Endocannabinoid system and periodontitis: mechanisms and therapeutic implications / Sistema endocanabinoide e periodontite: mecanismos e implicações terapêuticas

Introdução: A periodontite é um importante problema de saúde pública. Embora o princípio da terapia da periodontite esteja focado principalmente na remoção do biofilme dental e dos fatores associados, sua fisiopatologia registra diferentes eventos moleculares e inflamatórios relacionados ao sistema imunológico do hospedeiro, como a participação do sistema endocanabinoide. Objetivo: Esta revisão teve como objetivo explorar e elucidar os mecanismos e papéis do sistema endocanabinoide na fisiopatologia da periodontite e suas possibilidades para futuras terapias relacionadas. Material e método: Realizou-se uma busca eletrônica na plataforma PubMed por estudos envolvendo a ação do sistema endocanabinoide sobre a periodontite. Resultado: Dezenove estudos clínicos e pré-clínicos foram incluídos nesta revisão narrativa. Conclusão: Os receptores canabinoides tipo 1 e 2 são componentes integrais do sistema endocanabinoide e manifestam-se de várias formas nos tecidos periodontais. As ações e mecanismos através dos quais os receptores canabinoides são ativados em locais saudáveis ou inflamados continuam a ser o foco de investigações em curso. Além disso, os fitocanabinoides e canabinoides sintéticos apresentam potencial como tratamentos, com estudos pré-clínicos indicando benefícios na redução da inflamação e na facilitação da reparação dos tecidos.

Introduction: Periodontitis is a major public health problem. Although the principle of periodontitis therapy is mainly focused on removing dental biofilm and associated factors, its physiopathology enrolls different molecular and inflammatory events related to the host immune system, as the participation of the endocannabinoid system. Objective: This review aimed to explore and elucidate the mechanisms and roles of the endocannabinoid system on periodontitis physiopathology and its possibilities for future related therapies. Material and method: An electronic search was carried out on the PubMed platform for studies involving the action of the endocannabinoid system on periodontitis. Result: Nineteen clinical and preclinical studies were included in this narrative review. Conclusion: Cannabinoid receptors type 1 and 2 are integral components of the endocannabinoid system, manifesting in various forms in the periodontal tissues. The actions and mechanisms through which cannabinoid receptors are activated in healthy or inflamed sites remain the focus of ongoing investigations. Moreover, phytocannabinoids and synthetic cannabinoids show therapeutic potential, with pre-clinical studies indicating benefits in reducing inflammation and facilitating tissue repair

Papel del sistema cannabinoide endógeno en el intestino / Role of the endogenous cannabinoid system in the gut / Papel do sistema canabinoide endógeno no intestino

RESUMEN El sistema cannabinoide endógeno es un nuevo sistema de comunicación intercelular que constituye una pieza crucial en la regulación de la función intestinal. Se realizó una revisión bibliográfica con el objetivo de describir cómo el sistema cannabinoide endógeno modula la función intestinal. Se consultaron un total de 31 referencias bibliográficas entre libros, revistas, tesis doctorales y artículos en internet. Se encontró que los endocannabinoides son inmunomoduladores a nivel intestinal, que el sistema cannabinoide endógeno regula la composición de la microbiota intestinal y esta a su vez determina la concentración de los endocannabinoides, además tanto la secreción como la motilidad intestinal disminuyen por estimulación del sistema cannabinoide endógeno. Los receptores de cannabinoides, los endocannabinoides anandamida y 2-araquidonoilglirerol y las proteínas responsables de su síntesis y degradación están ampliamente distribuidos en el intestino en condiciones fisiológicas, aumentando su expresión en la enfermedad inflamatoria intestinal lo que le permite regular la función intestinal en ambas condiciones. El sistema cannabinoide endógeno tiene un enorme potencial terapéutico en la enfermedad inflamatoria intestinal debido a los efectos inmunosupresores, antiinflamatorios y analgésicos que posee.

