Sleep, Glial Function, and the Endocannabinoid System: Implications for Neuroinflammation and Sleep Disorders.

The relationship between sleep, glial cells, and the endocannabinoid system represents a multifaceted regulatory network with profound implications for neuroinflammation and cognitive function. The molecular underpinnings of sleep modulation by the endocannabinoid system and its influence on glial cell activity are discussed, shedding light on the reciprocal relationships that govern these processes. Emphasis is placed on understanding the role of glial cells in mediating neuroinflammatory responses and their modulation by sleep patterns. Additionally, this review examines how the endocannabinoid system interfaces with glia-immune signaling to regulate inflammatory cascades within the central nervous system. Notably, the cognitive consequences of disrupted sleep, neuroinflammation, and glial dysfunction are addressed, encompassing implications for neurodegenerative disorders, mood disturbances, and cognitive decline. Insights into the bidirectional modulation of cognitive function by the endocannabinoid system in the context of sleep and glial activity are explored, providing a comprehensive perspective on the potential mechanisms underlying cognitive impairments associated with sleep disturbances. Furthermore, this review examines potential therapeutic avenues targeting the endocannabinoid system to mitigate neuroinflammation, restore glial homeostasis, and normalize sleep patterns. The identification of novel therapeutic targets within this intricate regulatory network holds promise for addressing conditions characterized by disrupted sleep, neuroinflammation, and cognitive dysfunction. This work aims to examine the complexities of neural regulation and identify potential avenues for therapeutic intervention.

Interplay between the Glymphatic System and the Endocannabinoid System: Implications for Brain Health and Disease.

The intricate mechanisms governing brain health and function have long been subjects of extensive investigation. Recent research has shed light on two pivotal systems, the glymphatic system and the endocannabinoid system, and their profound role within the central nervous system. The glymphatic system is a recently discovered waste clearance system within the brain that facilitates the efficient removal of toxic waste products and metabolites from the central nervous system. It relies on the unique properties of the brain's extracellular space and is primarily driven by cerebrospinal fluid and glial cells. Conversely, the endocannabinoid system, a multifaceted signaling network, is intricately involved in diverse physiological processes and has been associated with modulating synaptic plasticity, nociception, affective states, appetite regulation, and immune responses. This scientific review delves into the intricate interconnections between these two systems, exploring their combined influence on brain health and disease. By elucidating the synergistic effects of glymphatic function and endocannabinoid signaling, this review aims to deepen our understanding of their implications for neurological disorders, immune responses, and cognitive well-being.

Scientific facts improve cannabis perception and public opinion: results from Sinaloa, México.

Cannabis, the most prevalent drug in Latin America, has long been associated with the state of Sinaloa, Mexico, known for its cultivation and distribution. Despite increasing global acceptance, cannabis use remains stigmatized in Mexican society, driven by perceptions of it as a highly psychoactive and addictive substance lacking medicinal or industrial value. This study investigates the impact of scientific information on societal perceptions of cannabis in Sinaloa. A large convenience sample of 3162 individuals from Sinaloa participated in this research, responding to a questionnaire on cannabis consumption and attitudes. Participants were then subjected to an intervention consisting of an informative briefing based on the documents "Using Evidence to Talk About Cannabis" and "State of the Evidence: cannabis use and regulation" by the International Centre for Science in Drug Policy. After the intervention, participants' attitudes were immediately reevaluated through the same questionnaire, allowing for a comparison of pre- and post-intervention responses. The results indicate that the intervention (providing scientific information) significantly influenced attitudes toward cannabis, with education and age playing prominent roles in its effectiveness. Notably, the intervention fostered more positive or more neutral attitudes, potentially reducing stigma and promoting a better-informed perspective on cannabis. This study highlights the pivotal role of evidence in shaping informed citizens' views, while underscoring the importance of countering misinformation for societal progress. These findings have significant implications for forthcoming cannabis policy modifications in Mexico, emphasizing the necessity of engaging knowledgeable individuals in policy decisions to address the violence and inequalities associated with the illicit drug trade, particularly in Sinaloa.

An insight of sleep disorders in Africa.

