Materiały źródłowe

• #1 Etiopathogenesis and Neurobiology of Narcolepsy: A Review

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3972560/

  Narcolepsy is a chronic lifelong sleep disorder and it often leaves a debilitating effect on the quality of life of the sufferer. […] For over 100 years, clinicians have recognised narcolepsy, but only in the last few decades have scientists been able to shed light on the true cause and pathogenesis of narcolepsy. Recent studies have shown that a loss of the hypothalamic neuropeptide Hypocretin/Orexin causes Narcolepsy with cataplexy and that an autoimmune mechanism may be responsible for this loss. Our present understanding of the pathogenesis of Narcolepsy is that an autoimmune mediated loss of a specific hypothalamic neuropeptide, Hypocretin causes this disorder. The loss of Hypocretin neurons has been definitely shown in Narcolepsy-Cataplexy. Evidence, such as a strong association with HLA (Human leukocyte antigen) DQB1*06:02, strongly suggest an autoimmune basis for Narcolepsy.

• #2 Narcolepsy – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK459236/

  Narcolepsy type 1 occurs when nearly all of the neurons that contain orexin (also called hypocretin) are lost. The reason for this is not fully understood, but it is thought to be an autoimmune process possibly triggered by an infection. HLA haplotype DQB1*0602 is present in 95% of narcolepsy type 1 patients, but this is also present in about 20% of the general population without narcolepsy. The cause of narcolepsy type 2 is not entirely clear. Current hypotheses include less destruction of orexin cells, impaired orexin receptor signaling, or an unknown mechanism. Some patients initially diagnosed with narcolepsy type 2 will develop cataplexy, indicating disease progression. Less commonly, trauma and tumors may result in narcolepsy. […] The mechanism of narcolepsy type 2 is less clear, but it is thought that it may be due to a similar but less severe loss of orexin neurons.

• #3 Narcolepsy pathophysiology: Explanation of processes

  https://www.medicalnewstoday.com/articles/narcolepsy-pathophysiology

  Complex systems in the brain control sleep and wakefulness. In narcolepsy, specific neurons related to sleep and wakefulness are absent or do not function correctly. This can affect how a person sleeps and wakes up. […] The pathophysiology of narcolepsy affects the neurological processes involved in keeping people awake and helping them fall asleep. […] Narcolepsy type 1 occurs when there is a permanent loss of hypocretin neurons. Because of this, the mechanisms separating sleep and awake states become unstable. […] The RAS no longer stimulates the release of wake-promoting neurotransmitters and inconsistently suppresses the VLCO, leading to EDS. […] When wake-promoting neurons are inconsistently activated, they do not suppress REM-promoting neurons. This can cause a person to experience abnormal REM sleep manifestations such as sleep paralysis, hypnopompic hallucinations, and hypnagogic hallucinations.

• #4 The Science of Narcolepsy | Sleep Medicine

  https://sleep.hms.harvard.edu/education-training/public-education/sleep-and-health-education-program/sleep-health-education-4

  Research has revealed that narcolepsy with cataplexy is caused by a lack of orexins (hypocretins), brain chemicals that help sustain alertness and prevent REM sleep from occurring at the wrong times. […] Genetics, age, and triggering infections or inflammation play important roles in the development of narcolepsy. […] Ongoing research is shedding light on many aspects of the disorder; as more is learned about the biology of narcolepsy, the door widens for more effective treatments. […] In people who have narcolepsy with cataplexy, most of the orexin-producing neurons die off. The consequent lack of orexins results in lasting sleepiness and poor control of REM sleep. […] Though much has been learned about narcolepsy with cataplexy, considerably less is known about the cause of narcolepsy without cataplexy. Most likely, it is caused by less severe injury to the orexin neurons, resulting in fewer and less severe symptoms.

• #5 Narcolepsy – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK459236/

  Narcolepsy type 1 occurs when nearly all of the neurons that contain orexin (also called hypocretin) are lost. The reason for this is not fully understood, but it is thought to be an autoimmune process possibly triggered by an infection. HLA haplotype DQB1*0602 is present in 95% of narcolepsy type 1 patients, but this is also present in about 20% of the general population without narcolepsy. The cause of narcolepsy type 2 is not entirely clear. Current hypotheses include less destruction of orexin cells, impaired orexin receptor signaling, or an unknown mechanism. Some patients initially diagnosed with narcolepsy type 2 will develop cataplexy, indicating disease progression. Less commonly, trauma and tumors may result in narcolepsy. […] The mechanism of narcolepsy type 2 is less clear, but it is thought that it may be due to a similar but less severe loss of orexin neurons.

• #6 Narcolepsy: Neural Mechanisms of Sleepiness and Cataplexy | Journal of Neuroscience

  https://www.jneurosci.org/content/32/36/12305

  Further research has demonstrated that 90% of the orexin-producing neurons are lost in human narcolepsy with cataplexy. […] Collectively, these studies provide strong evidence that some process selectively destroys the orexin neurons. […] This type of narcolepsy affects approximately half of all patients with narcolepsy, and the severity of symptoms is often less than in patients with cataplexy. […] Though little is known about the underlying neuropathology, narcolepsy without cataplexy may simply be caused by less severe injury to the orexin neurons, resulting in mainly sleepiness and a small reduction in CSF orexin level. […] In addition to controlling sleep/wake states, the orexin neurons also regulate metabolism, feeding, reward, and autonomic tone, resulting in additional symptoms.