ABSTRACT The endogenous cannabinoid system is a new intercellular communication system that constitutes a crucial piece in the regulation of intestinal function. A bibliographic review was carried out in order to describe how the endogenous cannabinoid system modulates intestinal function. A total of 31 bibliographic references were consulted between books, magazines, doctoral theses and articles on the internet. It was found that endocannabinoids are immunomodulatory at the intestinal level, that the endogenous cannabinoid system regulates the composition of the intestinal microbiota and this in turn determines the concentration of endocannabinoids, in addition both secretion and intestinal motility decrease by stimulation of the endogenous cannabinoid system. The cannabinoid receptors, the endocannabinoids anandamide and 2-arachidonoylglirerol, and the proteins responsible for their synthesis and degradation are widely distributed in the intestine under physiological conditions, increasing their expression in inflammatory bowel disease, which allows it to regulate intestinal function in both conditions. The endogenous cannabinoid system has enormous therapeutic potential in inflammatory bowel disease due to its immunosuppressive, anti-inflammatory and analgesic effects.

RESUMO O sistema canabinoide endógeno é umnovo sistema de comunicação intercelular que constitui uma peça crucial na regulação da função intestinal. Foi realizada uma revisão bibliográfica para descrever como o sistema canabinoide endógeno modula a função intestinal. Foram consultadas 31referências bibliográficas entre livros, revistas, teses de doutorado e artigosna internet. Verificou-se que os endocanabinoides são imunomoduladores em nível intestinal, que o sistema canabinoide endógeno regula a composição da microbiota intestinal e esta, por sua vez, determina a concentração de endocanabinoides, além da diminuição da secreção e da motilidade intestinal pela estimulação do sistema canabinoide endógeno. Os receptores canabinoides, os endocanabinoides anandamida e 2-araquidonoilglirerol e as proteínas responsáveis ​​por sua síntese e degradação estão amplamente distribuídos no intestino em condições fisiológicas, aumentando sua expressão em doenças inflamatórias intestinais que permitem regular a função intestinal em ambas as condições. O sistema canabinoide endógeno apresenta enorme potencial terapêutico na doença inflamatória intestinal devido aos seus efeitos imunossupressores, antiinflamatórios e analgésicos.

The influence of the cannabinoid receptor CB1 on the periaqueductal gray in mice treated with photobiomodulation after chronic constriction injury of the sciatic nerve: a placebo-controlled trial / Influência do receptor canabinóide CB1 na substância cinzenta periaquedutal em camundongos tratados por fotobiomodulação após constrição crônica do nervo ciático: ensaio controlado por placebo

ABSTRACT BACKGROUND AND OBJECTIVES: Studies have demonstrated that the cannabinoid CB1 receptor is involved in the modulation of pain, mainly by activating the descending pain control pathway. However, the role of photobiomodulation in this process is not well elucidated. Thus, the present study aimed to investigate the involvement of the CB1 receptor in the supraspinal photobiomodulation-induced antinociception. METHODS: Male albino swiss mice were submitted to chronic constriction injury and treated with photobiomodulation. To evaluate the supraspinal involvement of the CB1 receptor in the photobiomodulation-induced antinociception, the cannabinoid CB1 receptor antagonist AM251 (0.1µg/vol 0.2µL) was injected 5 minutes before the photobiomodulation treatment. The photobiomodulation treatment was performed on the fifth day after the stereotactic surgery and chronic constriction injury at a dose of 50J/cm2 in acute condition. The hot plate and von Frey monofilaments tests were performed to evaluate the thermal and mechanical pain sensitivity, respectively. RESULTS: The thermal and mechanical nociceptive threshold was higher in mice with chronic constriction injury, injected with saline and treated with photobiomodulation at the dose of 50J/cm2 in both the hot plate (p<0.001) and von Frey (p>0.001) tests. These antinociceptive effects were not detected in mice with chronic constriction injury pre-treated with AM251. CONCLUSION: The present study suggests that CB1 receptors located in Supraspinal structures, participate in the control of neuropathic pain following photobiomodulation treatment in animals undergoing chronic constriction injury.

