Antiparkinsonian Agents Research Articles

Characterising a New Sheep Model of Parkinson's Disease Using Unilateral Intracerebral Injection of 6-Hydroxydopamine Into the Substantia Nigra.

New therapeutic agents developed for treating neurological disorders are often tested successfully on rodents. Testing in an appropriate large animal model where there is longer lifespan and comparable brain size to humans should improve translational success and is frequently expected by regulatory bodies. In this project, we aimed to establish a novel sheep model of Parkinson's disease as a large-brained experimental model for translational research. Our objective was to create a sheep model of Parkinson's disease by unilaterally infusing the neurotoxin 6-hydroxydopamine into the substantia nigra pars compacta. This approach, previously used to induce parkinsonism in rat and non-human primate models, causes dopaminergic imbalance and induces rotational behaviour in quadrupeds challenged with dopaminergic receptor agonists. In the present sheep study, the mixed dopamine receptor agonist apomorphine, 0.25 mg/kg, and dopamine D2 agonist ropinirole, 0.16 mg/kg, were used to induce rotational behaviour and confirm dopamine depletion. Behavioural signs were then measured and characterised in the field using automated movement tracking with simultaneous video recordings. Post-mortem, the extent of the 6-hydroxydopamine lesions was evaluated through tyrosine hydroxylase immunohistochemistry and quantifying levels of catecholamines (dopamine, 3,4-dihydroxyphenylacetic acid and homovanilic acid) quantified using high-performance liquid chromatography. Our new sheep model of Parkinson's disease using 6-hydroxydopamine is safe and offers a number of regulatory, ethical and financial advantages over non-human primate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine models. It provides a platform to evaluate novel antiparkinsonian agents and medical devices in a large brain with the promise of greater success for translation into clinical application.

Multilayered screening for multi-targeted anti-Alzheimer's and anti-Parkinson's agents through structure-based pharmacophore modelling, MCDM, docking, molecular dynamics and DFT: a case study of HDAC4 inhibitors.

Alzheimer's disease (AD) and Parkinson's disease (PD) are neurological conditions that primarily impact the elderly having distinctive traits and some similarities in terms of symptoms and progression. The multifactorial nature of AD and PD encourages exploring potentiality of multi-target therapy for addressing these conditions to conventional, the "one drug one target" strategy. This study highlights the searching of potential HDAC4 inhibitors through multiple screening approaches. In this context, structure-based pharmacophore model, ligand profiler mapping and MCDM approaches were performed for target prioritization. Similarly, ligand profiler, MCDM and Docking studies were performed to prioritize multi-targeted HDAC4 inhibitors. These comprehensive approaches unveiled 5 common targets and 5 multi-targeted prioritized compounds consensually. MD simulations, DFT and binding free energy calculations corroborated the stability and robustness of propitious compound 774 across 5 prioritized targets. In conclusion, the screened compound 774 (ChEMBL 4063938) could be a promising multi-targeted therapy for managing AD and PD further rendering experimental validation. The online version contains supplementary material available at 10.1007/s40203-024-00302-4.

Catalytic Reductive Amination and Tandem Amination–Alkylation of Esters Enabled by a Cationic Iridium Complex

Reported herein is a convenient and efficient method for one‐pot, catalytic reductive amination, as well as the first multi‐component tandem reductive amination ‐ functionalization of bench‐stable and readily available common carboxylic esters. This method is based on the cationic [Ir(COD)2]BArF‐catalyzed chemoselective hydrosilylation of esters, followed by one‐pot acid‐mediated amination and nucleophilic addition. The reaction was conducted under mild conditions at a very low catalyst loading (0.1 mol% of Ir), which could be further reduced to 0.001 mol%, as demonstrated by a reaction at a 15 g scale. The method is highly versatile, allowing the use of esters with or without α‐protons for the N‐mono‐alkylation of primary and secondary amines to produce diverse secondary and tertiary amines, as well as α‐branched/functionalized amines. The method is highly chemoselective and tolerates a variety of functional groups such as bromo, trifluoromethyl, ester, and cyano groups. The value of the method was demonstrated by the one‐step catalytic synthesis of two bio‐relevant N‐mono‐methyl α‐amino esters and the antiparkinsonian agent piribedil, as well as by the use of two shorter chain triglycerides as alkylating feedstock.