Sleep is a recurrent physiologic and fundamental process in every human being, regardless of ethnicity, gender, birthplace, or occupation; however, the features of sleep are swayed by genetic background and environmental influences. All these factors have an intricate relationship, and arise from a complex and assorted genetic repertoire in the alleles that promote a higher genetic variation in human populations. Sleep disorders have become an uprising public health problem in the modern society; in addition, the correlation between sleep disorders and the development of late chronic diseases has been extensively studied, finding an important causality between them. Therefore, an adequate evaluation of the current situation in a developing continent such as Africa is essential to develop satisfactory health policies. In this review, we will reprise several aspects that influence the sleep-wake cycle in individuals with African heritage (including African Americans and sub-Saharan Africans), such as genetic background, HIV infection, tropical diseases, immunological markers, cultural aspects, and place them into Africa's context in order to have a better comprehension of its situation.

Narcolepsy as an immune-mediated disease.

Narcolepsy is a neurological disorder characterized by excessive daytime sleepiness, cataplexy, hypnagonic hallucinations, sleep paralysis, and disturbed nocturnal sleep patterns. This disease is secondary to the specific loss of hypothalamic hypocretin (orexin)-producing neurons in the lateral hypothalamus. An autoimmune basis for the disease has long been suspected based on its strong association with the genetic marker DQB1∗06:02, and current studies greatly support this hypothesis. Narcolepsy with hypocretin deficiency is associated with human leukocyte antigen (HLA) and T cell receptor (TCR) polymorphisms, suggesting that an autoimmune process targets a peptide unique to hypocretin-producing neurons via specific HLA-peptide-TCR interactions. This concept has gained a lot of notoriety after the increase of childhood narcolepsy in 2010 following the 2009 H1N1 pandemic (pH1N1) in China and vaccination with Pandemrix, an adjuvanted H1N1 vaccine that was used in Scandinavia. The surge of narcolepsy cases subsequent to influenza A H1N1 infection and H1N1 vaccination suggests that processes such as molecular mimicry or bystander activation might be crucial for disease development.

CD4+ T cell autoimmunity to hypocretin/orexin and cross-reactivity to a 2009 H1N1 influenza A epitope in narcolepsy.

Narcolepsy, a disorder strongly associated with human leukocyte antigen (HLA)-DQA1*01:02/DQB1*06:02 (DQ0602), is characterized by excessive daytime sleepiness, cataplexy, and rapid eye movement sleep abnormalities. It is caused by the loss of ~70,000 posterior hypothalamic neurons that produce the wake-promoting neuropeptide hypocretin (HCRT) (orexin). We identified two DQ0602-binding HCRT epitopes, HCRT56-68 and HCRT87-99, that activated a subpopulation of CD4(+) T cells in narcolepsy patients but not in DQ0602-positive healthy control subjects. Because of the established association of narcolepsy with the 2009 H1N1 influenza A strain (pH1N1), we administered a seasonal influenza vaccine (containing pH1N1) to patients with narcolepsy and found an increased frequency of circulating HCRT56-68- and HCRT87-99-reactive T cells. We also identified a hemagglutinin (HA) pHA1 epitope specific to the 2009 H1N1 strain, pHA1275-287, with homology to HCRT56-68 and HCRT87-99. In vitro stimulation of narcolepsy CD4(+) T cells with pH1N1 proteins or pHA1275-287 increased the frequency of HCRT56-68- and HCRT87-99-reactive T cells. Our data indicate the presence of CD4(+) T cells that are reactive to HCRT in narcolepsy patients and possible molecular mimicry between HCRT and a similar epitope in influenza pH1N1, pHA1275-287.

Current and emerging options for the drug treatment of narcolepsy.

Narcolepsy/hypocretin deficiency (now called type 1 narcolepsy) is a lifelong neurologic disorder with well-established diagnostic criteria and etiology. Narcolepsy is a chronic sleep disorder characterized by excessive daytime sleepiness (EDS) and symptoms of dissociated rapid eye movement sleep such as cataplexy (sudden loss of muscle tone), hypnagogic hallucinations (sensory events that occur at the transition from wakefulness to sleep), sleep paralysis (inability to perform movements upon wakening or sleep onset), and nocturnal sleep disruption. As these symptoms are often disabling, most patients need life-long treatment. The treatment of narcolepsy is well defined, and, traditionally, amphetamine-like stimulants (i.e., dopaminergic release enhancers) have been used for clinical management to improve EDS and sleep attacks, whereas tricyclic antidepressants have been used as anticataplectics. However, treatments have evolved to better-tolerated compounds such as modafinil or armodafinil (for EDS) and adrenergic/serotonergic selective reuptake inhibitors (as anticataplectics). In addition, night-time administration of a short-acting sedative, c-hydroxybutyrate (sodium oxybate), has been used for the treatment for EDS and cataplexy. These therapies are almost always needed in combination with non-pharmacologic treatments (i.e., behavioral modification). A series of new drugs is currently being tested in animal models and in humans. These include a wide variety of hypocretin agonists, melanin- concentrating hormone receptor antagonists, antigenspecific immunopharmacology, and histamine H3 receptor antagonists/inverse agonists (e.g., pitolisant), which have been proposed for specific therapeutic applications, including the treatment of Alzheimer's disease, attention-deficit hyperactivity disorder, epilepsy, and more recently, narcolepsy. Even though current treatment is strictly symptomatic, based on the present state of knowledge of the pathophysiology of narcolepsy, we expect that more pathophysiology-based treatments will be available in the near future.

