Uso terapêutico da cannabis medicinal em pessoas com doença neurológica degenerativa / Therapeutic use of medicinal cannabis in people with degenerative neurological disease / Uso terapéutico de cannabis medicinal en personas con enfermedad neurológica degenerativa

Objetivo: apresentar o estado da arte das publicações expressas na literatura cientifica mundial sobre a temática, bem como identificar os benefícios terapêuticos da Cannabis medicinal no tratamento dos sintomas das doenças neurodegenerativas especificamente doenças de Parkinson, esclerose múltipla e Alzheimer. Método: trata-se de uma revisão integrativa da literatura, cuja busca de dados foi realizada nas bibliotecas virtuais. Web of Science, Scopus, Medline, Lilacs, Cochrane Library e Scielo no período de agosto a outubro de 2021. Resultados: foram encontrados 158 artigos. Vinte e tres artigos foram selecionados para serem lidos na íntegra e 8 atenderam aos critérios desta revisão. Conclusão: as evidências mostram que embora cada vez mais prescritos ou autorizados, a cannabis medicinal ou os Canabinóides para a doenças neurodegenerativas continuam a ser controversos para muitos médicos.

Objective: to present the state of the art of publications expressed in the world Scientific literature on the subject, as well as to identify the therapeutic benefits of medicinal cannabis in the treatment of neurodegenerative diseases, specifically, Parkinson's diseases, multiple sclerosis and Alzheimer's. Method: this is an integrative literature review, whose data search was performed in virtual librares. Web of Science, Scopus, Medline, Lilacs, Cochrane Library and Scielo from August to October 2021. Results:158 articles were found. Twenty-three articles were selected to be read in full and 8 met the criteria of this review. Conclusion: evidence shows that although increasingly prescribed or authorized, medical cannabis or Cannabinoids for chronic pain remain controversial for many physicians.

Objetivo: presentar el estado del arte de las publicaciones expresadas en la literatura científica mundial sobre el tema, así como identificar los beneficios terapéuticos del cannabis medicinal en el tratamiento de enfermedades neurodegenerativas, en concreto, las enfermedades de Parkinson, la esclerosis múltiple y el Alzheimer. Método: se trata de una revisión integradora de la literatura, cuya búsqueda de datos se realizó en bibliotecas virtuales. Web of Science, Scopus, Medline, Lilacs, Cochrane Library y Scielo de agosto a octubre de 2021. Resultados: se encontraron 158 artículos. Se seleccionaron veintitrés artículos para ser leídos en su totalidad y ocho cumplieron los criterios de esta revisión. Conclusión: la evidencia muestra que, aunque cada vez más se prescribe o autoriza, el cannabis medicinal o los cannabinoides para el dolor crónico siguen siendo controvertidos para muchos médicos.

Neuroprotective natural products: promising candidates against neurodegenerative diseases / Productos naturales con propiedades neuroprotectivas: posibles candidatos para el tratamiento de enfermedades neurodegenerativas

Neurodegeneration is a progressive loss of neurons both structurally and functionally causing neuronal cell death ultimately leading to development of various neurodegenerative diseases. Due to poor pharmacokinetic profile of neurotrophins, there still remains a challenge in their neurotrophic therapy where plants, bacteria and fungi, as natural products, could act as promising candidates against various neurological disorders by modulating the neurotrophic activity. Therefore, these natural products that mimic neurotrophins, could develop novel therapeutic approaches to herbal drug that can ameliorate neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and other associated neurological disorders. Taking into account the failure of strategies involving single neurotrophins for the treatment of neurodegenerative diseases, we propose a combination of small molecules of natural products that may work synergistically to restore neuronal functions, minimize side effects and target multiple pathways for a more effective treatment.