• #7 Etiopathogenesis and Neurobiology of Narcolepsy: A Review

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3972560/

  Current evidence on the pathogenesis of narcolepsy comes from much of studies being focused on narcolepsy with cataplexy with pointers towards both genetic and environmental factors. […] The combination of HLA antigens, hypocretin neuron loss and hypocretin deficiency and onset in the second decade of life strongly points towards an autoimmune etiology. Given that genetic susceptibility to narcolepsy is linked to a specific HLA type; many investigators have suspected an immunologic basis for the disease, either by an autoimmune mechanism or in response to external antigens. […] Several studies have shown that a loss of hypocretin neurons definitely causes Narcolepsy with cataplexy. The evidence for Hypocretin deficiency in narcolepsy is as follows. […] Approximately 90% of patients of narcolepsy with cataplexy have low CSF (Cerebrospinal fluid) hypocretin levels while only 10% to 20% of patients classified as having narcolepsy without cataplexy show low CSF Hypocretin levels. […] Despite the body of evidence clearly implicating the immune system, future studies will be required to confirm the autoimmune basis of narcolepsy as no key target antigen or humoral/cellular mechanism of immunity that could attack the hypocretin neurons has been identified.

• #8 Narcolepsy pathophysiology: Explanation of processes

  https://www.medicalnewstoday.com/articles/narcolepsy-pathophysiology

  In people with narcolepsy type 1, disruption of these systems leads to unwanted or rapid transitions between sleep and awake states, causing sleep disruption. […] The pathophysiology of narcolepsy type 2 is not well understood. […] However, experts believe it relates to the neurotransmitter hypocretin. […] About 90% of people with narcolepsy type 1 have a low to unmeasurable hypocretin level in their cerebrospinal fluid. […] A 2018 meta-analysis of recent studies suggests that an autoimmune mechanism may destroy a person’s hypocretin neurons, causing narcolepsy. […] Narcolepsy is a rare sleep disorder that disrupts regular sleep and awake cycles and makes the transitions unstable, leading to sleep disruptions and fragmentation. This also causes abnormal elements of one cycle to intrude into the other, which can cause a person to experience abnormal REM sleep manifestations, including cataplexy, hypnagogic hallucinations, and sleep paralysis.

• #9

  https://omim.org/entry/161400

  A number sign (#) is used with this entry because of evidence that narcolepsy-1 (NRCLP1) is caused by heterozygous mutation in the HCRT gene (602358) on chromosome 17q21. One such patient has been reported. […] In contrast to animal models, human narcolepsy is not a simple genetic disorder. Most human cases of narcolepsy are sporadic and carry a specific HLA haplotype (Peyron et al., 2000). Familial cases are the exception rather than the rule, and monozygotic twins show only partial concordance (25 to 31%) (Mignot, 1998). […] Thannickal et al. (2000) studied the hypothalamus of 16 human brains, including those of 4 narcoleptics. The human narcoleptics had an 85 to 95% reduction in the number of HCRT neurons. […] Nishino et al. (2000) measured immunoreactive HCRT in the cerebrospinal fluid of 9 patients with narcolepsy and 8 age-matched controls.

• #10 Etiopathogenesis and Neurobiology of Narcolepsy: A Review

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3972560/

  Narcolepsy is a chronic lifelong sleep disorder and it often leaves a debilitating effect on the quality of life of the sufferer. […] For over 100 years, clinicians have recognised narcolepsy, but only in the last few decades have scientists been able to shed light on the true cause and pathogenesis of narcolepsy. Recent studies have shown that a loss of the hypothalamic neuropeptide Hypocretin/Orexin causes Narcolepsy with cataplexy and that an autoimmune mechanism may be responsible for this loss. Our present understanding of the pathogenesis of Narcolepsy is that an autoimmune mediated loss of a specific hypothalamic neuropeptide, Hypocretin causes this disorder. The loss of Hypocretin neurons has been definitely shown in Narcolepsy-Cataplexy. Evidence, such as a strong association with HLA (Human leukocyte antigen) DQB1*06:02, strongly suggest an autoimmune basis for Narcolepsy.

• #11 The immunopathogenesis of narcolepsy type 1 | Nature Reviews Immunology

  https://www.nature.com/articles/s41577-023-00902-9

  Narcolepsy type 1 (NT1) is a chronic sleep disorder resulting from the loss of a small population of hypothalamic neurons that produce wake-promoting hypocretin (HCRT; also known as orexin) peptides. An immune-mediated pathology for NT1 has long been suspected given its exceptionally tight association with the MHC class II allele HLA-DQB1*06:02, as well as recent genetic evidence showing associations with polymorphisms of T cell receptor genes and other immune-relevant loci and the increased incidence of NT1 that has been observed after vaccination with the influenza vaccine Pandemrix. […] Increased T cell reactivity against HCRT has been consistently reported in patients with NT1, but data demonstrating a primary role for T cells in neuronal destruction are currently lacking. […] Elucidation of the pathogenesis of NT1 will allow for the development of targeted immunotherapies at disease onset and could serve as a model for other immune-mediated neurological diseases.

