various other activities. Throughout the review, 3D graphs illustrating the activity of individual steroids are presented alongside images of selected terrestrial or marine organisms. Additionally, the review provides explanations for specific types of biological activity associated with these compounds. The data presented in this review hold scientific interest for academic science as well as practical implications in the fields of pharmacology and practical medicine. The analysis of the biological activity and structural diversity of steroids and related isoprenoid lipids provides valuable insights that can contribute to advancements in both theoretical understanding and applied research.

The adenosine A2A receptor antagonist/inverse agonist, KW-6356 enhances the anti-parkinsonian activity of L-DOPA with a low risk of dyskinesia in MPTP-treated common marmosets

The adenosine A2A receptor antagonist/inverse agonist, KW-6356 has been shown to be effective in Parkinson's disease (PD) patients as monotherapy and as an adjunct therapy to L-3,4-dihydroxyphenylalanine (L-DOPA)/decarboxylase inhibitor. However, the effects of KW-6356 combined with L-DOPA on anti-parkinsonian activity and established dyskinesia has not been investigated in preclinical experiments. We examined the effects of combination of KW-6356 with L-DOPA in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets. Oral administration of KW-6356 (1 mg/kg) enhanced the anti-parkinsonian activities of various doses of L-DOPA (2.5–10 mg/kg). In MPTP-treated common marmosets primed with L-DOPA to show dyskinesia, KW-6356 (1 mg/kg) also enhanced the anti-parkinsonian activities of various doses of L-DOPA (1.25–10 mg/kg) but not dyskinesia. Chronic co-administration of KW-6356 (1 mg/kg) with a low dose of L-DOPA (2.5 mg/kg) for 21 days increased the degree of dyskinesia induced by the low dose of L-DOPA, but the amplitude of dyskinesia induced by combined administration of KW-6356 (1 mg/kg) with L-DOPA (2.5 mg/kg) was lower than that induced by an optimal dose of L-DOPA (10 mg/kg). These results suggest that KW-6356 can be used to potentiate the effects of a wide range of L-DOPA doses with a low risk of dyskinesia for the treatment of PD.

POTENTIAL ACTIVITY OF KAEMPFEROL AS ANTI-PARKINSON’S; MOLECULAR DOCKING AND PHARMACOPHORE MODELLING STUDY

Objective: This study examined molecular docking and pharmacophore modeling to evaluate the potential antiparkinson activity of Kaempferol on various types and classes of receptors. Methods: The molecular docking was performed on various classes of receptors, namely transcription factor Nrf2, A2A Adenosine, and catechol-O-methyl transferase, using auto dock 4.0.1 software. Results: Kaempferol exhibited potential effects on two of the three tests (A2A adenosine and COMT receptors) as indicated by the lowest free energy binding values (-5.42 kcal/mol,-7.16 kcal/mol, and-8.33 kcal/mol, respectively). Kaempferol also had lower inhibitory constant values on transcription factor Nrf2, A2A adenosine, and COMT receptors (106.06 µM, 5.63 µM, and 779.51 nM, respectively). Kaempferol and the natural ligand had similar functional groups according to the critical components of the interaction between amino acid residues. The pharmacophore modeling revealed that hydroxyl functional groups strongly interact with crucial amino acid residues of the receptors. Conclusion: This study concludes that kaempferol is a potential antiparkinson agent against multiple receptors.

