DYRK1A Inhibitors and Perspectives for the Treatment of Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is a chronic neurodegenerative disease and the most common form of dementia, especially in the elderly. Due to the increase in life expectancy, in recent years, there has been an excessive growth in the number of people affected by this disease, causing serious problems for health systems. In recent years, research has been intensified to find new therapeutic approaches that prevent the progression of the disease. In this sense, recent studies indicate that the dual-specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) gene, which is located on chromosome 21q22.2 and overexpressed in Down syndrome (DS), may play a significant role in developmental brain disorders and early onset neurodegeneration, neuronal loss and dementia in DS and AD. Inhibiting DYRK1A may serve to stop the phenotypic effects of its overexpression and, therefore, is a potential treatment strategy for the prevention of ageassociated neurodegeneration, including Alzheimer-type pathology. OBJECTIVE: In this review, we investigate the contribution of DYRK1A inhibitors as potential anti-AD agents. METHODS: A search in the literature to compile an in vitro dataset including IC50 values involving DYRK1A was performed from 2014 to the present day. In addition, we carried out structure-activity relationship studies based on in vitro and in silico data. RESULTS: molecular modeling and enzyme kinetics studies indicate that DYRK1A may contribute to AD pathology through its proteolytic process, reducing its kinase specificity. CONCLUSION: further evaluation of DYRK1A inhibitors may contribute to new therapeutic approaches for AD.

Feira das Cartas: integrando promoção, regionalização e gestão em saúde em atividade lúdica e interativa / Letters fair: integrating regionalization, health promotion and management in a playful and interactive activity

Resumo Introdução: A educação médica, por meio de metodologias ativas, proporciona o ensino e a aplicação integrada de conceitos da saúde coletiva, como regionalização, promoção e gestão em saúde. Durante a pandemia de Covid-19, ao considerar a necessidade de adaptações de ensino para a manutenção da qualidade do aprendizado, o módulo de Saúde Coletiva III do curso de graduação em Medicina implementou a atividade remota "Feira Virtual das Cartas de Promoção da Saúde", a qual proporcionou o desenvolvimento de habilidades importantes. Dessa maneira, objetiva-se, neste relato, expor o ensino teórico e a aplicação prática integrada dos conceitos e princípios de promoção, regionalização e gestão da saúde, importantes no estudo da saúde coletiva, por meio dessa atividade no ensino remoto. Relato de experiência: A atividade "Feira Virtual das Cartas de Promoção da Saúde", desenvolvida no terceiro período, contou com quatro etapas. A etapa 0 consistiu em um encontro síncrono para que os docentes explicassem aos discentes as demais etapas e o desenvolvimento da atividade. A primeira compreendeu a leitura das "Cartas de Promoção da Saúde" e a confecção de produto ou ação factível, executável e aplicável para apresentarem na feira. A segunda parte foi composta por gerenciamento de recursos fictícios por cada equipe, considerando a qualidade e as necessidades dos produtos ofertados na feira. A última etapa consistiu na avaliação, por meio de feedback, entre docentes e discentes. Discussão: Por meio dessa dinâmica, os discentes aprofundaram seus conhecimentos acerca das "Cartas de Promoção da Saúde" e puderam aplicar, a partir delas, as diretrizes do Sistema Único de Saúde (SUS) em um contexto mais amplo e globalizado. Os estudantes potencializaram suas habilidades de gestão e criatividade, embora algumas limitações tenham sido observadas, como a falta de um conhecimento mais abrangente sobre "gestão em saúde", o qual poderia ter aprimorado o aproveitamento durante a atividade. Conclusão: Os discentes puderam atuar de forma ativa na construção do conhecimento ao longo do processo, desenvolvendo habilidades imprescindíveis para a prática profissional. A atividade, de forma lúdica, proporcionou a integração de diversos conceitos em saúde coletiva, representando um exemplo de como a educação médica pode atuar de maneira integrativa e prática.

Abstract Introduction: Medical education, through active methodologies, provides the teaching and integrated application of Collective Health concepts, such as Regionalization, Health Promotion and Management. During the COVID-19 pandemic, considering the need for adaptations in teaching methods to maintain the quality of learning, the Collective Health Module III of the undergraduate medical course implemented the remote activity "Virtual Fair of Health Promotion Letters", which provided the development of important skills. Thus, the aim of this report is to expose the theoretical teaching and the integrated practical application of the concepts and principles of health promotion, regionalization and health management, which are important in the study of Collective Health, through this remote learning activity. Experience report: The activity "Virtual Fair of Health Promotion Letters", developed in the third term, had 4 stages. Stage zero consisted of a synchronous meeting for the teachers to explain the other stages and the development of the activity to the students. The first stage included reading the "Health Promotion Letters" and making a feasible, executable and applicable product or action to present at the Fair. The second part consisted of each team managing fictitious resources, considering the quality and needs of the products offered at the fair. The final stage was an evaluation based on feedback between teachers and students. Discussion: Through this dynamic, the students deepened their knowledge about the "Health Promotion Letters" and were able to apply the guidelines of the Unified Health System (SUS) in a broader, globalised context. Students enhanced their management and creativity skills, although some limitations were observed, such as the lack of more comprehensive knowledge about "Health management", which could have improved their performance during the activity. Conclusion: The students were able to play an active role in the construction of knowledge throughout the process, developing essential skills for professional practice. The activity, in a playful way, provided the integration of several concepts in Collective Health; representing an example of how medical education can act in an integrative and practical way.