Catalytic Reductive Amination and Tandem Amination-Alkylation of Esters Enabled by a Cationic Iridium Complex.

Reported herein is a convenient and efficient method for one-pot, catalytic reductive amination, as well as the first multi-component tandem reductive amination-functionalization of bench-stable and readily available common carboxylic esters. This method is based on the cationic [Ir(COD)2]BArF-catalyzed chemoselective hydrosilylation of esters, followed by one-pot acid-mediated amination and nucleophilic addition. The reaction was conducted under mild conditions at a very low catalyst loading (0.1 mol % of Ir), which could be further reduced to 0.001 mol %, as demonstrated by a reaction at a 15 g scale. The method is highly versatile, allowing the use of esters with or without α-protons for the N-mono-alkylation of primary and secondary amines to produce diverse secondary and tertiary amines, as well as α-branched/functionalized amines. The method is highly chemoselective and tolerates a variety of functional groups such as bromo, trifluoromethyl, ester, and cyano groups. The value of the method was demonstrated by the one-step catalytic synthesis of two bio-relevant N-mono-methyl α-amino esters and the antiparkinsonian agent piribedil, as well as by the use of two shorter chain triglycerides as alkylating feedstock.

Dopamine-conjugated extracellular vesicles induce autophagy in Parkinson's disease.

The application of extracellular vesicles (EVs) as vehicles for anti-Parkinson's agents represents a significant advance, yet their clinical translation is hampered by challenges in efficient brain delivery and complex blood-brain barrier (BBB) targeting strategies. In this study, we engineered dopamine onto the surface of adipose-derived stem cell EVs (Dopa-EVs) utilizing a facile, two-step cross-linking approach. This engineering enhanced neuronal uptake of the EVs in primary neurons and neuroblastoma cells, a process shown to be competitively inhibited by dopamine pretreatment and dopamine receptor antibodies. Notably, Dopa-EVs demonstrated increased brain accumulation in mouse Parkinson's disease (PD) models. Therapeutically, Dopa-EVs administration led to the rescue of dopaminergic neuronal loss and amelioration of behavioural deficits in both 6-hydroxydopamine (6-OHDA) and α-Syn PFF-induced PD models. Furthermore, we observed that Dopa-EVs stimulated autophagy evidenced by the upregulation of Beclin-1 and LC3-II. These findings collectively indicate that surface modification of EVs with dopamine presents a potent strategy for targeting dopaminergic neurons in the brain. The remarkable therapeutic potential of Dopa-EVs, demonstrated in PD models, positions them as a highly promising candidate for PD treatment, offering a significant advance over current therapeutic modalities.

The effect of prescription and over-the-counter medications on core temperature in adults during heat stress: a systematic review and meta-analysis