Anti-parkinsonian activity of the adenosine A2A receptor antagonist/inverse agonist KW-6356 as monotherapy in MPTP-treated common marmosets

KW-6356 is a novel adenosine A2A receptor antagonist/inverse agonist that not only blocks binding of adenosine to adenosine A2A receptor but also inhibits the constitutive activity of adenosine A2A receptor. The efficacy of KW-6356 as both monotherapy and an adjunct therapy to L-3,4-dihydroxyphenylalanine (L-DOPA)/decarboxylase inhibitor in Parkinson's disease (PD) patients has been reported. However, the first-generation A2A antagonist istradefylline, which is approved for use as an adjunct treatment to L-DOPA/decarboxylase inhibitor in adult PD patients experiencing OFF episodes, has not shown statistically significant efficacy as monotherapy. In vitro pharmacological studies have shown that the pharmacological properties of KW-6356 and istradefylline at adenosine A2A receptor are markedly different. However, the anti-parkinsonian activity and effects on dyskinesia of KW-6356 in PD animal models and the differences in the efficacy between KW-6356 and istradefylline are unknown. The present study investigated the anti-parkinsonian activity of KW-6356 as monotherapy in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets, and its efficacy was directly compared with that of istradefylline. In addition, we investigated whether or not repeated administration of KW-6356 induced dyskinesia. Oral administration of KW-6356 reversed motor disability in a dose-dependent manner up to 1 mg/kg in MPTP-treated common marmosets. The magnitude of anti-parkinsonian activity induced by KW-6356 was significantly greater than that of istradefylline. Repeated administration of KW-6356 induced little dyskinesia in MPTP-treated common marmosets primed to exhibit dyskinesia by prior exposure to L-DOPA. These results indicate that KW-6356 can be a novel non-dopaminergic therapy as monotherapy without inducing dyskinesia in PD patients.

Evaluation of antiparkinsonian activity of water yam tuber (Dioscorea alata L.) extract on haloperidol-induced Parkinson’s disease in mice

Parkinson’s disease (PD) appears as motor dysfunction that is attributed to depleting dopamine levels due to cell death in the extrapyramidal system that is comprised of the basal ganglia’s motor neurons. Oxidative stress is central in triggering cell death. Water yam (Dioscorea alata L.) contains anthocyanins with potential antioxidative and neuroprotective activities that can ameliorate oxidative stress in PD. This research aimed to assess the antiparkinsonian activity of the water yam’s ethanol extract by observing motor (bar test, rotarod test, negative geotaxis reflex test, cliff avoidance test) and sensory activities (olfactory testing) in vivo in mice with haloperidol-induced PD. Water yam tubers were extracted by maceration with the solvent 70% ethanol. This experimental research employed a posttest-only control group design where 35 mice were equally distributed into 7 treatment groups, containing 5 each: Group 1 (normal group) was administered Carboxymethyl Cellulose Sodium (CMC-Na) orally (p.o.) and aqua pro injection intraperitoneally (i.p.); Group 2 (negative group) was given CMC-Na p.o.; Groups 3 and 4 (positive groups) received, respectively, levodopa p.o. and curcumin p.o.; and then, finally, Groups 5, 6, and 7 (test groups) were given the water yam extracts at varying doses: 100, 200, and 400 mg/kg BW. CMC-Na, levodopa, and the extract were given once a day for 7 days. Fifteen minutes after receiving their respective treatments on the last day, all the test animals, except for Group 1, were injected with haloperidol solution at 2 mg/kg BW i.p. Then, a bar test, rotarod test, geotaxis reflex test, olfactory testing, and cliff avoidance test were performed to examine their motor and sensory responses in the 5, 60, 120, and 180th minutes. The data obtained were inputted and analyzed statistically with a One-Way ANOVA and then continued with an LSD test. In addition, thin-layer chromatography was employed as the anthocyanin screening test for the ethanol extract of water yam tubers. Results showed that the ethanol extract contained pelargonidin, and when given at 200 and 400 mg/kg, it substantially shortened the exploration time and prolonged latency to first fall in all the tests relative to the haloperidol, levodopa, and curcumin groups. (p&lt;0.05). Thus, it can be inferred that the ethanol extract of water yam contains pelargonidin (an anthocyanin compound) and has the activity of preventing haloperidol-induced PD in mice when administered at 200 and 400 mg/kg BW.

Synthesis, in silico Studies and Pharmacological Evaluation of a New Series of Indanone Derivatives as Anti-Parkinsonian and Anti-Alzheimer's Agents.