• #12 Narcolepsy – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK459236/

  Narcolepsy type 1 occurs when nearly all of the neurons that contain orexin (also called hypocretin) are lost. The reason for this is not fully understood, but it is thought to be an autoimmune process possibly triggered by an infection. HLA haplotype DQB1*0602 is present in 95% of narcolepsy type 1 patients, but this is also present in about 20% of the general population without narcolepsy. The cause of narcolepsy type 2 is not entirely clear. Current hypotheses include less destruction of orexin cells, impaired orexin receptor signaling, or an unknown mechanism. Some patients initially diagnosed with narcolepsy type 2 will develop cataplexy, indicating disease progression. Less commonly, trauma and tumors may result in narcolepsy. […] The mechanism of narcolepsy type 2 is less clear, but it is thought that it may be due to a similar but less severe loss of orexin neurons.

• #13 Narcolepsy – Wikipedia

  https://en.wikipedia.org/wiki/Narcolepsy

  Some researches indicated that people with type 1 narcolepsy (narcolepsy with cataplexy) have a lower level of orexin (hypocretin), which is a chemical contributing to the regulation of wakefulness and REM sleep. […] The primary genetic factor that has been strongly implicated in the development of narcolepsy involves an area of chromosome 6 known as the human leukocyte antigen (HLA) complex. […] Specific variations in HLA genes are strongly correlated with the presence of narcolepsy (HLA DQB1*06:02, frequently in combination with HLA DRB1*15:01); however, these variations are not required for the condition to occur and sometimes occur in individuals without narcolepsy. […] These genetic variations in the HLA complex are thought to increase the risk of an auto-immune response to orexin-releasing neurons in the lateral hypothalamus.

• #14

  https://link.springer.com/article/10.1007/s11910-018-0851-5

  After the connection between AS03-adjuvanted pandemic H1N1 vaccine Pandemrix and narcolepsy was recognized in 2010, research on narcolepsy has been more intensive than ever before. […] There is more and more evidence that narcolepsy is an autoimmune disease. […] Narcolepsy type 1 is most likely an autoimmune disease, but the mechanisms have remained elusive. […] A large genome-wide association (GWAS) study with over 1200 narcolepsy patients and 3500 controls. It was shown that the majority of the genetic risk of narcolepsy is explained by the HLA DQB1 locus only. HLA DQB1*06:02 positive individuals carry a 251-fold increased risk of developing narcolepsy. […] One of the first reports to find HLA class I associations in narcolepsy. […] One of the first reports to find HLA class I associations in narcolepsy.

• #15

  https://link.springer.com/article/10.1007/s00281-022-00933-9

  Narcolepsy is suggested to be the results of an autoimmune process occurring in genetically predisposed individuals upon triggering by environmental factors that would lead to a selective loss of HCRT-neurons in the lateral hypothalamus. […] Converging lines of evidence from studies in humans and animal models strongly reinforce the notion of a T cell contribution to the pathophysiology of narcolepsy. […] Autoreactive CD4+ T cells may take part to the immunopathology in the initial phases of the disease by promoting a local inflammatory environment in the CNS, which would in turn induce the expression of MHC class I molecules on neurons as well as alter the blood-brain barrier integrity with consequent recruitment of other immune cell types. […] Cytotoxic self-reactive CD8+ T cells may then also reach the CNS where they would recognize the cognate antigens on MHC class I molecules on HCRT-neurons, thus resulting in their selective disruption.

• #16 The Role of T Cells in the Pathogenesis of Narcolepsy Type 1: A Narrative Review

  https://www.mdpi.com/1422-0067/25/22/11914

  Narcolepsy type 1 (NT1) is an uncommon, persistent sleep disorder distinguished by significant daytime sleepiness, episodes of cataplexy, and irregularities in rapid eye movement sleep. The etiology of NT1 is linked to the destruction of hypothalamic neurons responsible for the synthesis of the wake-promoting neuropeptide known as hypothalamic orexin. The pathophysiological mechanisms underlying NT1 remain inadequately elucidated; however, a model that incorporates the interplay of genetic predisposition, environmental influences, immune system factors, and a deficiency in hypocretin (HCRT) provides a framework for elucidating the pathogenesis of NT1. […] The strong association between narcolepsy and the HLA-DQB1*06:02 allele strongly indicates an autoimmune etiology for this condition. Increasing evidence suggests that T cells play a critical role in this autoimmune-mediated HCRT neuronal loss. Studies have identified specific T cell subsets, including CD4+ and CD8+ T cells, that target HCRT neurons, contributing to their destruction. Clarifying the pathogenesis of NT1 driven by autoimmune T cells is crucial for the development of effective therapeutic interventions for this disorder.

