Las orexinas como biomarcadores para demencia tipo Alzheimer y relación con síntomas neuropsiquiátricos / Orexins as biomarkers for Alzheimer dementia and their relationship with neuropsychiatric symptoms

RESUMEN: Los biomarcadores más estudiados en la demencia tipo Alzheimer (DA) son los niveles elevados de Aβ42 y de proteína Tau en líquido cefalorraquídeo. Dada la complejidad de la sintomatología cognitiva y síntomas neuropsiquiátricos (SNP) de esta patología, algunos estudios recientes proponen sustancias como las orexinas, como blanco terapéutico de DA y SNP. El presente trabajo tiene como objetivo revisar publicaciones científicas recientes que hayan analizado la asociación entre orexinas, SNP y DA en humanos, algunos modelos animales y que hayan evaluado a las orexinas como posibles biomarcadores tanto para investigación como en el área clínica. En esta revisión también se describen los estudios que sugieren a las orexinas como un posible biomarcador en la DA, dada su relación con el Aβ42 y la proteína Tau, y otros estudios que las asocian con presencia de SNP, especialmente alteración del sueño. Se plantea la hipótesis de que la presencia de SNP en DA se asocia con las orexinas, debido a que este sistema influye en el funcionamiento hipotalámico y de forma indirecta en áreas cerebrales que regulan el comportamiento. Sin embargo, aún falta mayor investigación, principalmente de estudios longitudinales para conocer claramente la influencia de las orexinas en los SNP.

ABSTRACT The most studied biomarkers in Alzheimer's dementia (AD) are elevated levels of Aβ42 and Tau protein in cerebrospinal fluid. Given the complexity of the cognitive symptomatology and neuropsychiatric symptoms (NPS) of this pathology, some recent studies propose substances such as orexins as a therapeutic target for AD and NPS. The present work aims to review recent scientific publications that have analyzed the association between orexins, PNS and AD in humans. There are some animal models that have evaluated orexins as possible biomarkers both for research and in the clinical area. This review also describes studies that suggest orexins as possible biomarkers in AD, given their relationship with Aβ42 and Tau protein, and other studies that associate them with the presence of SNPs, especially sleep disturbance. It is hypothesized that the presence of SNPs in AD is associated with orexins, because this system influences hypothalamic functioning and indirectly in brain areas that regulate behavior. However, further research is still lacking, mainly longitudinal studies to clearly know the influence of orexins on SNPs.

Fasting levels of appetite regulating hormones predict caloric intake at breakfast in a group of Chilean adolescents / Los niveles en ayunas de hormonas reguladoras del apetito predicen la ingesta energética en el desayuno en adolescentes

BACKGROUND: Appetite regulation is integral to food intake and is modulated by complex interactions between internal and external stimuli. Hormonal mechanisms which stimulate or inhibit intake have been characterized, but the physiologic effects of serum levels of such hormones in short-term appetite regulation have received little attention. AIM: To evaluate whether fasting levels of orexigenic/anorexigenic hormones were associated with energy intake at breakfast, served soon after drawing a fasting blood sample, in a group of adolescents. MATERIAL AND METHODS: Anthropometry, body composition and fasting blood levels of leptin, insulin, ghrelin, and orexin-A were measured in 655 Chilean adolescents aged 16.8 ± 0.3 years (52% males). Energy intake was measured at a semi-standardized breakfast. Associations between hormone levels and energy intake were studied using multivariate linear models. RESULTS: Thirty nine percent of participants were overweight/ obese. After an overnight fast, median values for leptin, insulin, ghrelin and orexin-A were 7.3 ng/mL, 6.7 IU/dL, 200.8 pg/mL, and 16.1 pg/mL, respectively. Participants ate on average 637 ± 239 calories at breakfast. In multivariable models, insulin levels were inversely and independently associated with caloric intake at breakfast (β = −18.65; p < 0.05), whereas leptin, ghrelin and orexin-A levels were positively and independently associated with intake: β= 5.56, β = 0.34 and β = 8.40, respectively, p < 0.05. CONCLUSIONS: Fasting leptin, ghrelin and orexin-A were positively associated with energy intake during breakfast provided soon after the blood draw. Insulin was negatively associated with energy intake. Modifiable factors influencing levels of appetite regulating hormones could be a potential target for influencing food intake.