Parkinson's disease (PD) and Alzheimer's disease (AD) are the most common forms of neurodegenerative disorders. The aim of the current work is to study the potential of some new indanone derivatives for the treatment of these neurological disorders. A new series of 4-(2-oxo-2-aminoethoxy)-2-benzylidene substituted indanone derivatives have been synthesized and studied for anti-Parkinsonian and anti-Alzheimer's effects. Substitution of different aminoalkyl functionalities at the para position of 2-benzylidene moiety of indanone ring resulted in the formation of potent anti-parkinsonian and anti-Alzheimer's agents (5-10). The neuroprotective effects of newly synthesized compounds were evaluated using perphenazine (PPZ)-induced catatonia in rats and LPS-induced cognitive deficits in mice models. Further, in silico molecular modelling studies of the new indanone derivatives were performed by docking against the 3D structures of various neuroinflammatory mediators, such as interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and monoamine oxidase-B (MAO-B), to gain the mechanistic insights of their anti-Alzheimer's and antiparkinsonian effects. The newly synthesized indanone analogues 5-10 were found effective against PPZinduced motor dysfunction and LPS-induced memory impairment in animal models. Among all the synthesized analogues, morpholine-substituted indanone 9 displayed maximum anti-parkinsonian activity, even better than the standard drug L-DOPA, while pyrrolidine and piperidine substituted analogues 5 and 6 were found to be the most potent anti-Alzheimer's agents. The new 2-arylidene-1-indanone analogues show good potential as promising leads for designing compounds against Parkinson's and Alzheimer's diseases.

Investigation of antiparkinsonian activity of new imidazole-4,5-dicarboxylic acid derivatives on the experimental model of catalepsy

Introduction: To study 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 catalepsy caused by haloperidolintraabdominal injections in rats. Materials and methods: The experiments were performed on Wistar rats weighing 300-350 g, obtained from the Rappolovo nursery of the Russian Academy of Medical Sciences (Leningrad Region). The animals were kept in standard plastic cages in vivarium conditions with free access to water and food at a temperature of 22±2 °C and in the experiment were divided into several groups (6 animals each). All the experiments were carried out in the autumn-winter period. The animals were kept in accordance with the rules of laboratory practice (GLP), regulatory documents ”Sanitary Rules for the Device, Equipment and Maintenance of Vivarium” and the Order of the Ministry of Health and Social Development of the Russian Federation dated 23.08.2010 No. 708n “On Approval of the Rules of Laboratory Practice”. Imidazole-dicarboxylic acid derivatives (IEM-2295, IEM-2296) were injected intraperitoneally at doses from 5 mg/kg to 40 mg/kg simultaneously with haloperidol at a dose of 1 mg/kg, after which the duration and severity of catalepsy were evaluated after 30, 60, 120 minutes from 0 to 6 points according to the Morpurgo method. Results: The severity of catalepsy with the injection of IEM-2295 decreased on average to 3 points, while in the control group it remained at the level of 6 points throughout the observation. However, the severity of catalepsy with the introduction of IEM-2296 decreased to an average of 4 points, but the effect itself lasted longer than with the introduction of IEM-2295. Thus, it was noted that by the 120th minute of observation, the severity of catalepsy in rats receiving the IEM-2295 compound averaged 5 points, whereas in animals receiving IEM-2296 – 3 points. Discussion: Basing on the results of our work and similar experiments, we can conclude that the studied compounds, which are not channel blockers, have an active effect on dopaminergic neurotransmission, because of which the symptoms of catalepsy that occur when haloperidol is injected to rats were stopped to one degree or another. Conclusion: The studied substances exhibit antiparkinsonian activity on an experimental haloperidol model of catalepsy in rats and are promising for development as potential therapies for neurodegenerative diseases. Further study of these compounds and other ligands from the NMDA-blocker group in a wider sample on the catalepsy model, as well as on other models of Parkinsonism, is required. Graphical Abstract

Curcumin Modulates p62-Keap1-Nrf2-Mediated Autophagy in Rotenone-Induced Parkinson's Disease Mouse Models.