Heat stress impacts are an escalating global health concern. Public health bodies such as the World Health Organization (WHO) warn that certain medications impair thermoregulation, with limited supporting evidence. Our aim was to investigate whether medications listed by the WHO increase core temperature responses during heat stress. For this systematic review and meta-analysis, MEDLINE, PubMed, Scopus, CINAHL, Web of Science, and EMBASE were searched up to Jan.30, 2024. Randomised studies exposing humans to exertional and/or passive heat stress that investigated a drug identified by WHO compared to no drug/placebo were eligible. The primary outcome was core temperature (e.g., rectal, oesophageal, aural, tympanic). We assessed risk of bias (Cochrane's Risk of Bias 2) and certainty of evidence (GRADE). The study was pre-registered on PROSPERO (CRD42020170684). Thirty-five studies were included enrolling 353 individuals (16 women; 4.5%). Twenty-seven unique medications were tested. The average age of participants across studies was <30 years, and only one study included a clinical population. Under heat stress, there was moderate quality evidence that drugs with high anticholinergic properties increased core temperature at air temperatures ≥30°C (+0.42°C; 95% CI 0.04, 0.79°C; p=0.03) alongside reduced sweating, although evidence is limited to the drug atropine. Similarly, non-selective beta-blockers (+0.11°C; 95% CI 0.02, 0.19°C; p=0.02), adrenaline (+0.41°C; 95% CI 0.21, 0.61°C) and anti-Parkinson's agents (+0.13°C; 95% CI 0.07, 0.19°C; p=0.02) elevated core temperature. Antidepressants, diuretics, or drugs with weak anticholinergic effects did not alter core temperature responses. Current evidence supports strong anticholinergics, non-selective beta-blockers, adrenaline, and anti-Parkinson's agents impairing thermoregulation during heat stress. No evidence indicated thermoregulation is impacted by other WHO-listed medications. Evidence is predominantly limited to healthy young men, with short heat stress exposures. Studies over longer durations, in women, older adults and those with chronic diseases are required to better inform the pharmaceutical management of patients during hot weather. This study was supported by a National Health and Medical Research Council (NHMRC) Investigator Grant (2021/GNT2009507; Holder: O. Jay).

Investigating In silico and In vitro Therapeutic Potential of Diosmetin as the Anti-Parkinson Agent.

This study aimed to investigate how diosmetin interacts with seven target receptors associated with oxidative stress (OS) and validate its antioxidant properties for the potential management of Parkinson's disease (PD). In PD, the degeneration of dopaminergic cells is strongly influenced by OS. This stressor is intricately connected to various mechanisms involved in neurodegeneration, such as mitochondrial dysfunction, neuroinflammation, and excitotoxicity induced by nitric oxide. The aim of this research was to establish a molecular connection between diosmetin and OS-associated target receptors was the goal, and it investigated how this interaction can lessen PD. Seven molecular targets - Adenosine A2A (AA2A), Peroxisome Proliferator-Activated Receptor Gamma (PPARγ), Protein Kinase AKT1, Nucleolar Receptor NURR1, Liver - X Receptor Beta (LXRβ), Monoamine Oxidase - B (MAO-B) and Tropomyosin receptor kinase B (TrkB) were obtained from RCSB. Molecular docking software was employed to determine molecular interactions, while antioxidant activity was assessed through in vitro assays against various free radicals. Diosmetin exhibited interactions with all seven target receptors at their binding sites. Notably, it showed superior interaction with AA2A and NURR1 compared to native ligands, with binding energies of -7.55, and -6.34 kcal/mol, respectively. Additionally, significant interactions were observed with PPARγ, AKT1, LXRβ, MAO-B, and TrkB with binding energies of -8.34, -5.42, -7.66, -8.82, -8.45 kcal/mol, respectively. Diosmetin also demonstrated antioxidant activity against various free radicals, particularly against hypochlorous acid (HOCl) and nitric oxide (NO) free radicals. Diosmetin possibly acts on several target receptors linked to the pathophysiology of PD, demonstrating promise as an OS inhibitor and scavenger.

Molecular Docking Studies of Substituted Aromatic N-(3-chloro-4-fluorophenyl)-1- phenylmethanimine Derivatives against Monoamine Oxidase-B as Potential Anti-parkinsonian Agents

Molecular Docking Studies of Substituted Aromatic N-(3-chloro-4-fluorophenyl)-1- phenylmethanimine Derivatives against Monoamine Oxidase-B as Potential Anti-parkinsonian Agents

Impact of the COVID-19 pandemic on antidepressant consumption in the Central region of Portugal: interrupted time series.