RESUMO JUSTIFICATIVA E OBJETIVOS: Estudos demonstraram que o receptor canabinóide CB1 está envolvido na modulação da dor, principalmente pela ativação da via descendente de controle da dor, porém o papel da fotobiomodulação nesse processo não é bem elucidado. Assim, o presente estudo teve como objetivo investigar o envolvimento do receptor CB1 na antinocicepção induzida pela fotobiomodulação a nível supraespinhal. MÉTODOS: Camundongos machos suíço albinos foram submetidos à lesão por constrição crônica e tratados com fotobiomodulação. Para avaliar o envolvimento supraespinhal do receptor CB1 na antinocicepção induzida por fotobiomodulação foi injetado o antagonista do receptor canabinóide CB1, AM251 (0,1µg/vol 0,2µL) 5 minutos antes do tratamento com fotobiomodulação. O tratamento de fotobiomodulação foi realizado no quinto dia após cirurgia estereotática e lesão por constrição crônica, na dose de 50J/cm2 em estado agudo. Os testes de placa quente e monofilamentos de von Frey foram realizados para avaliar a sensibilidade térmica e mecânica à dor, respectivamente. RESULTADOS: O limiar térmico e mecânico nociceptivo foi maior nos camundongos com lesão por constrição crônica, injetados com solução salina e tratados com fotobiomodulação na dose de 50J/cm2 nos testes de placa quente (p<0,001) e von Frey (p>0,001). Esses efeitos antinociceptivos não foram detectados em camundongos com lesão por constrição crônica tratados com AM251. CONCLUSÃO: O presente estudo sugere que os receptores CB1 localizados nas estruturas supraespinhais participam do controle da dor neuropática, após tratamento com fotobiomodulação em animais submetidos à lesão por constrição crônica.

Maconha e gravidez: síndrome da hiperêmese por canabinoide - Relato de caso / Marijuana and pregnancy: cannabis hyperemesis syndrome - Case report

RESUMO Os autores relatam um caso da enfermaria psiquiátrica do Hospital Geral Santa Casa de Misericórdia de Sorocaba-SP. Paciente gestante, de 19 anos, usuária crônica de maconha que apresenta náuseas e vômitos intensos não responsivos aos antieméticos, associados a dor abdominal, agitação psicomotora e hábito compulsivo de tomar banhos quentes para alívio dos sintomas, quadro que caracteriza a SHC. Trata-se de uma síndrome rara, com efeito paradoxalmente emetogênico da maconha. É subdiagnosticada e relacionada ao uso crônico e intenso de maconha. Destacamos que não foi encontrada descrição de caso na literatura brasileira. A conclusão deste relato reporta a importância do reconhecimento e categorização da síndrome e sua correlação com a dependência de maconha, pois o tratamento implica a suspensão do uso de maconha, tratamento da dependência, além da prevenção de suas complicações clínicas.

ABSTRACT The authors report a case from the psychiatric department of a general hospital (Santa Casa de Misericordia at Sorocaba city, São Paulo, Brazil). A patient, 19-year-old, pregnant woman, marijuana chronic user, presenting abdominal pain, psychomotor agitation, unmanageable nausea, severe vomiting, not responsive to antiemetic drugs, associated with compulsive hot water showering. Cannabinoid hyperemesis syndrome is sub-diagnosed and rare, characterized by those three symptoms: heavy marijuana use, vomiting and repeated hot showering. There is no prior report in Brazilian medical literature. This paper aims to emphasize the importance of recognizing and categorizing this syndrome and its correlation to marijuana use. Main treatment is supportive care, withdrawing substance and supportive carries to suspension of marijuana use as well as clinical complications prevention.