Autophagy mediates self-digestion of abnormally aggregated proteins and organelles present in the cytoplasm. This mechanism may prove to be neuroprotective against Parkinson's disease (PD) by clearing misfolded α-synuclein (α-syn) aggregates from dopaminergic neurons. p62, an adaptor protein acts as a selective substrate for autophagy and regulates the formation as well as the degradation of protein aggregates. p62 sequesters keap1 freeing Nrf2 and consequently activating the transcription of its target genes. In the present study, we aimed to investigate the anti-parkinsonian activity of curcumin targeting primarily activation of autophagy via the Nrf2-Keap1 pathway. The mice were subcutaneously injected with rotenone (2.5 mg/kg bodyweight) and co-treated with oral administration of curcumin (80 mg/kg bodyweight) for 35 days. Following completion of dosing, motor activities, anti-oxidative potential, mitochondrial dysfunction, and various protein expressions, including Nrf2, Keap1, p62, LC3, Bcl2, Bax, and caspase 3, were assessed. The results revealed that curcumin restored the motor coordination and anti-oxidative activity while improving the mitochondrial functioning in PD mice. Autophagy was evaluated by the change in the expression of autophagic markers, p62 and LC3-II. Reduced p62 and LC3-II expressions in the rotenone mouse model of PD confirmed the compromised autophagy pathway, consequently increasing the aggregation of misfolded protein α-syn. Whereas, curcumin treatment-enhanced autophagy-mediated clearance of misfolded α-syn proteins by increasing the LC3-II expression and blocked apoptotic cascade. Curcumin administration upregulated the Nrf2 expression and normalized the Nrf2-Keap1 pathway, which justifies the improved anti-oxidative activity. Therefore, the findings reveal that curcumin is a Nrf2-inducer and is endowed with neuroprotective potential, which may prove to be a potential candidate for the anti-Parkinson's disease treatment therapy.

Antiparkinsonian Potential of Natural Products: Molecular Docking, Prediction of Pharmacokinetic and Toxicological Properties

Background: Parkinson's disease (PD) is a neurodegenerative pathology common in the elderly, and it may be related to several factors, such as excessive and continuous use of drugs, alcoholism, cerebral ischemia, among others. Emphasizing that there is still no cure for PD, current pharmacological treatment aims to restore reduced dopaminergic activity in the central nervous system and manage symptoms. However, due to the different side effects caused by antiparkinsonian drugs, their use is recommended just when symptoms are considerably impairing professional performance or the patient's daily tasks. Therefore, studies for the development of new drugs have been conducted, and natural products are gaining importance due to the possibility of discovering new bioactive molecular. In this sense, this research aimed to perform the in silico study of molecules of natural origin for the treatment of PD. Methods: A search for molecules from medicinal plants was carried out, they underwent a pharmacokinetic and toxicological prediction with subsequent molecular docking study, being coupled with the MAO-B enzyme and the dopamine receptor 2. Results: The ginsenosides compounds present an unfavorable pharmacokinetic pattern, which can be explained by their molecular mass, while the other molecules present average patterns, with the exception of kavains, which obtained very satisfactory results. When it comes to toxicity, the molecules curcumin, dihydrokavain, vitexin, kavain and tetrahydrocurcumin did not exhibit any toxic alert. As for the molecular docking study, the compound curcumin stood out with a considerable number of interactions at many amino acid residues relevant to antiparkinsonian activity, both in the MAO-B enzyme and in the D2 receptor. Conclusion: Of 25 molecules of natural products, 3 are good candidates for studies of oral drugs, owing to their excellent pharmacokinetic profile and low probability of being toxic. The curcumin molecule has a great notoriety, as it obtained relevant interactions with the two proteins studied in molecular docking, speciallyin the MAO-B enzyme.

Curcumin modulation of L-dopa and rasagiline-induced neuroprotection in rotenone model of Parkinson's disease.