ANTECEDENTES: La regulación del apetito es parte integral de la ingesta alimentaria y es modulada por complejas interacciones entre estímulos internos y externos. Se han caracterizado los mecanismos hormonales que estimulan o inhiben la ingesta, pero los efectos fisiológicos de los niveles séricos de tales hormonas en la regulación del apetito a corto plazo han recibido poca atención. OBJETIVO: Evaluar si los niveles en ayunas de hormonas orexigénicas/ anorexigénicas se asocian con la ingesta energética en el desayuno, entregado inmediatamente después de una muestra de sangre en ayunas, en un grupo de adolescentes. MATERIAL Y MÉTODO: Se efectuaron mediciones antropométricas, composición corporal y medición de niveles en ayunas de leptina, insulina, grelina y orexina-A en 655 adolescentes de 16,8 ± 0,26 años. La ingesta energética se midió en un desayuno semiestandarizado. Se estudiaron las asociaciones entre los niveles hormonales y la ingesta energética mediante modelos lineales multivariados. RESULTADOS: Los valores de leptina, insulina, grelina y orexina-A fueron 7,3 ng/mL, 6,7 UI/dL, 200,8 pg/mL y 16,1 pg/mL respectivamente. Los participantes comieron un promedio de 637 ± 239 calorías en el desayuno. Los niveles de insulina se asociaron inversa e independientemente con la ingesta del desayuno (β = −18,65; p < 0,05), mientras que los niveles de leptina, grelina y orexina-A se asociaron positiva e independientemente con la ingesta: β = 5,65; β = 0,34; β = 8,40, (p < 0,05). CONCLUSIONES: La leptina, grelina y orexina-A en ayunas se asociaron positivamente con la ingesta de energía durante el desayuno proporcionado poco después de la muestra de sangre. La insulina se asoció negativamente con la ingesta de energía. Los factores modificables que influyen en las hormonas reguladoras del apetito podrían ser un objetivo potencial para influir en la ingesta de alimentos.

Health-related quality of life in patients with narcolepsy types 1 and 2 from a Sleep Center in Brazil / Qualidade de vida relacionada à saúde em pacientes com narcolepsia tipos 1 e 2 de um Centro de Sono no Brasil

ABSTRACT Introduction: Narcolepsy patients have higher prevalence of comorbidities, such as obesity, depression, and pain. Narcolepsy symptoms and concomitant medical conditions can impact the daily activities of patients. The objective of this study is to describe the quality of life in a sample of patients with narcolepsy, and the influence of the nutritional status in health domains. Methods: At Unifesp, two groups of 33 patients (narcolepsy types 1 and 2 meeting 2014 criteria, concerning hypocretin-1) and 33 controls without sleepiness, matched by age and sex, filled out the SF-36. Results: Narcolepsy groups, regardless of their nutritional status, had significantly lower scores in all domains, compared to controls, mainly in Role-physical, Role-emotional, and Energy/Fatigue. Role-physical score was lower in type 1 than in type 2 and controls (37.8±1.0 vs. 50.0±1.2 vs. 85.6±1.6; p<0.0001). Obese with type 2 narcolepsy scored lower than type 1 in physical scales. Conclusion: In a Sleep Center in São Paulo, Brazil, physical and mental health were impaired in narcolepsy types 1 and 2. The first report of the poor health status in Brazilians with narcolepsy type 2 suggests that obesity negatively affects physical domains.