• #17 Frontiers | Narcolepsy and H1N1 influenza immunology a decade later: What have we learned?

  https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.902840/full

  Current hypotheses suggest that activation and expansion of cross-reactive T-cells by H1N1/09 influenza infection could have been amplified following the administration of the adjuvanted vaccine, giving rise to a “two-hit” hypothesis. […] The prevailing consensus is that NT1 has an autoimmune origin, similar to type 1 diabetes which is caused by autoimmunity to the secreted hormone prepro-insulin. […] The occurrence of NT1 is strongly linked to positivity for certain HLA class II (HLA-II) alleles. […] The tight association of NT1 with the HLA-II DQ0602 allele and its function in CD4+ T-cell antigen presentation, suggested a disease mechanism involving CD4+ T cells with T-cell receptors (TCRs) specifically recognizing peptides from HCRT-secreting neurons, bound to the endogenous DQ0602 allele.

• #18 Frontiers | Narcolepsy and H1N1 influenza immunology a decade later: What have we learned?

  https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.902840/full

  In the wake of the A/California/7/2009 H1N1 influenza pandemic vaccination campaigns in 2009-2010, an increased incidence of the chronic sleep-wake disorder narcolepsy was detected in children and adolescents in several European countries. […] Narcolepsy with cataplexy (defined as type-1 narcolepsy, NT1) is characterized by an irreversible and chronic deficiency of hypocretin peptides in the hypothalamus. […] An autoimmune origin of NT1 is broadly assumed. This is based on its strong association with a predisposing allele (the human leucocyte antigen DQB1*0602) carried by the large majority of NT1 patients, and on links with other immune-related genetic markers affecting the risk of NT1. […] Presently, hypotheses on the underlying potential immunological mechanisms center on molecular mimicry between hypocretin and peptides within the A/California/7/2009 H1N1 virus antigen.

• #19 Narcolepsy: What It Is, Causes, Symptoms & Treatment

  https://my.clevelandclinic.org/health/diseases/12147-narcolepsy

  According to further research, the most likely reason those neurons stopped working is an autoimmune problem. That means your immune system attacked the neurons that make and use orexins, the orexins themselves or both. […] About 90% to 95% of people with type 1 narcolepsy have a specific genetic mutation (the identifier for this mutation is HLA-DQB1*06:02) that affects their immune system. However, about 25% of all people also have this mutation but dont have narcolepsy. As a result, experts rarely test for this mutation and they arent certain what role it plays. […] However, people can also develop type 1 narcolepsy after certain viral and bacterial infections, especially strains of H1N1 influenza and bacteria like those that cause strep throat. Experts suspect thats because infections can sometimes trigger changes and malfunctions in your immune system.

• #20 Narcolepsy: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1188433-overview

  Further evidence for impaired hypocretin functioning in humans was found with the discovery of low levels of hypocretin in the cerebrospinal fluid (CSF) of narcoleptic patients. […] Subsequently, abnormal immune modulation was associated with the clinical development of narcolepsy in children in Scandinavia and Finland. After vaccination against the H1N1 influenza virus with a vaccine using a potent ASO3 adjuvant, narcolepsy in Finnish children increased 8- to 12-fold. All affected children who underwent HLA typing were found to have the HLA DQB*0602 allele. […] Dysfunction and inappropriate regulation of rapid eye movement (REM) sleep are thought to exist in narcolepsy. […] The hypocretin system plays an important role in the pathophysiology of human narcolepsy. Patients with narcolepsy have been found to have little or no hypocretin in their CSF.

• #21 Recent Advances in Narcolepsy | ACNR Journal

  https://acnr.co.uk/articles/recent-advances-in-narcolepsy/

  Evidence from several countries that the swine ‘flu vaccine, Pandemrix, given to several million people in 2009 and early 2010 led to an abnormal surge in childhood and, to a lesser degree, adult cases of typical narcolepsy has further fuelled the “autoimmune” theory. If correct, however, it remains unclear whether the pathogenic process reflects a reaction to the strong adjuvant chemicals added to the vaccine or is simply molecular mimicry, related to proteins within the vaccine or indeed the virus itself. Equally unexplained is the frequent considerable delay between any proposed vaccine-related inflammatory reaction in the hypothalamus and narcolepsy symptom onset. One speculative theory is that any initial minor damage to the hypocretin neurons may promote a subsequent slow degenerative process, perhaps by an excitotoxic mechanism given the extremely high metabolic energy demands of these particular neurons.

• #22 Immune response to a flu protein yields new insights into narcolepsy | News Center

  https://med.stanford.edu/news/all-news/2015/07/side-effect-of-flu-vaccine-yields-new-insights-into-narcolepsy.html

  The authors propose a hit-and-run autoimmune mechanism for how both swine flu and Pandemrix might cause narcolepsy. […] They suggest that in genetically predisposed people, high levels of the H1N1 protein stimulate the production of large amounts of antibodies to both the virus and the hypocretin receptor. […] There, the antibodies may latch onto hypocretin receptors, possibly directing the immune system to destroy or suppress brain cells critical to regulating sleep-wake cycles. […] Indeed, compared to Pandemrix, Focetria contains 72 percent less of the H1N1 protein and, for this reason, it doesn’t appear to have stimulated specific flu antibodies capable of binding to the receptor, according to the researchers. […] The work advances the understanding of narcolepsy, but Steinman said he isn’t claiming they have nailed down the cause.