Parkinson's disease (PD) is one of the most incurable, chronic, and progressive neurodegenerative disorders Worldwide. Curcumin, a natural polyphenolic anti-oxidant compound, has a long history in traditional medicine. We investigate the effect of curcumin on brain oxidative stress, DNA fragmentation, and motor changes in rotenone-induced PD in mice. The possible modulation of the anti-parkinsonian action of drugs L-dopa and rasagiline by curcumin was also studied. Mice received rotenone 1.5 mg/kg and were treated with curcumin (150 mg/kg), L-dopa (25 mg/kg), rasagiline (1 mg/kg), L-dopa+curcumin, or rasagiline+curcumin. Striatal malondialdehyde, reduced glutathione, nitric oxide, tyrosine hydroxylase, and brain DNA fragmentations were measured. Histopathological examination of brain tissues was done. Motor coordination and behavioral tests such as wire-hanging, stair, and wood-waking tests were included. Rotenone caused elevation in brain malondialdehyde and nitric oxide contents, depletion of reduced glutathione accompanied by a reduction in rearing behavior, and impairment of motor activity in wire-hanging, stair, and wood-waking tests. Also, severe DNA fragmentation in the striatum, marked decrease of substantia nigra pigmented neurons, neuronal degeneration in the cerebral cortex and hippocampus, decreased glial fibrillary acidic protein reaction (GFAP) and glial cell size in the cerebral cortex were caused by rotenone. In rotenone-treated mice, brain oxidative stress was decreased by curcumin, L-dopa, rasagiline, curcumin+L-dopa, and curcumin+rasagiline. These treatments also prevented DNA fragmentation and markedly improved the motor and behavioral impairment caused by rotenone. Rotenone-induced histopathological changes were ameliorated by curcumin which had an additive effect to that of l-dopa or rasagiline. These data indicate that curcumin showed additive neuroprotective effects to L-dopa or rasagiline and ameliorated neurodegeneration, DNA fragmentation, and motor defects caused by rotenone in mice.

(1R,2R,6S)-2(4-(4-Isopropylbenzyl)piperazin-1-yl)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-enol

Parkinson’s disease (PD) is a progressive neurodegenerative disorder mainly characterized by movement dysfunction. Earlier, it was found that (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol (Prottremin) demonstrated antiparkinsonian activity in vivo on different animal models of PD. The paper presents synthesis of new Prottremin derivative, (1R,2R,6S)-2(4-(4-isopropylbenzyl)piperazin-1-yl)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-enol. The derivative was obtained by epoxide ring opening reaction with 1-(4-isopropylbenzyl)piperazine. The product yield was 48% after purification.

Screening of Spirulina Components for Anti-Parkinson's and Anti-Alzheimer's Activity byin Silico Methods and Docking Studies.

Spirulina platensis was first isolated from Lake Texcoco by Aztecs in the sixteenth century. In 2012, spirulina was considered to be safe dietary supplement by the Food and Drug Administration (FDA). Spirulina is a cyanophytic microalgae that is often considered as single cell protein. It contains many essential amino acids, proteins, fatty acids, antioxidant pigments, carotenoids, and cyanogenic pigments, that is, phycocyanobilins and phycocyanins (Eriksen, Appl Microbiol Biotechnol, 80(1):1-4, 2008). Components of spirulina are investigated for many health benefits and for pharmaceutical uses (Karkos et al., Spirulina in clinical practice: evidence-based human applications). Spirulina has been found to have a role in growth, immunity (Wu et al., Arch Toxicol, 90(8):1817-40, 2016), antioxidant (Wu et al., Arch Toxicol, 90(8):1817-40, 2016), antiviral (Ayehunie et al., J Acquir Immune Defic Syndr Hum Retrovirol, 18(1):7-12, 1998), antitoxicologic, anti-cancerogenic (Hirahashi et al., Int Immunopharmacol, 2(4):423-34, 2002), antidiabetic (Layam and Reddy, Diabetol Croat, 35(2):29-33, 2006), and neuroprotective properties. In this study, we focused on spirulina components in anti-Parkinson's and anti-Alzheimer's activity. Four potential targets, two for each activity, that is, structure of parkinE3 ligase (PDB ID:4I1H) and structure of BACE bound to 5-(3-(5-chloropyridin-3-yl)phenyl)-5-cyclopropyl-2-imino-3-methylimidazolidin-4one (PDBI D:4DJx) for anti-Parkinson's activity and structure of human MAO B in complex with selective inhibitor safinamide (PDB ID:2V5Z) and crystal structure of human BACE-1 in complex with CNP520(PDB ID:6EQM) for anti-Alzheimer's activity, have been selected. The in silico results and scoring of virtual screening, that is, molecular docking, were compared with commonly used marketed drugs such as levodopa for Parkinson's disease (PD) and rivastigmine (Rösler et al., BMJ, 318(7184):633-40, 1999) for Alzheimer's disease.