La neurodegeneración es una pérdida progresiva de neuronas, tanto estructural como funcional, que causa la muerte neuronal, lo que conduce al desarrollo de diversas enfermedades neurodegenerativas. Debido al pobre perfil farmacocinético de las neurotrofinas, existe un desafío en su terapia neurotrófica donde plantas, bacterias y hongos, como productos naturales, podrían actuar como candidatos contra diversos trastornos neurológicos al modular la actividad neurotrófica. Estos productos naturales que asemejan a las neurotrofinas podrían desarrollar enfoques terapéuticos novedosos como medicamentos a base de hierbas que pueden mejorar enfermedades neurodegenerativas como: Parkinson, Alzheimer y otros trastornos neurológicos asociados. Teniendo en cuenta el fracaso de las estrategias terapéuticas de neurotrofinas para las enfermedades neurodegenerativas, proponemos una combinación de pequeñas moléculas de productos naturales que pueden funcionar sinérgicamente para restaurar las funciones neuronales, minimizar los efectos secundarios y apuntar a múltiples vías para un tratamiento más efectivo.

Medicinal plants used in Brazil Public Health System with neuroprotective potential: a systematic review / Plantas medicinales utilizadas en el Sistema de Salud Pública de Brasil con potencial neuroprotector: una revisión sistemática

Current pharmacological therapies to treat neurological diseases are at best palliative and manage only the symptoms. Unfortunately, few therapies can affect diseases outcomes and alternative strategies such as stem cell therapy, neurotransplantation and deep brain stimulation are still in progress. Diseases such as Alzheimer's and Parkinson's disease become major public health challenge worldwide. In this way, the interest in the development of neuroprotective drugs of natural origin grows. Hence, this systematic review has quantified the studies that refer neuroprotective potential of plants listed in the Brazilian National List of Medicinal Plants of Interest to the Unified Health System (RENISUS). Searches were performed in two scientific databases (PubMed and Science Direct) from 2010 to 2016. A total of 4.532 articles met the inclusion criteria. 445 studies were considered eligible and were reviewed as full text. Following full analysis, 63 studies were included in this review. The studies covered 12 of the 71 plants belonging to RENISUS. In addition, two species are currently available in the Brazilian public health system as herbal medicine. This review may encourage and contribute to the proper use of medicinal plants in public health system.

Las terapias farmacológicas actuales para tratar enfermedades neurológicas son, en el mejor de los casos, paliativas y sólo controlan los síntomas. Desafortunadamente, pocas terapias pueden afectar los avances de las enfermedades y las estrategias alternativas tales como terapia con células madre, neurotransplantate y la estimulación profunda del cerebro están todavía en curso. Enfermedades como el Alzheimer y la enfermedad de Parkinson se convierten en un reto importante para la salud pública en todo el mundo. De esta manera, crece el interés en el desarrollo de fármacos neuroprotectores de origen natural. Por lo tanto, esta revisión sistemática ha cuantificado los estudios que hacen referencia al potencial neuroprotector de las plantas incluidas en la Lista Nacional Brasileña de Plantas Medicinales de Interés para el Sistema Único de Salud (RENISUS). Las búsquedas se realizaron en dos bases de datos científicas (PubMed y Science Direct) de 2010 a 2016. Un total de 4,532 artículos cumplieron los criterios de inclusión. 445 estudios se consideraron elegibles y se revisaron como texto completo. Después del análisis completo, se incluyeron 63 estudios en esta revisión. Los estudios abarcaron 12 de las 71 plantas pertenecientes a RENISUS. Además, actualmente hay dos especies disponibles en el sistema de salud pública brasileño como medicina herbaria. Esta revisión puede alentar y contribuir al uso adecuado de las plantas medicinales en el sistema de salud pública.

Mecanismos neuroprotectores de los canabinoides en la isquemia cerebral y las enfermedades neurodegenerativas / Neuroprotective mechanisms of cannabinoids in brain ischemia and neurodegenerative disorders