RESUMO Introdução: Pacientes com narcolepsia têm maior prevalência de comorbidades, como obesidade, depressão e dor. Sintomas de narcolepsia e condições médicas concomitantes podem afetar as atividades diárias dos pacientes. O objetivo deste estudo é escrever a qualidade de vida em uma amostra de pacientes com narcolepsia e a influência do estado nutricional nos domínios de saúde. Métodos: Na Unifesp, dois grupos de 33 pacientes (narcolepsia tipos 1 e 2 compatível com os critérios de 2014, em relação a hipocretina-1) e 33 controles sem sonolência, pareados por idade e sexo, preencheram o SF-36. Resultados: Os grupos de narcolepsia, independentemente do estado nutricional, apresentaram pontuações significantemente menores em todos os domínios, comparados aos controles, principalmente nos quesitos físico, emocional e energia/fadiga. A pontuação do critério físico foi menor no tipo 1 do que no tipo 2 e nos controles (37,8±1,0 vs. 50,0±1,2 vs. 85,6±1,6; p<0,0001). Obesos com tipo 2 tiveram pontuação menor do que os com tipo 1 nas escalas físicas. Conclusão: Em um Centro de Sono de São Paulo, Brasil, as saúdes física e mental estavam comprometidas na narcolepsia tipos 1 e 2. O primeiro relato de estado de saúde ruim em brasileiros com narcolepsia tipo 2 sugere que a obesidade afeta negativamente os domínios físicos.

The effect of CA1 administration of orexin-A on hippocampal expression of COX-2 and BDNF in a rat model of orofacial pain / O efeito da administração de CA1 de orexina-A na expressão hipocampal de COX-2 e BDNF em um modelo de dor orofacial em ratos

ABSTRACT The neuropeptide orexin-A and its receptors are widely distributed in both hippocampal circuitry and pain transmission pathways. Objective: Involvement of the CA1 orexin 1 receptor (OX1R) on the modulation of orofacial pain and pain-induced changes in hippocampal expression of cyclooxygenase-2 (COX-2) and brain-derived neurotrophic factor (BDNF) was investigated. Methods: Orofacial pain was induced by an intra-lip injection of capsaicin (100 μg). Reverse transcription polymerase chain reaction and immunoblot analysis were used to indicate changes in hippocampal BDNF and COX-2 expression, respectively. Results: Capsaicin induces a significant pain response, which is not affected by either orexin-A or SB-334867-A, an OX1R antagonist. However, an increased expression of COX-2 and decreased expression of BDNF was observed in the hippocampus of animals that received capsaicin or SB-334867-A (80 nM) plus capsaicin. Meanwhile, orexin-A (40 pM) attenuated the effects of capsaicin on the expression of COX-2 and BDNF. Conclusions: CA1 OX1R activation moderates capsaicin-induced neuronal inflammation and neurotrophic deficiency.

RESUMO O neuropeptídeo orexina-A e seus receptores estão amplamente distribuídos nos circuitos do hipocampo e nas vias de transmissão da dor. Objetivo: O envolvimento do receptor de orexina 1 CA1 (OX1R) na modulação da dor orofacial e alterações induzidas pela dor na expressão do hipocampo de ciclooxigenase-2 (COX-2) e fator neurotrófico derivado do cérebro (BDNF) foi investigado. Métodos: A dor orofacial foi induzida por injeção intra-labial de capsaicina (100 μg). A reação em cadeia da polimerase de transcrição reversa e a análise de imunotransferência foram utilizadas para indicar alterações na expressão de BDNF e COX-2 no hipocampo, respectivamente. Resultados: A capsaicina induz uma resposta significativa à dor, que não é afetada pela orexina-A ou pelo SB-334867-A, um antagonista do OX1R. No entanto, uma expressão aumentada de COX-2 e uma expressão diminuída de BDNF foi observada no hipocampo de animais que receberam capsaicina ou SB-334867-A (80 nM) mais capsaicina. Enquanto isso, a orexina A (40 pM) atenuou os efeitos da capsaicina na expressão de COX-2 e BDNF. Conclusões: A ativação de CA1 OX1R modera a inflamação neuronal induzida por capsaicina e a deficiência neurotrófica.