Potencial neuroprotetor, antioxidante e anti-inflamatório do Canabidiol: relevância e perspectivas para o tratamento de doenças neurodegenerativa / Potential neuroprotective, antioxidant and anti-inflammatory of Cannabidiol: relevance and prospects for the treatment of neurodegenerative diseases

Introdução: a incidência de doenças neurodegenerativas tem aumentado nos últimos anos, passando a constituir um problema de saúde pública. Frente a isso se faz necessário o desenvolvimento de novas modalidades terapêuticas visando evitar, recuperar ou impedir as alterações celulares que possam levar à morte neuronal. Objetivo: realizar uma revisão bibliográfica acerca do potencial neuroprotetor, antioxidante e anti-inflamatório do Canabidiol (CBD) investigando sua ação sobre processos neurodegenerativos associados à doença de Alzheimer, Parkinson e Huntington. Metodologia: foi realizado um estudo descritivo e qualitativo desenvolvido na forma de revisão bibliográfica onde foram utilizados artigos disponíveis nos bancos de dados PubMed, Scielo e Scopus com o período de referência compreendido entre os anos de 1998 e 2016. Resultados: foram selecionados 10 artigos que tratavam do tema e todos eles mostraram que o CBD induziu neuroproteção e possuiu propriedades antioxidantes e anti-inflamatórios em diferentes modelos de citotoxicidade, estresse oxidativo e neurodegeneração. Conclusão: o CBD pode ser um importante agente terapêutico no tratamento, na prevenção e na reversão de lesões oriundas de doenças neurodegenerativas. Entretanto, há necessidade de reforçar estudos e ensaios em modelos animais antes de transpor o uso do CBD para humanos.

Introduction: the incidence of neurodegenerative diseases has increased in recent years, becoming a public health problem. In view of this, it is necessary to develop new therapeutic modalities in order to avoid, recover or prevent cell changes that may lead to neuronal death. Objective: to perform a literature review on the neuroprotective, antioxidant and anti-inflammatory potential effects of Canabidiol (CBD), investigating its action on neurodegenerative processes associated with Alzheimer's disease, Parkinson's and Huntington´s disease. Methodology: a descriptive and qualitative study was developed in the form of a bibliographic review where articles available on PubMed, Scielo e Scopus database with the reference period from 1998 to 2016 were used. Results: ten articles were selected that addressed the theme and they all showed that CBD induced neuroprotection and possessed antioxidant and anti-inflammatory properties in different models of cytotoxicity, oxidative stress and neurodegeneration. Conclusion:CBD may be an important therapeutic agent in the treatment, prevention and reversal of lesions from neurodegenerative diseases. However, there is a need to reinforce studies and trials in animal models prior to transposing CBD to humans.