Phytochemical Analysis and Antinociceptive Properties of Hydroalcoholic Extracts of Aleurites moluccanus Bark.

Aleurites moluccanus is used in folk medicine to treat many diseases including pain and inflammatory processes in general. Considering the potential of the leaf extract, evidenced in a previous study, the present study investigates the antinociceptive and anti-inflammatory properties of the hydroethanolic extract of A. moluccanus bark and isolated compounds in animal models of pain. The antinociceptive and anti-inflammatory activities of A. moluccanus bark were evaluated through hyperalgesia induced by carrageenan, PGE2, cytokines, bradykinin, epinephrine, Freund's complete adjuvant, and lipopolysaccharide. Five compounds were isolated from the dichloromethane bark extract: acetyl aleuritolic acid, atraric acid, spruceanol, (5ß,10α)-12-hydroxy-13-methoxy-8,11,13-podocarpatrien-3-one and sonderianol. To optimize the extraction conditions, ethanol 50, 70, and 90°GL were used as extracting solvent, in a 1 : 20 (w/v) drug : solvent ratio, under stirring at room temperature for 4 h. The extracts were named AMC50, AMC70, and AMC90, respectively. These extracts were administered to mice (250 mg/kg, p. o.) with reduced mechanical hyperalgesia activity in the carrageenan test. Of these, AMC90 showed the best results. Pure (5ß,10α)-12-hydroxy-13-methoxy-8,11,13-podocarpatrien-3-one showed a beneficial effect for up to 48 hours after the administration of carrageenan, while acetyl aleuritolic acid was effective only in the first hour. AMC90 was able to reverse the analgesia induced only by prostaglandin E2 and tumor necrosis factor. We also induced hyperalgesia using the lipopolysaccharide and Freund's complete adjuvant models, with positive results. These results support the antinociceptive and anti-inflammatory activity of A. moluccanus bark extract. The observed effects are partly due to the presence of acetyl aleuritolic acid, atraric acid, and (5ß,10α)-12-hydroxy-13-methoxy-8,11,13-podocarpatrien-3-one.

Structure-activity relationships of sulfonamides derived from carvacrol and their potential for the treatment of Alzheimer's disease.

Five synthetic sulfonamides derived from carvacrol, a natural product and a small molecule with druglike properties, were evaluated with respect to their effects on the cognitive deficits of animals with streptozotocin (STZ)-induced Alzheimer's disease (AD). Memory, ambulation, anxiety and oxidative stress were evaluated. In vitro assays were performed to assess the inhibition of acetylcholinesterase (AChE), and the data were combined with molecular docking for the establishment of structure-activity relationships. The memories of animals treated with the compounds derived from morpholine (1), hydrazine (3) and 2-phenol (5) were improved. Compound 3 was the most promising, yielding excellent results in the inhibitory avoidance test. Moreover, the compounds did not exhibit any deleterious effects on the animals' ambulation in the open field test. Molecular docking confirmed the results obtained in the AChE inhibition assay. In short, compounds 1, 3 and 5 can reduce STZ-induced deficits and show potential for the treatment of Alzheimer's. In addition, these agents produce significant anxiolytic and antioxidant effects.

Taraxerol as a possible therapeutic agent on memory impairments and Alzheimer's disease: Effects against scopolamine and streptozotocin-induced cognitive dysfunctions.

Alzheimer's disease (AD) is a neurodegenerative disorder associated with cognitive impairment and cholinergic neuronal death, characteristic of the effect of time on biochemical neuronal function. The use of medicinal plants as an alternative form of prevention, or even as a possible treatment of AD, is therefore interesting areas of research, since the standard drugs have many side effects. Taraxerol (TRX) is a triterpene that has been isolated from several plant species, and its various pharmacological properties have already been identified, such the acetylcholinesterase (AChE) inhibition activity in vitro. There is a lack of information in literature that confirms the effect of TRX in an animal AD-like model. Seeking to fill this gap in the literature, in the present work we assessed the effect of TRX on AChE activity in the animals' encephalon and hippocampus. We also investigated the effect of TRX (1.77 µM/side, 0.5 µL) isolated from leaves of Eugenia umbelliflora Berg. on aversive memory impairments induced by scopolamine (2 µg/side, 0.5 µL) infused into rat hippocampus, and the effect of TRX (0.89 and 1.77 µM/side, 0.5 µL) on aversive memory impairments induced by streptozotocin (STZ) (2.5 mg/mL, 2.0 µL) infused i.c.v. into mice, using the step-down inhibitory avoidance task. We found that TRX significantly inhibited AChE activity in the animal's hippocampus. Furthermore, TRX significantly improved scopolamine and STZ-induced memory impairment. Taking together, these results confirms its AChE activity inhibition in animals and indicate that TRX has anti-amnesic activity that may hold significant therapeutic value in alleviating certain memory impairments observed in AD.