• #23 Narcolepsy – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK459236/

  During normal wakefulness, orexin-containing neurons in the lateral hypothalamus increase the activity of the nuclei of the Reticular Activating System (RAS), which increases wake-promoting neurotransmitters in the cortex; dopamine, norepinephrine, serotonin, and histamine inhibit REM and acetylcholine is increased in both wakefulness and REM. The RAS also inhibits the sleep-promoting ventrolateral preoptic area (VLPO), suppressing GABA, which in turn increases the activity of motor neurons and muscle tone. Heightened emotions increase activity in the amygdala and subsequently the orexin-containing neurons, which suppresses REM. The wake-promoting and the sleep-promoting systems are usually mutually inhibitory to ensure complete transitions. […] In narcolepsy type 1, the mechanism that separates wake from sleep becomes unstable without sufficient levels of orexin. The RAS no longer consistently causes the release of wake-promoting neurotransmitters to the cortex and inconsistently inhibits the VLPO. This results in rapid transitions between sleep and wake and allows the intrusion of REM-related phenomena into wakefulness. The pathophysiology of narcolepsy type 2 is not well understood.

• #24 Narcolepsy pathophysiology: Explanation of processes

  https://www.medicalnewstoday.com/articles/narcolepsy-pathophysiology

  Complex systems in the brain control sleep and wakefulness. In narcolepsy, specific neurons related to sleep and wakefulness are absent or do not function correctly. This can affect how a person sleeps and wakes up. […] The pathophysiology of narcolepsy affects the neurological processes involved in keeping people awake and helping them fall asleep. […] Narcolepsy type 1 occurs when there is a permanent loss of hypocretin neurons. Because of this, the mechanisms separating sleep and awake states become unstable. […] The RAS no longer stimulates the release of wake-promoting neurotransmitters and inconsistently suppresses the VLCO, leading to EDS. […] When wake-promoting neurons are inconsistently activated, they do not suppress REM-promoting neurons. This can cause a person to experience abnormal REM sleep manifestations such as sleep paralysis, hypnopompic hallucinations, and hypnagogic hallucinations.

• #25 Narcolepsy – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK459236/

  During normal wakefulness, orexin-containing neurons in the lateral hypothalamus increase the activity of the nuclei of the Reticular Activating System (RAS), which increases wake-promoting neurotransmitters in the cortex; dopamine, norepinephrine, serotonin, and histamine inhibit REM and acetylcholine is increased in both wakefulness and REM. The RAS also inhibits the sleep-promoting ventrolateral preoptic area (VLPO), suppressing GABA, which in turn increases the activity of motor neurons and muscle tone. Heightened emotions increase activity in the amygdala and subsequently the orexin-containing neurons, which suppresses REM. The wake-promoting and the sleep-promoting systems are usually mutually inhibitory to ensure complete transitions. […] In narcolepsy type 1, the mechanism that separates wake from sleep becomes unstable without sufficient levels of orexin. The RAS no longer consistently causes the release of wake-promoting neurotransmitters to the cortex and inconsistently inhibits the VLPO. This results in rapid transitions between sleep and wake and allows the intrusion of REM-related phenomena into wakefulness. The pathophysiology of narcolepsy type 2 is not well understood.

• #26 Narcolepsy pathophysiology: Explanation of processes

  https://www.medicalnewstoday.com/articles/narcolepsy-pathophysiology

  Complex systems in the brain control sleep and wakefulness. In narcolepsy, specific neurons related to sleep and wakefulness are absent or do not function correctly. This can affect how a person sleeps and wakes up. […] The pathophysiology of narcolepsy affects the neurological processes involved in keeping people awake and helping them fall asleep. […] Narcolepsy type 1 occurs when there is a permanent loss of hypocretin neurons. Because of this, the mechanisms separating sleep and awake states become unstable. […] The RAS no longer stimulates the release of wake-promoting neurotransmitters and inconsistently suppresses the VLCO, leading to EDS. […] When wake-promoting neurons are inconsistently activated, they do not suppress REM-promoting neurons. This can cause a person to experience abnormal REM sleep manifestations such as sleep paralysis, hypnopompic hallucinations, and hypnagogic hallucinations.

• #27

  https://www.narcolepsylink.com/about-narcolepsy/pathophysiology/

  Narcolepsy occurs when these neurons do not interact properly, resulting in a dysregulation of the sleep/wake states. This allows elements of the sleep state to intrude on wakefulness and vice versa. […] Narcolepsy type 1 is thought to be due to the permanent loss of hypocretin neurons. Patients with narcolepsy type 1 have low or undetectable levels of cerebrospinal fluid (CSF) hypocretin-1. […] Based on animal models, loss of hypocretin neurons is thought to lead to inconsistent signaling of wake-promoting neurons responsible for maintaining wakefulness and muscle tone and inhibit NREM and REM-sleep promoting neurons (eg, dopaminergic, noradrenergic, serotonergic neurons). […] Wake-promoting neurons fail to activate cortical and subcortical arousal regions and fail to inhibit sleep-promoting neurons (ie, GABAergic neurons), resulting in excessive daytime sleepiness.