Una de las causas más importantes de morbilidad y mortalidad es la disfunción neurológica; su alta incidencia ha estimulado una intensa búsqueda de mecanismos para proteger al sistema nervioso central de situaciones que producen hipoxia e isquemia. El mayor reto es interrumpir los eventos bioquímicos que involucra y que llevan a la muerte neuronal. Esto puede conseguirse a través de la neuroprotección que tiene por objeto frenar las cascadas inmunológica y metabólica que aparecen después de un daño neurológico agudo. Cuando esto sucede, se producen eventos fisiopatológicos que incluyen la producción de citocinas, el estrés oxidante y la excitotoxicidad. Respecto a todos esos mecanismos, se han reportado efectos protectores de los endocanabinoides, los cuales parecen ser neuroprotectores en modelos animales de isquemia cerebral, excitotoxicidad, trauma cerebral y en enfermedades neurodegenerativas. Algunos análogos de canabinoides se encuentran actualmente en evaluación (fases clínicas I-III) para el tratamiento de enfermedades agudas que involucran a la muerte neuronal (isquemia y trauma cerebrales). El estudio del sistema canabinoide podría generar agentes neuroprotectores efectivos de amplio espectro de acción para el tratamiento de afecciones neurológicas en un futuro cercano.

One of the most important causes of morbidity and mortality is neurologic dysfunction; its high incidence has led to an intense research of the mechanisms that protect the central nervous system from hypoxia and ischemia. The mayor challenge is to block the biochemical events leading to neuronal death. This may be achieved by neuroprotective mechanisms that avoid the metabolic and immunologic cascades that follow a neurological damage. When it occurs, several pathophysiological events develop including cytokine release, oxidative stress and excitotoxicity. Neuroprotective effects of cannabinoids to all those mechanisms have been reported in animal models of brain ischemia, excitotoxicity, brain trauma and neurodegenerative disorders. Some endocannabinoid analogs are being tested in clinical studies (I-III phase) for acute disorders involving neuronal death (brain trauma and ischemia). The study of the cannabinoid system may allow the discovery of effective neuroprotective drugs for the treatment of neurological disorders.

The role of mitochondrial DNA mutation on neurodegenerative diseases

Many researchers have reported that oxidative damage to mitochondrial DNA (mtDNA) is increased in several age-related disorders. Damage to mitochondrial constituents and mtDNA can generate additional mitochondrial dysfunction that may result in greater reactive oxygen species production, triggering a circular chain of events. However, the mechanisms underlying this vicious cycle have yet to be fully investigated. In this review, we summarize the relationship of oxidative stress-induced mitochondrial dysfunction with mtDNA mutation in neurodegenerative disorders.

Degradation of misfolded proteins in neurodegenerative diseases: therapeutic targets and strategies

Mammalian cells remove misfolded proteins using various proteolytic systems, including the ubiquitin (Ub)-proteasome system (UPS), chaperone mediated autophagy (CMA) and macroautophagy. The majority of misfolded proteins are degraded by the UPS, in which Ub-conjugated substrates are deubiquitinated, unfolded and cleaved into small peptides when passing through the narrow chamber of the proteasome. The substrates that expose a specific degradation signal, the KFERQ sequence motif, can be delivered to and degraded in lysosomes via the CMA. Aggregation-prone substrates resistant to both the UPS and the CMA can be degraded by macroautophagy, in which cargoes are segregated into autophagosomes before degradation by lysosomal hydrolases. Although most misfolded and aggregated proteins in the human proteome can be degraded by cellular protein quality control, some native and mutant proteins prone to aggregation into beta-sheet-enriched oligomers are resistant to all known proteolytic pathways and can thus grow into inclusion bodies or extracellular plaques. The accumulation of protease-resistant misfolded and aggregated proteins is a common mechanism underlying protein misfolding disorders, including neurodegenerative diseases such as Huntington's disease (HD), Alzheimer's disease (AD), Parkinson's disease (PD), prion diseases and Amyotrophic Lateral Sclerosis (ALS). In this review, we provide an overview of the proteolytic pathways in neurons, with an emphasis on the UPS, CMA and macroautophagy, and discuss the role of protein quality control in the degradation of pathogenic proteins in neurodegenerative diseases. Additionally, we examine existing putative therapeutic strategies to efficiently remove cytotoxic proteins from degenerating neurons.

Special issue on neurodegenerative diseases and their therapeutic approaches

No abstract available.