Neuropharmacological and acute toxicological evaluation of ethanolic extract of Allamanda cathartica L. flowers and plumieride.

Psychiatric diseases affect more than 350 million people all over the world, and medicinal plants have been considered the basis for pharmacological research. The study investigates the anticonvulsant and antidepressant-like activities and acute toxicological effects of ethanolic extract of Allamanda cathartica flowers, and plumieride. The extract was analyzed by HPLC and plumieride was isolated. Toxicity studies were carried out on females Wistar rats (2000 mg/kg). Toxicity was evaluated by measuring biochemical parameters and conducting histopathological analysis. For pharmacological evaluation different doses of the extract (100, 150 and 300 mg/kg, p.o.) and plumieride (0.5, 1 and 2 µg/kg, i.p.) were administered before the Forced-Swimming Test (FST), pentylenetetrazole seizure test (PTZT) or Tail-Suspension Test (TST) in mice. Furthermore, hemolytic activity, cytotoxicity and micronucleus test were performed. In addition, mutagenicity and reproductive/developmental toxicity were estimated by TEST-software analysis. Data show that both treatments induce significant antidepressive-like effect in FST and TST, but not anticonvulsant effect. The effect of plumieride last up to 4 h after treatment. No signs of toxicity, mutagenicity, cytotoxicity or hemolytic activity were observed. The TEST-software demonstrated that plumieride present reproductive/developmental toxicity. Together, the data obtained show that the flowers extract and plumieride present antidepressant-like effect and did not present signals of acute toxicity.

Inhibitory effect of sesquiterpene lactones and the sesquiterpene alcohol aromadendrane-4ß,10α-diol on memory impairment in a mouse model of Alzheimer.

Alzheimer's disease (AD), a progressive neurodegenerative disorder of the aged brain with no known cause or cures, has become a major medical and social problem for industrialized countries. Cerebral deposition of amyloid-ß peptide (Aß) is a critical feature of AD. The use of medicinal plants as an alternative form of prevention, or even as a possible treatment of AD, is therefore interesting areas of research. Sesquiterpene lactones and a sesquiterpene alcohol are compounds found in H. brasiliense that have several anti-oxidative and anti-inflammatory effects. In the present study, we investigated whether these compounds have neuroprotective effects in an amyloid-ß peptide-induced Alzheimer's disease mouse model. Mice were injected with Aß1-42 peptide intracerebroventricularly and were subsequently injected (i.c.v.) with 1µg/site of IGM-A (15-acetoxy-isogermafurenolide), IGM-H (15-hydroxy-isogermafurenolide), PDA (Podoandin), EHP (1,2-epoxy-10α-hydroxy-podoandin), HDS (13-hydroxy-8,9-dehydroshizukanolide), and ARD (aromadendrane-4ß,10α-diol). Seven days after treatments the animals had their memory tested in the inhibitory avoidance. After the behavioral testing of animals the brains were removed and subjected to biochemical tests for oxidative stress. The results showed that ARD, HDS and PDA significantly ameliorated the Aß1-42 peptide-induced memory impairment in the passive avoidance task (P<0.05). In addition, GSH activity was increased while the TBARS levels were decreased by treatment with these compounds. These results suggest that these compounds inhibit the cognitive deficit of animals induced peptide amyloid and may be potential candidates for Alzheimer's disease therapy.

The antidepressant-like effect of Hedyosmum brasiliense and its sesquiterpene lactone, podoandin in mice: evidence for the involvement of adrenergic, dopaminergic and serotonergic systems.

We have recently shown that the ethanol extract of the leaves of Hedyosmum brasiliense exhibits an antidepressant-like effect in the tail suspension and forced swimming tests in mice. The present study investigates the mechanisms involved in the antidepressant-like effect of H. brasiliense extract, together with the antidepressant potential of podoandin, an isolated sesquiterpenoid. H. brasiliense (50mg/kg, i.p.) and podoandin (10mg/kg, i.p.) decreased the immobility time in the forced swimming test, without any accompanying changes in ambulation in the open-field test. The anti-immobility effect of the H. brasiliense extract was prevented by pre-treating the mice with ondansetron, NAN 190, pindolol, prazosin, yohimbine, haloperidol, SCH23390, and sulpiride. On the other hand, pre-treating the mice with: p-chlorophenylalanine (4 consecutive days), ketanserin, naloxone, naltrindole, bicuculline, phaclofen, or l-arginine did not block the antidepressant-like effect of H. brasiliense. In addition, pre-treatment of the animals with methylene blue, NG-nitro-l-arginine or 7-nitroindazole, at subeffective doses, did not cause a synergistic effect with H. brasiliense extract at an effective dose in the forced swimming test. The anti-immobility effect of podoandin was also prevented by pre-treating the mice with NAN-190, ondansetron, prazosin, yohimbine, sulpiride and haloperidol. The results indicate that the antidepressant-like effect of H. brasiliense (and podoandin) is dependent on the serotonergic, noradrenergic and dopaminergic systems, but not on the GABAergic, opioid and oxidonitrergic systems.