• #28 Pathophysiology of Narcolepsy | Know Narcolespy HCP

  https://knownarcolepsyhcp.com/pathophysiology-of-narcolepsy

  People living with narcolepsy experience frequent and unpredictable transitions between wakefulness, non-REM sleep, and REM sleep. […] Loss of hypocretin leads to sleep-wake state instability. […] See how loss of hypocretin leads to unstable boundaries between sleep-wake states. […] People living with narcolepsy type 1 have low levels of hypocretin. […] A group of neurons located in the hypothalamus that are essential for promoting non-REM sleep. These neurons project to all wake-promoting regions to inhibit wakefulness and promote non-REM sleep during the night.

• #29 Narcolepsy pathophysiology: Explanation of processes

  https://www.medicalnewstoday.com/articles/narcolepsy-pathophysiology

  Complex systems in the brain control sleep and wakefulness. In narcolepsy, specific neurons related to sleep and wakefulness are absent or do not function correctly. This can affect how a person sleeps and wakes up. […] The pathophysiology of narcolepsy affects the neurological processes involved in keeping people awake and helping them fall asleep. […] Narcolepsy type 1 occurs when there is a permanent loss of hypocretin neurons. Because of this, the mechanisms separating sleep and awake states become unstable. […] The RAS no longer stimulates the release of wake-promoting neurotransmitters and inconsistently suppresses the VLCO, leading to EDS. […] When wake-promoting neurons are inconsistently activated, they do not suppress REM-promoting neurons. This can cause a person to experience abnormal REM sleep manifestations such as sleep paralysis, hypnopompic hallucinations, and hypnagogic hallucinations.

• #30

  https://www.narcolepsylink.com/about-narcolepsy/pathophysiology/

  Certain wake-promoting neurons that also suppress REM signaling fail to inhibit REM-promoting neurons, resulting in cataplexy and other abnormal manifestations of REM sleep such as hypnagogic/hypnopompic hallucinations and sleep paralysis. […] Disruption of mutually inhibitory sleep-wake circuits may also lead to unwanted transitions from sleep to wakefulness and to associated sleep disruption. […] Narcolepsy type 2 is likely a heterogeneous disorder. […] The exact cause of narcolepsy type 2 is unknown.

• #31 Narcolepsy – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK459236/

  The cataplexy seems to have its origin in the pons and the mesocorticolimbic dopaminergic system. […] The hypocretin system now appears to play a vital role in narcolepsy. Many patients with narcolepsy have no or little hypocretin in the CSF. The deficiency in hypocretin is believed to produce intermittent wake and sleep states. Unfortunately, many other neurotransmitters play a role in the sleep-wake cycle, and making a correlation with any one of them is difficult.

• #32 Narcolepsy: Diagnosis and management | Cleveland Clinic Journal of Medicine

  https://www.ccjm.org/content/85/12/959

  Narcolepsy type 1 has been linked to a deficiency in hypocretin in the central nervous system. Hypocretin (also known as orexin) is a hormone produced in the hypothalamus that acts on multiple brain regions and maintains alertness. For unclear reasons, hypothalamic neurons producing hypocretin are selectively reduced in narcolepsy type 1. Hypocretin also stabilizes wakefulness and inhibits REM sleep; therefore, hypocretin deficiency can lead to inappropriate intrusions of REM sleep onto wakefulness, leading to the hallmark features of narcolepsycataplexy, sleep-related hallucinations, and sleep paralysis. […] According to one theory, cataplexy is triggered by emotional stimuli because of a pathway between the medial prefrontal cortex and the amygdala to the pons. […] Cerebrospinal fluid levels of hypocretin in patients with narcolepsy type 2 tend to be normal, and the biologic underpinnings of narcolepsy type 2 remain mysterious. However, in the subgroup of those with narcolepsy type 2 in which hypocretin is low, many individuals go on to develop cataplexy, thereby evolving to narcolepsy type 1.

• #33 Narcolepsy and emotional experience: a review of the literature | Behavioral and Brain Functions | Full Text

  https://behavioralandbrainfunctions.biomedcentral.com/articles/10.1186/s12993-018-0151-x

  Narcolepsy is a chronic sleep disorder characterized by excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis. […] Neurophysiological and neurochemical findings suggest the involvement of emotional brain circuits in the physiopathology of cataplexy, which seems to depending on the dysfunctional interplay between the hypothalamus and the amygdala associated with an alteration of hypocretin levels. […] It is well known that in NC patients the sudden drop in muscle tone is triggered by emotional factors such as laughing, joking, a pleasant surprise, and also anger. […] This clinical feature suggests a close interaction between emotions and related anomalies in NC brain. […] The amygdala is a limbic structure critically involved in emotional information processing in both animals and humans, as shown by neuroimaging, neurophysiological, and clinical studies.

• #34 This Neurotransmitter Inhibits Cataplexy in Narcolepsy Model Mice | Sleep Review

  https://sleepreviewmag.com/sleep-disorders/hypersomnias/narcolepsy/neurotransmitter-inhibits-cataplexy-narcolepsy-model-mice/

  Orexin is important in regulating the switch between sleep and wakefulness in the brain. If a person lacks adequate orexin neurons, then they have narcolepsy, where sleep and wakefulness are inadequately switched on and off. […] An international research team led by Kanazawa University previously found two types of neurons preventing narcolepsy by receiving orexin from orexin neurons: one is noradrenaline neurons in the locus coeruleus of the brain, suppressing strong sleepiness; and the other is serotonin neurons in the dorsal raphe nucleus of the brain, inhibiting cataplexy. […] In a new study published in PNAS [Proceedings of the National Academy of Sciences], the research team has discovered that serotonin neurons in the dorsal raphe nucleus inhibit catalepsy by reducing activities of the amygdala, a brain region essential in processing emotional responses as well as in emotional memory.