To evaluate the impact of the pandemic on the consumption of antidepressive agents in Central Portugal. To estimate the causal effect of the pandemic an interrupted time series analysis was conducted. Data of antidepressant drugs monthly dispensed in community pharmacies between Jan-2010 and Dec-2021 were provided by the regional Health Administration. Anti-Parkinson dopaminergic agents and statins, theoretically not influenced by COVID-19 pandemics, were used as comparator series. The number of packages was converted into defined daily doses and presented as defined daily doses/1000 inhabitants/day. A Bayesian structural time-series model with CausalImpact on R/RStudio was used to predict the counterfactual. Analyses with different geographical granularity (9 sub-regions and 78 municipalities) were performed. When compared to counterfactual, regional consumption non-significantly increased after the pandemic declaration, with a relative effect of + 1.30% [95%CI -1.6%:4.2%]. When increasing the granularity, differences appeared between sub-region with significant increases in Baixo Mondego + 6.5% [1.4%:11.0%], Guarda + 4.4% [1.1%:7.7%] or Cova da Beira + 4.1% [0.17%:8.3%], but non-significant variation in the remaining 6 sub-regions. Differences are more obvious at municipality level, ranging from increases of + 37.00% [32.00%:42.00%] to decreases of -11.00% [-17.00%:-4.20%]. Relative impact positively correlated with percentage of elderly in the municipality (r = 0.301; p = 0.007), and negatively with population density (r=-0.243; p = 0.032). No other predicting variables were found. Antidepressant consumption suffered very slight variations at regional level after the COVID-19 pandemic declaration. Analysis with higher granularity allowed identifying municipalities with higher impact (increase or decrease). The absence of clear association patterns suggests other causal hypotheses of the differences.

Association between Parkinson’s disease and cardiovascular disease mortality: a prospective population-based study from NHANES

Background and aimConflicting results have been reported on the association between Parkinson's disease (PD) and cardiovascular disease (CVD) mortality in different populations. Therefore, studying the relationship between PD and CVD mortality is crucial to reduce mortality caused by the former.MethodsIn this cohort investigation, we enrolled 28,242 participants from the National Health and Nutrition Examination Survey spanning from 2003 to 2018. The 380 cases of PD in the cohort were identified by documenting ‘ANTIPARKINSON AGENTS’ in their reported prescription medications. Mortality outcomes were ascertained by cross-referencing the cohort database with the National Death Index, which was last updated on 31 December 2019. Cardiovascular disease mortality was categorised according to the 10th revision of the International Classification of Diseases by using a spectrum of diagnostic codes. Weighted multivariable Cox regression analysis was used to examine the association between PD and the risk of CVD mortality.ResultsA total of 28,242 adults were included in the study [mean age, 60.156 (12.55) years, 13,766 men (48.74%)], and the median follow-up period was 89 months. Individuals with PD had an adjusted HR of 1.82 (95% CI, 1.24–2.69; p = 0.002) for CVD mortality and 1.84 (95% CI, 1.44–2.33; p < 0.001) for all-cause mortality compared with those without PD. The association between PD and CVD mortality was robust in sensitivity analyses, after excluding participants who died within 2 years of follow-up and those with a history of cancer at baseline [HR,1.82 (95% CI, 1.20–2.75; p = 0.005)].ConclusionsPD was associated with a high long-term CVD mortality rate in the US population.

Real-World Data-Derived Pharmacovigilance on Drug-Induced Cognitive Impairment Utilizing a Nationwide Spontaneous Adverse Reporting System.