The autoimmune basis of narcolepsy.

Narcolepsy is a neurological disorder characterized by excessive daytime sleepiness, cataplexy, hypnagonic hallucinations, sleep paralysis, and disturbed nocturnal sleep patterns. Narcolepsy is caused by the loss of hypocretin (orexin)-producing neurons in the lateral hypothalamus. Evidence, such as a strong association with HLA DQB1*06:02, strongly suggests an autoimmune basis targeting hypocretin neurons. Genome-wide association studies have strengthened the association between narcolepsy and immune system gene polymorphisms, including the identification of polymorphisms in the T cell receptor alpha locus, TNFSF4 (also called OX40L), Cathepsin H (CTSH) the purinergic receptor P2RY11, and the DNA methyltransferase DNMT1. Recently, attention has been raised regarding a spike in cases of childhood narcolepsy in 2010 following the 2009 H1N1 pandemic (pH1N1) in China and vaccination with Pandemrix, an adjuvanted H1N1 vaccine that was used in Europe. How the immune system may be involved in disease initiation and/or progression remains a challenge to researchers. Potential immunological pathways that could lead to the specific elimination of hypocretin producing neurons include molecular mimicry or bystander activation, and are likely a combination of genetic and environmental factors, such as upper airway infections.

2-AG into the lateral hypothalamus increases REM sleep and cFos expression in melanin concentrating hormone neurons in rats.

Orexins/hypocretins (OX) and melanin-concentrating hormone (MCH) neurons located in the lateral hypothalamus seem to modulate different stages of the sleep-wake cycle. OX are necessary for wakefulness and MCH appears to regulate rapid eye movement sleep (REMS). Likewise, endocannabinoids, the endogenous ligands for cannabinoid receptors 1 and 2 (CB1R, CB2R), also modulate REMS in rats. Moreover, it has been shown that the activation of the CB1R in the lateral hypothalamus of rats excites MCH neurons while inhibiting OX neurons in in vitro preparations. Hence, we assessed the effects of 2-arachidonoylglicerol (2-AG, an endocannabinoid) in the lateral hypothalamus on the sleep-wake cycle of rats. We also utilized the CB1R inverse agonist AM251 to further support the involvement of this receptor, and we performed double immunofluorescence experiments to detect c-Fos, as a marker of neural activation, in OX and in MCH neurons to determine which neurons were activated. Our results indicate that 2-AG increases REMS through CB1R activation, and increases c-Fos expression in MCH neurons. These results suggest that endocannabinoid activation of the CB1R in the lateral hypothalamus, which activates MCH neurons, is one mechanism by which REMS is triggered.

Orexin receptor antagonists as therapeutic agents for insomnia.

Insomnia is a common clinical condition characterized by difficulty initiating or maintaining sleep, or non-restorative sleep with impairment of daytime functioning. Currently, treatment for insomnia involves a combination of cognitive behavioral therapy (CBTi) and pharmacological therapy. Among pharmacological interventions, the most evidence exists for benzodiazepine (BZD) receptor agonist drugs (GABAA receptor), although concerns persist regarding their safety and their limited efficacy. The use of these hypnotic medications must be carefully monitored for adverse effects. Orexin (hypocretin) neuropeptides have been shown to regulate transitions between wakefulness and sleep by promoting cholinergic/monoaminergic neural pathways. This has led to the development of a new class of pharmacological agents that antagonize the physiological effects of orexin. The development of these agents may lead to novel therapies for insomnia without the side effect profile of hypnotics (e.g., impaired cognition, disturbed arousal, and motor balance difficulties). However, antagonizing a system that regulates the sleep-wake cycle may create an entirely different side effect profile. In this review, we discuss the role of orexin and its receptors on the sleep-wake cycle and that of orexin antagonists in the treatment of insomnia.