Consumo de aminoácido de cadeia ramificada na esclerose lateral amiotrófica: suplemento proteico ou substância neurotóxica? / Branched-chain amino acid consumption in amyotrophic lateral sclerosis: protein supplement or neurotoxic substance?

Estudos demonstraram efeito positivo principalmente no ganho ponderalem pacientes com esclerose lateral amiotrófica (ELA), suplementadoscom aminoácidos de cadeia ramificada (AACR). Achados recentes têm mostrado que o consumo excessivo e crônico de AACR pode contribuir para a progressão da doença, provavelmente devido a estes serem precursores do glutamato. O objetivo deste estudo foi avaliar a evidência acerca da utilização dos AACR por pacientes com ELA, a fim de elucidar questões pertinentes a sua ingestão. Foi feita busca em base de dados de artigos científicos relacionados ao consumo de AACR na ELA, no período de 1988 a 2013. Foram encontrados seis artigos relacionados ao consumo de AACR por pacientes com ELA. Desses, um referiu melhora da força, enquanto os outros relataram ganho ponderal ou não mostraram resultados significativosem relação aos desfechos. Além disso, foi possível observar uma estreita relação entre o consumo excessivo e crônico dos AACR com o agravamento da doença. À luz dos conhecimentos ora disponíveis, a suplementação com AACR não é recomendada devido aos possíveis efeitos nocivos. O consumo adequado de alimentos proteicos, fontes desses aminoácidos, deve ser utilizado pelos pacientes, respeitando as recomendações estabelecidas. No entanto, estudos adicionais devem ser desenvolvidos em virtude do escasso número de publicações disponíveis.

Studies have shown positive effect mainly in weight gain inpatients with amyotrophic lateral sclerosis (ALS) supplemented with branched chain amino acids (BCAA). However, recent studies have shown that excessive and chronic intake has contributed to the worsening of the disease progression, probably because the amino acids are glutamate precursors. The objective of this study was to assess the evidence about the use of BCAA by patients with ALS, with the aim to clarify pertinent issues for its intake. A search was conducted in data bases for scientific papers related to the intake of BCAA in ALS, between 1988 and 2013. For these review six articles related to the use of BCAA in ALS were found. Of these, one described strength improvement, while the remaining reported weight gain or no significant effects in relation to the outcome. Additionally, it waspossible to observe a close relationship between the excessive and chronic BCAA intake with the worsening of the disease. Considering the presente day available knowledge BCAA supplementation should not be indicated due to the possible harmful effect. The intake of appropriated protein foods should be consumed by these patients, respecting the suggested recommendation. However, more studies are necessary due to the scarce papers in this area.

APE1/Ref-1 as an emerging therapeutic target for various human diseases: phytochemical modulation of its functions

Apurinic/apyrimidinic endonuclease 1 (APE1) is a multifunctional enzyme involved in the base excision repair (BER) pathway, which repairs oxidative base damage caused by endogenous and exogenous agents. APE1 acts as a reductive activator of many transcription factors (TFs) and has also been named redox effector factor 1, Ref-1. For example, APE1 activates activator protein-1, nuclear factor kappa B, hypoxia-inducible factor 1alpha, paired box gene 8, signal transducer activator of transcription 3 and p53, which are involved in apoptosis, inflammation, angiogenesis and survival pathways. APE1/Ref-1 maintains cellular homeostasis (redox) via the activation of TFs that regulate various physiological processes and that crosstalk with redox balancing agents (for example, thioredoxin, catalase and superoxide dismutase) by controlling levels of reactive oxygen and nitrogen species. The efficiency of APE1/Ref-1's function(s) depends on pairwise interaction with participant protein(s), the functions regulated by APE1/Ref-1 include the BER pathway, TFs, energy metabolism, cytoskeletal elements and stress-dependent responses. Thus, APE1/Ref-1 acts as a 'hub-protein' that controls pathways that are important for cell survival. In this review, we will discuss APE1/Ref-1's versatile nature in various human etiologies, including neurodegeneration, cancer, cardiovascular and other diseases that have been linked with alterations in the expression, subcellular localization and activities of APE/Ref-1. APE1/Ref-1 can be targeted for therapeutic intervention using natural plant products that modulate the expression and functions of APE1/Ref-1. In addition, studies focusing on translational applications based on APE1/Ref-1-mediated therapeutic interventions are discussed.