Background and Objectives: Despite high incidences of cognitive impairment with aging, evidence on the prevalence and the seriousness of drug-induced cognitive impairment is limited. This study aims to evaluate the prevalence and the severity of drug-induced cognitive impairment and to investigate the clinical predictors of increased hospitalization risk from serious drug-induced cognitive impairment. Materials and Methods: Adverse drug events (ADEs) regarding drug-induced cognitive impairment reported to the Korean Adverse Event Reporting System Database (KAERS DB) from January 2012 to December 2021 were included (KIDS KAERS DB 2212A0073). The association between the etiologic classes and the reporting serious adverse events (SAEs) was evaluated using disproportionality analysis, and the effect was estimated with reporting odds ratio (ROR). Clinical predictors associated with increased risk of hospitalization from SAEs were identified via multivariate logistic analysis, and the effect was estimated with odds ratio (OR). Results: The most etiologic medication class for drug-induced cognitive impairment ADEs was analgesics, followed by sedative-hypnotics. Anticancer (ROR 57.105, 95% CI 15.174-214.909) and anti-Parkinson agents (ROR 4.057, 95% CI 1.121-14.688) were more likely to report serious drug-induced cognitive impairments. Male sex (OR 19.540, 95% CI 2.440-156.647) and cancer diagnosis (OR 18.115, 95% CI 3.246-101.101) are the major clinical predictors for increased risk of hospitalizations due to serious drug-induced cognitive impairment. Conclusions: This study highlights the significant prevalence and severity of drug-induced cognitive impairment with cancer diagnosis and anticancer agents. However, further large-scaled studies are required because of the potential underreporting of drug-induced cognitive impairments in real practice settings, which is further contributed to by the complexity of multiple contributing factors such as comorbidities.

Synthesis, In-Vitro, In-Vivo screening, and molecular docking of disubstituted aminothiazole derivatives and their selenium nanoparticles as potential antiparkinson agents

Neurological illnesses are among the leading causes of mortality across the world. In the present work, the synthesis of a new series of substituted aminothiazole derivatives (3a-e) as antiparkinsonian agents is reported. Furthermore, aminothiazoles 3a-e were used for in-situ synthesis of selenium nanoparticles 3a(SeNP)-3e(SeNP) to boost the CNS activities and potency. Selenium nanoparticles were confirmed using UV–Vis spectrophotometry, TEM, particle size distribution, and zeta potential. All selenium nano-sized forms elicited greater in-vitro inhibitory activity against both hMAO isoforms when compared to their corresponding normal-sized ones. Compound 3b was the most potent MAO-B inhibitor with an IC50 value of 0.11 µM. Its nano-sized form 3b(SeNP) showed improved hMAO-B inhibitory activity with an IC50 value of 0.033 µM which surpasses its normal-sized action (3b) by 70%. Molecular docking studies of compound 3b displayed interaction at the active sites of both hMAO-A and hMAO-B isoforms in an inhibitory mode similar to co-crystalized ligands. The antiparkinson effect of both 3b and 3b(SeNP) was further screened by using an in-vivo model of haloperidol-induced Parkinson's disease in rats. Behavioral tests in rats revealed that the nanoparticle formulation showed a superior effect on exploratory activity as an antiparkinsonian agent. Accordingly, this nanotechnology-based approach can be a promising lead for developing novel and potent treatments for neurodegenerative diseases.

Gene Expression, Oxidative Stress, and Neurotransmitters in Rotenone-induced Parkinson’s Disease in Rats: Role of Naringin from Citrus aurantium via Blocking Adenosine A2A Receptor

Background:: Lack of control in voluntary movements, resting tremor, postural instability, and stiffness are the hallmarks of Parkinson's disease (PD). Objective:: The current work's objective is to assess naringin isolated from Citrus aurantium L. peels as an anti-parkinsonism agent in rats. Methods:: The HPLC and LC-ESI-MS analysis of Citrus aurantium L. peels methanol extract was done. The behavioral, biochemical, genetic, and histopathological analysis were evaluated in parkinsonism rats. Results:: Fourteen phenolics and nine flavonoids were found in the extract, according to the HPLC analysis, while LC-ESI-MS analysis revealed the presence of twenty-six flavonoids. The dominant flavonoid subclasses were 4 aglycones, 11 monoglycosides, 5 diglycosides, and 6 polymethoxy flavonoids, beside 4 coumarines, 4 alkaloids and a limonin triterpene. Adenosine A2A receptor (A2AR) gene expression, malondialdehyde (MDA), interleukin-6 (IL-6), caspase-3 (Cas-3) and DNA fragmentation levels significantly increased in rotenone-treated rats. Dopamine (DA), norepinephrine (NE), serotonin (5-HT), reduced glutathione (GSH), succinate, and lactate dehydrogenase (SDH &amp;LDH) levels all significantly decreased. Treatment with naringin and A2AR antagonists enhanced the animals’ behavior and improved all the selected parameters. The brain hippocampal features confirmed our results. Conclusion:: Naringin could be considered a nutraceutical agent by attenuating the neurodegeneration associated with PD via blocking adenosine A2AR.