Insomnio, estrés y canabinoides / Insomnia, stress and cannabinoids

Sleep is a universal experience and a necessary ingredient to life. Young adult humans benefit from spending 8 h a day, every day, sleeping. While the function(s) of sleep is not completely understood, it is known that sleep is critical to the survival of the species. In humans, it restores alertness, helps consolidate memory and «recharge¼ cognitive abilities which are impaired at the end of the activity-phase of the cycle. Humans who do not pay their toll to sleep, for one night, for example, experience difficulties maintaining wakefulness the next day. This condition may put in danger their lives, particularly if they work in the transportation industry (i. e. taxi cabs, truck or trailers-drivers, pilots and/or operating heavy machinery among many other activities). In the past, when humans were more exposed to predators, to be sleepy in the savannah was synonymous with dying. Interestingly enough, the maladaptive strategies exhibited by a sleepy subject (which put at risk his life), are reversed by sleep. It is widely believed that sleep has a restorative function. However, what precisely is being restored during sleep remains a topic of speculation and on-going research. Sleep deprivation in humans results in cognitive deterioration and increased sleepiness, which might compromise survival as aforementioned. It is known that in rats prolonged sleep deprivation leads to death. In humans, it results in sleepiness, decreased attention, compromises memory and learning skills, and may affect motor control. The negative effects of sleep loss are reversed by recovery sleep, which may show features of delta and/or REM-sleep rebound. In this context, insomnia is a condition with known negative consequences to the health of the affected individual and frequently conveys negative effects to the family nucleus and to society in general. It has been estimated that 9% to 15% of the adult population suffers from chronic insomnia. Psychophysiologic insomnia (or primary insomnia) is likely the most prevalent type of insomnia. The patient with insomnia frequently develops an aversive response to sleep and to all aspects related to this activity. The manifestations of insomnia may include difficulty falling (and staying) asleep, frequent awakenings, early morning awakenings and/or un-refreshing quality of sleep. As a result, affected individuals frequently complain of daytime consequences such as decreased concentration, negative effects on memory (and learning), and daytime fatigue. They may also complain of headaches, fuzziness (or grogginess) and might experience manifestations of excessive sleepiness (which might represent a hazard when driving and/or operating machinery). Stress and anxiety frequently represent precipitating and/or perpetuating factors in the development of insomnia. In regards to stress, the role of the hypothalamus-pituitary-adrenal (HPA) axis in preserving homeostasis has been amply studied. The HPA axis involves the participation of peptides such as corticotropin-releasing hormone (CRH), corticotropin itself and cortisol. The autonomic nervous system activates the amygdaloid complex further enhancing the stress response. When patients are unable to control their stress response, the magnified response may be manifested as an anxiety disorder. According to the DSM-IV, the diagnosis of generalized anxiety disorder (GAD) is based on persistent symptoms of excessive anxiety and worry. Patients with GAD as well as those suffering from other anxiety disorders such as PTSD and panic attacks may manifest symptoms of insomnia. Several models of stress have been proposed to better understand these conditions. For example, prenatal stress has been suggested to increase vulnerability to life events and some reports have suggested impaired sleep among some of the animal models that have been studied. Specifically, it has been reported that rats who are deprived of maternal care suffer from dysregulation of the orexinergic system. Consequently, affected rats may have manifestations of sleep-wake dysregulation. There is more. Rats born to a low care maternal provider (which induces an early stress response) have been found to have methylated the gene that encodes the glucocorticoid receptors, which is reflected in a low expression of receptors. As a result, these animals release more corticosterone in response to stressful situations and are less efficient in managing stress. Furthermore, they have a lower expression of the CB1 receptor in several areas of the brain, thus suggesting that the systems responsible for reducing excitability of the brain (and consequently reducing the subjective sensation of fear and anxiety) are shattered. Models of insomnia evaluating the possible role of an inadequate stress-response have not been thoroughly studied. Potential pharmacologic interventions using such a theoretical framework have not been systematically studied and thus offer a venue for novel pharmacological interventions. The addition of new therapies would be particularly useful as the clinical management of patients with chronic insomnia remains a challenging area in medical practice. This despite the availability of multiple approved hypnotic medications in the physician's armamentarium. To date there is no hypnotic medication which can be considered ideal for the treatment of chronic insomnia. Issues of tolerance and dependence remain relevant concerns for those hypnotic medications, which are considered most effective in the treatment of this condition. Research identifying new compounds based on molecules whose physiologic action is to induce sleep may render safer, more efficient pharmacological interventions to treat insomnia. Following this line of thinking, we have tested the effects of endocannabinoids (eCBs). The eCBs represent a family of molecules, lipids in nature, which bind to the same receptors to which marijuana is known to bind. The active metabolite of marijuana (delta-9-tetrahydrocannabinol [THC]) is known to bind to the CB1 receptors and produce a series of effects including relaxation and sleep. Following the discovery of several eCBs by the research groups of Mechoulam and Lerner, we have tested anandamide and oleamide as sleep inducers. Results have indicated that both molecules and a third one, 2-arachidonyl glycerol, induce sleep (mainly REM sleep). In the present review insomnia is speculated to be a consequence of chronic stress. Several animal models of early stress are also discussed to better understand the role of stress in the causation of insomnia. The current limitations in the availability of ideal hypnotic medications prompt us to argue in favor of continued efforts to find additional, novel pharmacologic interventions to treat this condition. In this context, the potential use of endocannabinoid compounds is proposed as a possible new line of hypnotic medications. While eCBs have been used so far only in animal models, they have been amply successful in promoting the expression of non-REM and REM sleep. The endocannabinoid system has the potential to induce sleep and thus suggest that endocannabinoid agonists offer a new research venue for the exploration of novel pharmacologic interventions in the treatment of insomnia.