Rho GTPasas como blancos terapéuticos relevantes en cáncer y otras enfermedades humanas / Rho GTPases as therapeutic targets in cancer and other human diseases

Las Rho GTPasas son una familia de proteínas clave en la transmisión de señales provenientes del exterior celular hacia efectores intracelulares tanto citoplasmáticos como nucleares. En los últimos año ha habido un desarrollo vertiginoso de múltiples herramientas genéticas y farmacológicas, lo que ha permitido establecer de manera mucho más precisa las funciones específicas de estas proteínas. El objetivo de la presente revisión es hacer foco en las múltiples funciones celulares reguladas por las Rho GTPasas, describiendo en detalle el mecanismo molecular involucrado. Se discute además la participación de estas proteínas en diversas enfermedades humanas haciendo énfasis en su vinculación con el cáncer. Por último, se hace una actualización detallada sobre las estrategias terapéuticas en experimentación que tienen a las Rho GTPasas como blancos moleculares.

Rho GTPases are a key protein family controlling the transduction of external signals to cytoplasmatic and nuclear effectors. In the last few years, the development of genetic and pharmacological tools has allowed a more precise definition of the specific roles of Rho GTPases. The aim of this review is to describe the cellular functions regulated by these proteins with focus on the molecular mechanism involved. We also address the role of Rho GTPases in the development of different human diseases such as cancer. Finally, we describe different experimental therapeutic strategies with Rho GTPases as molecular targets.

Coenzyme Q10 and its effects in the treatment of neurodegenerative diseases: [review] / A coenzima Q10 e seus efeitos no tratamento de doenças neurodegenerativas: [revisão]

According to clinical and pre-clinical studies, oxidative stress and its consequences may be the cause or, at least, a contributing factor, to a large number of neurodegenerative diseases. These diseases include common and debilitating disorders, characterized by progressive and irreversible loss of neurons in specific regions of the brain. The most common neurodegenerative diseases are Parkinson's disease, Huntington's disease, Alzheimer's disease and amyotrophic lateral sclerosis. Coenzyme Q10 (CoQ10) has been extensively studied since its discovery in 1957. It is a component of the electron transportation chain and participates in aerobic cellular respiration, generating energy in the form of adenosine triphosphate (ATP). The property of CoQ10 to act as an antioxidant or a pro-oxidant, suggests that it also plays an important role in the modulation of redox cellular status under physiological and pathological conditions, also performing a role in the ageing process. In several animal models of neurodegenerative diseases, CoQ10 has shown beneficial effects in reducing disease progression. However, further studies are needed to assess the outcome and effectiveness of CoQ10 before exposing patients to unnecessary health risks at significant costs.

De acordo com estudos clínicos e pré-clínicos, o estresse oxidativo e suas conseqüências podem ser a causa, ou, no mínimo, o fator que contribui para grande número de doenças degenerativas. Estas doenças incluem problemas comuns e debilitantes, caracterizados por perda progressiva e irreversível de neurônios em regiões específicas do cérebro. As doenças degenerativas mais comuns são doença de Parkinson, de Hutington, de Alzheimer e esclerose amiotrófica lateral. A Coenzima Q10 (CoQ10) tem sido intensamente estudada desde sua descoberta, em 1957. É um componente da cadeia de transporte eletrônico e participa da respiração aeróbica celular, gerando energia na forma de trifosfato de adenosina (ATP). A propriedade da CoQ10 de atuar como antioxidante ou pró-oxidante sugere papel importante na modulação do estado redox celular sob condições fisiológicas e patológicas, desempenhando, também, papel no processo de envelhecimento. Em vários modelos animais de doenças neurodegenerativas, a CoQ10 mostrou efeitos benéficos na redução do curso da doença. Entretanto, há necessidade de estudos adicionais para avaliar o efeito e a eficácia da CoQ10 antes de expor os pacientes a riscos de saúde desnecessários e de alto custo.