Study of new p-tolylpiperidin-4-one as an anti-Parkinson agent: Synthesis, spectral, XRD-crystal, in silico study, electronic and intermolecular interaction investigations by the DFT method

This study thoroughly investigated the potential of using 3,3-dimethyl-2,6-di-p-tolylpiperidin-4-one, (DMeTP) as an anti-Parkinson medicine against Parkinson's disease. To accomplish this, DMeTP was synthesized and characterized by various spectral techniques such as FT-IR, NMR, and Mass. The Hirshfeld analysis and finger plot were used in this study to reveal important insights about the intermolecular relations of the compounds. The theoretical analyses of the compound was carried out using Density Functional Theory (DFT) at the level of theory B3LYP/6–311++G (**). The frontier orbital and the molecular electrostatic potential studies proved the chemical stability of the DMeTP structure. Then, weak interactions like hydrogen and Vdw interactions were investigated throughout the topological study (AIM and RDG). The alpha-synuclein protein was used in a molecular docking analysis to uncover inhibitory properties against Parkinson's disease. Additionally, the pharmacokinetic and physicochemical characteristics of the DMeTP molecule were examined using the SwissADME online program.

Synthesis and Monoamine Oxidase Inhibition Properties of 4-(2-Methyloxazol-4-yl)benzenesulfonamide

4-(2-Methyloxazol-4-yl)benzenesulfonamide was synthesized by the reaction of 4-(2-bromoacetyl)benzenesulfonamide with an excess of acetamide. The compound was evaluated as a potential inhibitor of human monoamine oxidase (MAO) A and B and was found to inhibit these enzymes with IC50 values of 43.3 and 3.47 μM, respectively. The potential binding orientation and interactions of the inhibitor with MAO-B were examined by molecular docking, and it was found that the sulfonamide group binds and interacts with residues of the substrate cavity. 4-(2-Methyloxazol-4-yl)benzenesulfonamide showed no cytotoxic effect against human stromal bone cell line (HS-5) in the concentration range of 1–100 µmol. Thus, the new selective MAO-B inhibitor was identified, which may be used as the lead compound for the development of antiparkinsonian agents.

Polyketides with α-glucosidase inhibitory and neuroprotective activities from Aspergillus versicolor associated with Pedicularis sylvatica.

Aspergillus versicolor, an endophytic fungus associated with the herbal medicine Pedicularis sylvatica, produced four new polyketides, aspeversins A-D (1-2 and 5-6) and four known compounds, O-methylaverufin (2), aversin (3), varilactone A (7) and spirosorbicillinol A (8). Their structures were elucidated by extensive spectroscopic data analysis, and their absolute configurations were determined by calculated electronic circular dichroism (ECD) and Mo2(AcO)4-induced CD data. Compound 5 was found to exhibit α-glucosidase inhibitory activity with an IC50 value of 25.57 μM. An enzyme kinetic study indicated that 5 was a typical uncompetitive inhibitor toward α-glucosidase, which was supported by a molecular docking study. Moreover, compounds 1-3 and 5 also improved the cell viability of PC12 cells on a 1-methyl-4-phenylpyridinium (MPP+)-induced Parkinson's disease model, indicating their neuroprotective potential as antiparkinsonian agents.