Models for narcolepsy with cataplexy drug discovery.

INTRODUCTION: Narcolepsy is a chronic sleep disorder, characterized by a disrupted nocturnal sleep, excessive daytime sleepiness (EDS) and symptoms of dissociated rapid eye movement (REM) sleep. These symptoms are often disabling, confining the patients to a life-long pharmacologic symptomatic treatment. Nowadays, it is well known that narcolepsy results from alterations in the genes involved in the physiology of the orexin ligand or its receptor. AREAS COVERED: This review recapitulates on the current approaches for treating narcolepsy with cataplexy and the use of narcolepsy models in order to address different aspects of the disease. EXPERT OPINION: Animal models are required for the study of human diseases when it is impractical or unethical to use humans; these models are useful for studying the underlying causes of a disease and are a common research tool for identifying potential drug targets. Current treatment for human narcolepsy is symptomatically based; interestingly, the existing approaches do not target the orexinergic circuit. The discovery of novel drug targets for treating narcolepsy remains the primary focus of study in sleep medicine research. New therapies will arise through the discovery of new animal models of narcolepsy, which will offer new insights into the understanding of its physiopathology.

Narcolepsy and orexins: an example of progress in sleep research.

Narcolepsy is a chronic neurodegenerative disease caused by a deficiency of orexin-producing neurons in the lateral hypothalamus. It is clinically characterized by excessive daytime sleepiness and by intrusions into wakefulness of physiological aspects of rapid eye movement sleep such as cataplexy, sleep paralysis, and hypnagogic hallucinations. The major pathophysiology of narcolepsy has been recently described on the bases of the discovery of the neuropeptides named orexins (hypocretins) in 1998; considerable evidence, summarized below, demonstrates that narcolepsy is the result of alterations in the genes involved in the pathology of the orexin ligand or its receptor. Deficient orexin transmission is sufficient to produce narcolepsy, as we describe here, animal models with dysregulated orexin signaling exhibit a narcolepsy-like phenotype. Remarkably, these narcoleptic models have different alterations of the orexinergic circuit, this diversity provide us with the means for making comparison, and have a better understanding of orexin-cell physiology. It is of particular interest that the most remarkable findings regarding this sleep disorder were fortuitous and due to keen observations. Sleep is a highly intricate and regulated state, and narcolepsy is a disorder that still remains as one of the unsolved mysteries in science. Nevertheless, advances and development of technology in neuroscience will provide us with the necessary tools to unravel the narcolepsy puzzle in the near future. Through an evaluation of the scientific literature we traced an updated picture of narcolepsy and orexins in order to provide insight into the means by which neurobiological knowledge is constructed.

Growth hormone improves hippocampal adult cell survival and counteracts the inhibitory effect of prolonged sleep deprivation on cell proliferation.

Sleep deprivation (SD) produces numerous deleterious changes in brain cells, including apoptosis. It has been demonstrated that growth hormone (GH) stimulates cell growth and counteracts apoptosis, although this anti-apoptotic effect has not been tested against SD. To determine the protective effect of GH administration on cell proliferation and survival in the dentate gyrus (DG) of the hippocampus after sleep deprivation; we injected Wistar adult rats with a low dose of recombinant human GH (rhGH 5 ng/kg) per seven days and then we gently sleep deprived the animals for 48 consecutive hours. 5-Bromodeoxiuridine (BrdU) was administered to assess cell proliferation after the GH treatment and NeuN was used as marker of cell fate. Our results indicate that GH produced a three fold increase in the number of BrdU positive cells within the DG [Control = 1044 ± 106.38 cells, rhGH = 2952 ± 99.84 cells, P<0.01]. In contrast, 48 h of SD significantly reduced cell proliferation but this effect was antagonized by the GH administration [SD = 540 ± 18.3 cells, rhGH + SD = 1116 ± 84.48 cells, P<0.004]. Paradoxically, SD and GH administration increased cell survival separately but no significantly compared with control animals. However, cell survival was increased in animals treated with rhGH+SD compared to rats injected with saline solution [P<0.04]. Within the survival cells, the percentage of neurons was higher in SD animals [95%] compared with saline group, while this percentage (NeuN positive cells) was increased in animals treated with rhGH+SD [120%] compared with rhGH [25%] alone. Our findings indicate that GH strongly promotes cell proliferation in the adult brain and also protects the hippocampal neuronal precursors against the deleterious effect of prolonged sleep loss.