Kaempferol counteracts toxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in D. melanogaster: An implication of its mitoprotective activity

The current study aimed to investigate whether kaempferol (KMP), the major bioactive component of green leafy vegetables, could counteract the toxicity elicited by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in Drosophila melanogaster or not. First, we performed a dose-response curve, where adult wild-type flies were fed on diet-containing different concentrations of KMP throughout their lifespan. Afterward, flies were fed on a diet containing MPTP (500 μM) and KMP (20 and 40 μM) for 7 days. The MPTP- fed flies presented a higher mortality rate, lower emergence rate, locomotor deficits, and disruption in circadian rhythm when compared to the control. MPTP exposure induced severe oxidative stress, which was marked by reduction in thiol content, overproduction of reactive species, lipid and protein oxidation, and disruption of enzymes of antioxidant and neurotransmission pathways. MPTP also compromised the mitochondrial dynamics and respiration of flies, affecting the electron transport chain, oxidative phosphorylation, and fusion/fission processes. Besides extending per se the lifespan of flies, KMP counteracted the toxic effects of MPTP on the circadian cycle, survival, climbing, and hatching rates. KMP was also effective in restoring the activities of acetylcholinesterase (AChE) and monoamine oxidase (MAO) enzymes, as well as in normalizing the levels of all oxidant/antioxidant markers disrupted in MPTP-fed flies. Indeed, KMP reestablished the mitochondrial functionality in MPTP- fed flies, restoring the electron transport system linked to mitochondrial complex I and II, and rescuing the mRNA transcription of genes associated with mitochondrial fusion and fission, namely OPA-1 (Optic atrophy 1) and DRP-1 (Dynamin related protein 1). Our results showed the efficacy of KMP in hindering the toxicity induced by MPTP in D. melanogaster and suggest that the mitoprotective action of flavonoid may be boosting its anti-parkinsonism activity in the model. Besides, the study showed that wild-type strains of D. melanogaster proved to be reproducible in vivo model to mimic parkinsonian phenotypes through exposure to the neurotoxin MPTP.

Biological Evaluation of Aminoindane Derivatives as Antibacterial Agents

The aminoindane ring is the most studied skeletal structure in synthetic chemistry, in the synthesis of intermediates and because it is a biologically active molecule. Bioactive properties of the aminoindane ring include antibacterial, antiviral, antiapoptotic, antipyretic, analgesic, anticonvulsant, and antiparkinsonian activities. The most important bacteria in responsibility of nosocomial infections obtained in hospitals across the world are Acinetobacter baumannii and Methicillin-resistant Staphylococcus aureus. MRSA and A. baumannii have become resistant to numerous antibiotics. The development of novel antibiotic drugs is thus urgently needed. This study as investigated at the antibacterial effects of previously synthsized compounds 8 and 9 on A. baumannii and MRSA disease microorganisms. Studies on antibacterial activity employed disc diffusion and microdilution techniques. The investigation revealed that whereas the pathogenic organisms of compounds 8 and 9 formed zones that inhibited bacterial development, no zones formed in compounds 5, 6, and 7. Compounds 8 and 9's zone diameters against A. baumannii and MRSA were estimated to be between 0.7 and 1.0 mm. The range of MIC values was 3.9025–15.625 µg/ml. These results was envisaged the conclusion that derivatives with an aminoindane ring may function as MRSA and A. baumannii antibacterial agents.