RECURRENT FALLS IN OLDER ADULTS ARE ASSOCIATED WITH MORTALITY AND HOSPITALIZATION

Abstract Annually, 1 in 4 older adults fall and roughly half have a second fall within 6 months. We studied 57 hospitals in the TriNetX Network. We included all older adults discharged home from the emergency department (ED) after a fall in 2022 for a total of 89,061 patients. Of these, 13,389 (15%) patients returned to the ED for another fall within 6 months. Patients with repeat falls were older (78.7 vs 76.5 years), more likely to have hypertension (76 vs 56%), prior myocardial infarction (14 vs 3%), heart failure (29 vs. 15%), peripheral vascular disease (18 vs 10%), cerebrovascular event (19 vs 10%), chronic obstructive pulmonary disease (COPD) (23 vs 14%), diabetes (40 vs 23%), liver disease (17 vs 11%), chronic kidney disease (30 vs 16%), and cancer (45 vs 32%); P&amp;lt; 0.001. Patients with recurrent falls were more likely to be prescribed cardiovascular medications (84 vs. 66%), central nervous system medications (87 vs 69%), opioids (71 vs 52%), sedatives/hypnotics (59 vs 42%), antipsychotics (23 vs 12%), antidepressants (51 vs 32%), antiparkinsonian agents (9 vs 4%), and antivertigo agents (15 vs 9%); P&amp;lt; 0.001. Patients with a recurrent fall within 6 months had higher hospital admission rate (46.2 vs 15.8%, OR 4.6 [95%CI, 4.4-4.7]) and higher mortality rate (6.2 vs 3.5%, OR 1.83 [95%CI 1.7-2.0]). Older adults discharged home from the ED after falling are at high risk of a second fall and those who have a repeat fall within 6 months are at higher risk of hospital admission and mortality.

A New Stereoselective Approach to the Substitution of Allyl Hydroxy Group in para-Mentha-1,2-diol in the Search for New Antiparkinsonian Agents.

Two approaches to the synthesis of para-menthene epoxide ((1S,5S,6R)-4) are developed. The first approach includes a reaction between chlorohydrin 7 and NaH in THF. The second involves the formation of epoxide in the reaction of corresponding diacetate 6 with sodium tert-butoxide. One possible mechanism of this reaction is proposed to explain unexpected outcomes in the regio- and stereospecificity of epoxide (1S,5S,6R)-4 formation. The epoxide ring in (1S,5S,6R)-4 is then opened by various S- and O-nucleophiles. This series of reactions allows for the stereoselective synthesis of diverse derivatives of the monoterpenoid Prottremine 1, a compound known for its antiparkinsonian activity, including promising antiparkinsonian properties.

Antidyskinetic activity of new derivatives of inydazol-4,5-dicarbonic acid in a parkinsonism experimental model due to administration of 6-hydroxydopapine

BACKGROUND: Levodopa therapy currently remains the clinical method of choice for patients with Parkinsons disease. However, in the late stages of the disease, approximately 80% of patients receiving treatment developed levodopa-induced dyskinesia. The studied substances are derivatives of imidazole-4,5-dicarboxylic acid. Their pharmacological effect is produced due to interaction with the recognition site of NMDA receptor, which, together with their high efficiency, implies that they are safer than previously available drugs in this pharmacological group.&#x0D; AIM: To study the antidyskinetic effect of IEM2295 and IEM2296 derivatives of imidazole-4,5-dicarboxylic acid.&#x0D; MATERIALS AND METHODS: The model is based on the toxic effect of 6-hydroxydopamine on rat brain tissue. The first (control) group of rats received injections of only Levodopa and Benserazide, the second group received injections of Levodopa, Benserazide, and the test substance IEM2295, and the third group received injections of Levodopa, Benserazide and the test substance IEM2296. Each group was evaluated based on three criteria: motor function violations, limb dyskinesia, and axial and chewing dyskinesia. The severity of motor functions was graded on a scale of 0 to 4 points at 35, 70, 105, and 140 minutes after injection of the above substances, where 0 and 4 represent the absence and most pronounced degree of pathological movements, respectively.&#x0D; RESULTS: The result analysis showed that the greatest effect on reducing the severity of limb dyskinesia, axial dyskinesia, and chewing dyskinesia in rats was observed at 105 and 140 minutes after injections of the studied substances. Statistically significant differences between the control group and rats receiving injections of the studied substances were revealed at all the time points for limb dyskinesia; i.e., at 35, 105, and 140 minutes for axial dyskinesia and at 105 and 140 minutes for chewing dyskinesia.&#x0D; CONCLUSIONS: In the experimental model of parkinsonism, IEM2295 and IEM2296 show antiparkinsonian and antidyskinetic activity because they reduce the severity of motor function disorders in rats with levodopa-induced dyskinesia. The results indicate the prospects for continued development of these substances and further research for effective and safe antiparkinsonian agents among compounds of this class.