La mala calidad de sueño es factor promotor de obesidad / Poor quality sleep is a contributing factor to obesity

La presente revisión tiene como objetivos presentar a la comunidad académica evidencias recientes que proponen una relación entre la mala calidad y cantidad de sueño y la propensión al sobrepeso y obesidad. Se presentan en este escrito evidencias obtenidas en estudios clínicos controlados y de investigación básica experimental que demuestran que una cantidad o calidad deficiente de sueño lleva a corto plazo a alteraciones de tipo metabólico y conductual conducentes a la sobre ingestión de alimentos y al sobrepeso. También se discuten los posibles mecanismos que pudieran subyacer a este fenómeno, a nivel cerebral, metabólico y celular. El objetivo de esta revisión es presentar a las horas de sueño como un factor poco considerado en los estudios epidemiológicos y experimentales y posible desencadenante de alteraciones metabólicas. Con este escrito esperamos poder interesar a otros profesionistas involucrados en el estudio de este fenómeno para incluir la calidad y cantidad de sueño entre sus variables de estudio y/o incluir la higiene del sueño entre sus propuestas de tratamiento y prevención.

The aim of this revisión is to highlight recent evidence that links low quality and quantity of sleep with an increased propensity to develop overweight or obesity. In this text we present evidence obtained with controlled clinical studies as well as with experimental models, both indicating that decreased hours of sleep lead to metabolic and behavioral changes that then induce overconsumption of food, which then results in weight gain. With this review we want to present sleep as an additional factor contributing to metabolic disease and we aim to raise interest in professional involved in the study of overweight and obesity in order to include this factor as an additional variable in their research and strategies of intervention.

El sistema orexinérgico/hipocretinérgico y su rol en los trastornos del sueño / Orexinergic (hypocretinergic) system and its role on sleep disorders

Las orexinas o hipocretinas son neuropéptidos recientemente descritos (1998), encontrados en mayor densidad en neuronas de las regiones lateral, posterior y perifornical del hipotála-mo, las cuales se han visto implicadas en procesos de modulación de la ingesta alimenticia y del ciclo sueño-vigilia. El sistema orexinérgico tiene amplias proyecciones a todo lo largo y ancho del SNC especialmente a centros monoaminérgicos, tales como el locus coeruleus, núcleo tuberomamilar, núcleos del rafé y el área tegmental ventral. Inicialmente se pensó en un papel fundamental de las orexinas en la regulación de la función alimenticia, sin embargo estudios recientes han implicado a estos neuropéptidos en la regulación del ciclo sueño-vigilia. Estos hallazgos permiten conocer mejor una región como el hipotálamo, al igual que brinda un mejor entendimiento de la patogenia y fisiopatología relacionadas con los trastornos de la alimentación y el sueño. Este artículo pretende presentar una revisión lo más completa posible de lo que se conoce hasta ahora de estos neuromoduladores y su papel en relación con los trastornos del sueño, especialmente su implicación en la narcolepsia.

Orexins or hypocretins are recently described (1998) neuropeptides found in greater density in hypothalamic neurons, wich have been shown to be important for modulating feeding and sleep-wakefulness cycle. Orexinergic system has broad projections throughout the length and breadth of the CNS specially to monoaminergic centers such as the locus coeruleus, tuberoamilar neclei, raphe nuclei, and ventral tegmental area. Initially it was thought a key role of orexin in feedin behavior regulation, however, recent studies give a leading role to these neuropeptides in regulating the sleep-wakefulness cycle, this discovery opens a door to help better understand the operation of an area so important for the homeostasis of the human body, such as the hypothalamus, and gives some basis for a better understanding of the pathogenesis and pathophysiology in relation to eating disorders and sleep. The aim of this paper is to provide an updated review of the morphological and functional aspects that are known so far in relation to these molecules and their relationship with sleep disorders, especially their involvement in narcolepsy.