Effect of Scutellaria flavonoids on KCN-induced damages in rat pheochromocytoma PC12 cells.

BACKGROUND & OBJECTIVE: Cerebral hypoxia is known to be involved in many neurodegenerative diseases such as Alzheimer's and cerebrovascular dementia. The present study was designed to investigate the effects of flavonoids from aerial part of Scutellaria baicalensis Georgi (SSF) on potassium cyanide (KCN) -induced hypoxic cytotoxicity in rat pheochromocytoma cell line PC12, and to understand the probable mechanism. METHODS: The rat pheochromocytoma cell line PC12 was subjected to hypoxia by 200 microM KCN for 30 min. The cytotoxicity of KCN was assessed by cell viability assay, morphological observation, lactate dehydrogenase (LDH) release, malondialdehyde (MDA) production, and the activities of superoxide dismutase (SOD) and Na+-K+-ATPase measurements. The effects of SSF on the changes induced by KCN in PC12 cells were detected. RESULTS: Treatment of PC12 cells with 200 micriM KCN for 30 min increased cell death when compared with control, as assayed by MTT reduction, morphological observation and lactate dehydrogenase release measurement. These cell lesions were accompanied by disorders in SOD and Na+-K+-ATPase activities as well as MDA production. In contrast, the PC12 cells pre-treated with SSF for 24 h prior to 200 microM KCN exposure have shown protection against hypoxic toxicity. The KCN - induced decreased cell viability and activities of SOD and Na+-K+-ATPase, as well as increased MDA production were reversed by SSF pre-treatment. INTERPRETATION & CONCLUSION: SSF exerted neuroprotections against KCN - induced hypoxic cytotoxicity in PC12 cells and the probable mechanisms involved free radicals and energy metabolism. Our findings may have implications in future in the treatment of neurodegenerative diseases.

Cerebellar degeneration and immune thrombocytopenic purpura associated with human immunodefi ciency virus infection (HIV)

Cerebellar disorders associated with HIV infection are usually caused by opportunistic infections, central nervous system lymphoma, and toxic effects of medicines, nutritional and metabolic disorders, and cerebrovascular disease. We present an unusual association of cerebellar degeneration and immune thrombocytopenic purpura in a 28-years-old woman HIV infected. An autoimmune aetiology is likely.

Transtornos cerebelares associados a infecção pelo HIV são comumente causados por infecções oportunistas, linfoma do sistema nervoso central, efeitos tóxicos de medicamentos anti-retrovirais, alterações metabólicas e nutricionais, e doença cerebrovascular. Apresentamos um caso incomum de associação de degeneração cerebelar e púrpura trombocitopênica imunológica em um mulher de 28 anos infectada pelo HIV. Discutimos uma possível etiologia autoimune para justificar o quadro.

Cntf: una citokina con potenciales efectos terapéuticos en patologías neurodegenerativas / Cntf: a cytokine with therapeutic potential for the treatment of neurodegenerative diseases

El factor neurotrófico ciliar (CNTF) es una citokina que tiene efectos tróficos sobre neuronas sensitivas y motoras, ya que modifica su expresión génica y afecta su supervivencia. Este trabajo es una revisión de los antecedentes de los efectos de la aplicación de CNTF en modelos animales de neuropatías degenerativas humanas,que han sugerido que esta citokina tiene potencialidades para convertirse en una herramienta para el tratamiento de pacientes con enfermedad de Huntington. También se describen los efectos de la aplicación experimental de CNTF a pacientes con esclerosis lateral amiotrófica. Entre las técnicas empleadas para aplicar CNTF en modelos animales se encuentran la implantación local de células modificadas genéticamente para secretar CNTF y el uso de vectores para insertar genes en neuronas. Estas técnicas de la biología molecular podrían emplearse como herramientas para el tratamiento preventivo de pacientes susceptibles de desarrollar una patología neurodegenerativa o para recuperar las funciones motoras y cognitivas en pacientes que hayan desarrollado la enfermedad.