Guidelines for pharmacotherapy in Alzheimer's disease - A primer on FDA-approved drugs.

The growing prevalence of dementia makes it important for us to better understand its pathophysiology and treatment modalities, to improve the quality of life of patients and caregivers. Alzheimer's disease (AD), a neurodegenerative disease, is the most common form of amnestic dementia in the geriatric population. Pathophysiology of AD is widely attributed to aggregation of amyloid-beta (Aβ) plaques and hyperphosphorylation of tau proteins. Initial treatment modalities aimed to increase brain perfusion in a non-specific manner. Subsequent therapy focused on rectifying neurotransmitter imbalance in the brain. Newer drugs modify the progression of the disease by acting against aggregated Aβ plaques. However, not all drugs used in therapy of AD have been granted approval by the United States Food and Drug Administration (FDA). This review categorizes and summarizes the FDA-approved drugs in the treatment of AD in a manner that would make it a convenient reference for researchers and practicing physicians alike. Drugs that mitigate symptoms of dementia may be categorized into mitigators of Behavioral and Psychological Symptoms of Dementia (BPSD), and mitigators of cognitive decline. BPSD mitigators include brexpiprazole, an atypical antipsychotic with a once-daily dosage suited to treat agitation in dementia patients, and suvorexant, an orexin receptor antagonist used to treat sleep disturbances. Cognitive decline mitigators include cholinesterase inhibitors such as donepezil, rivastigmine, and galantamine and glutamate inhibitors such as memantine. Donepezil is the most commonly prescribed drug. It is cheap, well-tolerated, and may be prescribed orally once daily, or as a transdermal patch once weekly. It increases ACh levels, enhances oligodendrocyte differentiation and also protects against Aβ toxicity. However, regular cardiac monitoring is required due to reports of cardiac conduction side effects. Rivastigmine requires a twice-daily oral dosage or once-daily replacement of transdermal patch. It has fewer cardiac side effects than donepezil, but local application-site reactions have been noted. Galantamine, in addition to improving cognitive symptoms in a short span of time, also delays the development of BPSDs and has minimal drug-drug interactions by virtue of having multiple metabolic pathways. However, cardiac conduction disturbances must be closely monitored for. Memantine, a glutamate regulator, acts as an anti-Parkinsonian agent and an antidepressant, in addition to improving cognition and neuroprotection, and requires a once-daily dosage in the form of immediate-release or sustained-release oral tablets. Disease-modifying drugs such as aducanumab and lecanemab reduce the Aβ burden. Both act by binding with fibrillary conformations of Aβ plaques in the brain. These drugs have a risk of causing amyloid-related imaging abnormalities, especially in persons with ApoE4 gene. Aducanumab is administered once every 4 weeks and lecanemab once every 2 weeks. The decision on the choice of the drug must be made after considering the availability of drug, compliance of patient (once-daily vs. multiple doses daily), cost, specific comorbidities, and the risk-benefit ratio for the particular patient. Other non-pharmacological treatment modalities must also be adopted to have a holistic approach toward the treatment of AD.