• #35 This Neurotransmitter Inhibits Cataplexy in Narcolepsy Model Mice | Sleep Review

  https://sleepreviewmag.com/sleep-disorders/hypersomnias/narcolepsy/neurotransmitter-inhibits-cataplexy-narcolepsy-model-mice/

  In this study, with an optogenetic tool, the team discovered that catalepsy was almost completely inhibited by artificial augmentation of serotonin release; the release was induced by selectively stimulating serotonin nerve terminals in the amygdala in narcolepsy model mice. […] Furthermore, the effect of orexin neurons inhibiting cataplexy was found to be abolished when serotonin release was inhibited selectively in the amygdala. […] This study reveals that serotonin neurons do not directly suppress muscle tone weakening but inhibit cataplexy by reducing and controlling activities of the amygdala, which is involved in communicating emotional excitement. […] By identifying this neuronal pathway, the team states that the current study has made a leap forward in understanding of the whole picture of narcolepsy’s mechanism.

• #36 Narcolepsy – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK459236/

  During normal wakefulness, orexin-containing neurons in the lateral hypothalamus increase the activity of the nuclei of the Reticular Activating System (RAS), which increases wake-promoting neurotransmitters in the cortex; dopamine, norepinephrine, serotonin, and histamine inhibit REM and acetylcholine is increased in both wakefulness and REM. The RAS also inhibits the sleep-promoting ventrolateral preoptic area (VLPO), suppressing GABA, which in turn increases the activity of motor neurons and muscle tone. Heightened emotions increase activity in the amygdala and subsequently the orexin-containing neurons, which suppresses REM. The wake-promoting and the sleep-promoting systems are usually mutually inhibitory to ensure complete transitions. […] In narcolepsy type 1, the mechanism that separates wake from sleep becomes unstable without sufficient levels of orexin. The RAS no longer consistently causes the release of wake-promoting neurotransmitters to the cortex and inconsistently inhibits the VLPO. This results in rapid transitions between sleep and wake and allows the intrusion of REM-related phenomena into wakefulness. The pathophysiology of narcolepsy type 2 is not well understood.

• #37 Pathophysiology and Risk Factors for Narcolepsy

  https://www.neurologylive.com/view/pathophysiology-and-risk-factors-for-narcolepsy

  The pathophysiology or pathobiology of narcolepsy is a deficiency of orexin. These neurons have low levels of orexin, especially in people with type 1 narcolepsy. […] The pathophysiology of type 1 narcolepsy, which is a narcolepsy with cataplexy or with a hypocretin deficiency, is somewhat more well delineated than the other phenotypes of central hypersomnia, such as narcolepsy type 2. […] The genetic predisposition for narcolepsy is conferred through the HLA gene, the DBQ10602, that confers a risk. […] With the actual mechanisms of narcolepsy that occur for individuals who have the genetic predisposition, there has to be some sort of an insult, environmental or through inoculation. […] That allele had action against the antibodies of the streptococcal antibody, and that was also destroying the hypocretin-producing cells in the hypothalamus. […] The ongoing hypothesis is that it is an autoimmune disorder, and for some odd reason, it is likely targeting the set of hypocretin neurons or orexin neurons in the hypothalamus.

• #38 Narcolepsy – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK459236/

  Narcolepsy type 1 occurs when nearly all of the neurons that contain orexin (also called hypocretin) are lost. The reason for this is not fully understood, but it is thought to be an autoimmune process possibly triggered by an infection. HLA haplotype DQB1*0602 is present in 95% of narcolepsy type 1 patients, but this is also present in about 20% of the general population without narcolepsy. The cause of narcolepsy type 2 is not entirely clear. Current hypotheses include less destruction of orexin cells, impaired orexin receptor signaling, or an unknown mechanism. Some patients initially diagnosed with narcolepsy type 2 will develop cataplexy, indicating disease progression. Less commonly, trauma and tumors may result in narcolepsy. […] The mechanism of narcolepsy type 2 is less clear, but it is thought that it may be due to a similar but less severe loss of orexin neurons.

• #39 Narcolepsy: What It Is, Causes, Symptoms & Treatment

  https://my.clevelandclinic.org/health/diseases/12147-narcolepsy

  While experts know much of why type 1 narcolepsy happens, thats not the case with type 2 narcolepsy. Experts still dont fully understand why type 2 narcolepsy happens. But they suspect it happens for similar reasons, like a less-severe loss of the neurons that use orexin, or a problem with how orexin travels in your brain. […] In rare cases, narcolepsy can happen because of damage to your hypothalamus. You can have this kind of damage from head injuries (such as concussions and traumatic brain injuries), strokes, brain tumors and other conditions.