El sueño es una actividad fundamental para el bienestar y la preservación del la salud. El no dormir resulta en consecuencias potencialmente letales. Por ejemplo, ratas experimentalmente privadas de sueño total (o de sueño MOR) mueren al cabo de algunas semanas de experimentación. Asimismo, en humanos, la privación de tan solo una noche de sueño conlleva consecuencias importantes. Hipersomnolencia y disminución de las habilidades cognoscitivas son consecuencias de la privación de sueño. El individuo privado de sueño corre el riesgo de cometer errores que potencialmente pueden poner en riesgo su vida o integridad física, así como la de otros. Se ha sugerido que el sueño cumple con la muy importante tarea de ofrecer las condiciones para que se lleven a cabo diversos procesos de restauración y de reorganización neuronal así como el procesamiento de información y consolidación de la memoria. La ausencia de sueño interfiere con estos procesos con el consecuente deterioro de la conducta adaptativa del sujeto. El insomnio es un trastorno que deteriora de manera importante la calidad de vida de las personas que lo padecen. Afecta aproximadamente al 10% de la población. El insomnio se presenta en diversas formas. La clasificación internacional de los trastornos del dormir considera 11 tipos de insomnio. Entre ellos, el insomnio psicofisiológico representa el tipo de insomnio que más frecuentemente se manifiesta en la población. Se trata de un padecimiento donde el paciente desarrolla una aversión a dormir y a todo lo que se relacione con ello. Este tipo de insomnio tiene un componente de estrés que precipita la aparición del insomnio y puede contribuir a los elementos que ayudan a perpetuarlo (insomnio crónico). Se han desarrollado diversos modelos animales para el estudio del estrés y sus consecuencias. Por ejemplo, el estrés temprano inducido por privación del cuidado maternal. Asimismo, por inducción de estrés en la madre (rata) gestante. Sin embargo, se han explotado poco para evaluar el insomnio y mejor aún, para ensayar fármacos que puedan beneficiar al paciente insomne. A pesar de contar con una gran variedad de medicamentos hipnóticos, en la actualidad no existe un hipnótico ideal. Los tratamientos más efectivos con los que contamos conllevan riesgos importantes de tolerancia, adicción y potencialmente efectos colaterales. Por ello, la búsqueda de nuevos fármacos con propiedades inductoras de sueño es inaplazable. Especialmente de fármacos que sean capaces de inducir las fases de sueño delta y sueño MOR sin causar sonambulismo, somnolencia residual y/o efectos negativos en la memoria. En este contexto se discute el potencial uso terapéutico de los endocanabinoides (eCBs), ya que son ansiolíticos e inductores de las fases profundas de sueño (delta y sueño MOR). Los eCBs son moléculas endógenas que tienen una actividad semejante a la de la mariguana. Esto es debido a que tanto la mariguana como los eCBs afectan a un mismo receptor, que es el receptor canabinoide 1 (CB1). Los eCBs tienen un potencial terapéutico que hasta ahora no se ha explotado en beneficio de los pacientes que sufren de insomnio y/o ansiedad. Por ello, en esta revisión se analiza el insomnio desde el punto de vista clínico, se detallan sus características para que el médico clínico no experto pueda reconocerlo y potencialmente tratarlo; también se persigue subrayar la influencia potencial del estrés en la fisiopatogénesis de este trastorno. A pesar de que hay cada vez más información acerca de la síntesis y degradación de los eCBs (lo que es muy importante porque estos mecanismos pueden ser afectados por fármacos que inhiban la degradación o la faciliten, dependiendo de las necesidades terapéuticas) no discutiremos estos temas que se vuelven más especializados. Sin embargo, es importante que se conozca y se discuta su posible uso para beneficio del paciente. Esta revisión se centra en discutir los potenciales beneficios causados por la activación del receptor CB1 en el paciente insomne para reducir su dolencia de mal dormir.