Anti-parkinsonian effect of the mGlu2 positive allosteric modulator LY-487,379 as monotherapy and adjunct to a low L-DOPA dose in the MPTP-lesioned marmoset

In previous experiments, we have discovered that positive allosteric modulation of metabotropic glutamate 2 (mGlu2) receptors enhances the anti-parkinsonian action of an optimal dose of L-3,4-dihydroxyphenylalanine (L-DOPA). Whether selective mGlu2 positive allosteric modulation would also alleviate parkinsonian disability as monotherapy or as adjunct to a sub-optimal dose of L-DOPA has not been determined. Here, we assessed the anti-parkinsonian effect of mGlu2 positive allosteric modulation as monotherapy and adjunct to a sub-optimal dose of L-DOPA in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets. The highly selective positive allosteric modulator (PAM) LY-487,379 was utilised to activate mGlu2 receptors. When administered as monotherapy, LY-487,379 10 mg/kg diminished global parkinsonism by 48% (P < 0.001) and increased duration of on-time by 7-fold, when compared to vehicle treatment (P < 0.05). When added to a sub-optimal dose of L-DOPA, LY-487,379 10 mg/kg decreased global parkinsonism by 44% (P < 0.001) and extended duration of on-time by 2.5-fold (P < 0.01). Our results indicate that selective mGlu2 positive allosteric modulation elicits anti-parkinsonian benefits as monotherapy and as adjunct to sub-optimal dose of L-DOPA paradigms, potentially suggesting that mGlu2 PAMs may have a therapeutic niche early in the treatment of PD as DOPA-sparing agents.

Evaluation of anti-parkinsonian activity of Pueraria tuberosa (Roxb. ex Willd.) DC. on experimental animals

Evaluation of anti-parkinsonian activity of Pueraria tuberosa (Roxb. ex Willd.) DC. on experimental animals

AV-101, a Pro-Drug Antagonist at the NMDA Receptor Glycine Site, Reduces L-Dopa Induced Dyskinesias in MPTP Monkeys.

N-methyl-D-aspartate (NMDA) receptors have been implicated in L-Dopa-induced dyskinesias (LID) in Parkinson's disease patients, but the use of antagonists that directly inhibit this receptor is associated with severe side effects. L-4-chlorokynurenine (4-Cl-KYN or AV-101) is a pro-drug of 7-chlorokynurenic acid (7-Cl-KYNA), a potent and specific antagonist of the glycine (GlyB) co-agonist site of NMDA receptors. The 7-Cl-KYNA has limited ability to cross the blood-brain barrier, whereas AV-101 readily accesses the brain. We investigated if AV-101 reduces LID in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys while maintaining the antiparkinsonian activity of L-Dopa. A first pilot study using three dyskinetic MPTP monkeys showed that acute AV-101 treatment (250 and 450 mg/kg) reduced LID and maintained the antiparkinsonian activity of L-Dopa. The main study using six additional dyskinetic MPTP monkeys showed that repeated AV-101 treatment (250 mg/kg, b.i.d. for 4 consecutive days) maintained their L-Dopa antiparkinsonian response. We measured significantly less LID when AV-101 was combined with L-Dopa treatment. AV-101 alone or with L-Dopa had no non-motor adverse effects in MPTP monkeys. Our study showed antidyskinetic activity of AV-101 in MPTP monkeys was comparable to amantadine tested previously in our laboratory in this model. We observed no adverse effects with AV-101, which is an improvement over amantadine, with its known side effects.