• #40 Narcolepsy – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK459236/

  Narcolepsy type 1 occurs when nearly all of the neurons that contain orexin (also called hypocretin) are lost. The reason for this is not fully understood, but it is thought to be an autoimmune process possibly triggered by an infection. HLA haplotype DQB1*0602 is present in 95% of narcolepsy type 1 patients, but this is also present in about 20% of the general population without narcolepsy. The cause of narcolepsy type 2 is not entirely clear. Current hypotheses include less destruction of orexin cells, impaired orexin receptor signaling, or an unknown mechanism. Some patients initially diagnosed with narcolepsy type 2 will develop cataplexy, indicating disease progression. Less commonly, trauma and tumors may result in narcolepsy. […] The mechanism of narcolepsy type 2 is less clear, but it is thought that it may be due to a similar but less severe loss of orexin neurons.

• #41 The Science of Narcolepsy | Sleep Medicine

  https://sleep.hms.harvard.edu/education-training/public-education/sleep-and-health-education-program/sleep-health-education-4

  By gaining a better understanding of this process, researchers hope to develop medications that can stop narcolepsy just as it begins and prevent further injury to the orexin neurons. […] Some of the greatest insights about narcolepsy have come from the laboratories of Dr. Emmanuel Mignot of Stanford University and Dr. Jerome Siegel of the University of California, Los Angeles. […] In 2000, each group independently discovered that narcolepsy with cataplexy is caused by a loss of orexins in the brain. […] Thus far, the cause of narcolepsy without cataplexy is less clear. Researchers have examined the brains of only a few people with this type of narcolepsy, and these seem to have only a moderate loss of the orexin neurons.

• #42 Etiopathogenesis and Neurobiology of Narcolepsy: A Review

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3972560/

  Current evidence on the pathogenesis of narcolepsy comes from much of studies being focused on narcolepsy with cataplexy with pointers towards both genetic and environmental factors. […] The combination of HLA antigens, hypocretin neuron loss and hypocretin deficiency and onset in the second decade of life strongly points towards an autoimmune etiology. Given that genetic susceptibility to narcolepsy is linked to a specific HLA type; many investigators have suspected an immunologic basis for the disease, either by an autoimmune mechanism or in response to external antigens. […] Several studies have shown that a loss of hypocretin neurons definitely causes Narcolepsy with cataplexy. The evidence for Hypocretin deficiency in narcolepsy is as follows. […] Approximately 90% of patients of narcolepsy with cataplexy have low CSF (Cerebrospinal fluid) hypocretin levels while only 10% to 20% of patients classified as having narcolepsy without cataplexy show low CSF Hypocretin levels. […] Despite the body of evidence clearly implicating the immune system, future studies will be required to confirm the autoimmune basis of narcolepsy as no key target antigen or humoral/cellular mechanism of immunity that could attack the hypocretin neurons has been identified.

• #43 Narcolepsy: Neural Mechanisms of Sleepiness and Cataplexy | Journal of Neuroscience

  https://www.jneurosci.org/content/32/36/12305

  The autoimmune hypothesis still has several weaknesses. […] Researchers have not yet identified a key target antigen or humoral or cellular mechanisms that could attack the orexin neurons. […] Clearly, much more needs to be done to determine whether an autoimmune process kills the orexin neurons, and if so, to discover how that process can be altered. […] The orexin neurons innervate a variety of nuclei in the brain and spinal cord, but it remains unclear which of these pathways are necessary for stabilizing wakefulness and muscle tone. […] The discovery of the orexin system sparked a surge of research that has substantially improved our understanding of narcolepsy, yet there remain many important and unanswered questions.

• #44 PATHOGENESIS OF NARCOLEPSY – тема научной статьи по фундаментальной медицине читайте бесплатно текст научно-исследовательской работы в электронной библиотеке КиберЛенинка

  https://cyberleninka.ru/article/n/pathogenesis-of-narcolepsy

  Based on these data, an autoimmune theory of damage to hypocretinergic neurons as a result of a genetic mutation was formulated. […] It is assumed that the autoimmune reaction in narcolepsy develops due to the fact that the abnormal HLA protein resulting from the mutation (HLA-DQB1 * 06:02), expressed on oligodendrocytes, through microglia, presents the antigen of orexinergic neurons to CD4 + cells, which is normal for the immune system. […] However, not all cases of clinically apparent narcolepsy show a mutation in the HLA system gene. What in such cases can cause the development of this disease? Another mutation is thought to be responsible, this time located on chromosome 19 in the P2RY11 gene. […] Conclusion: The leading role in the development of narcolepsy is played by the hypothalamic peptide „orexin”, a decrease in the amount of which leads to the development of symptoms of narcolepsy.

• #45 PATHOGENESIS OF NARCOLEPSY – тема научной статьи по фундаментальной медицине читайте бесплатно текст научно-исследовательской работы в электронной библиотеке КиберЛенинка

  https://cyberleninka.ru/article/n/pathogenesis-of-narcolepsy

  Based on these data, an autoimmune theory of damage to hypocretinergic neurons as a result of a genetic mutation was formulated. […] It is assumed that the autoimmune reaction in narcolepsy develops due to the fact that the abnormal HLA protein resulting from the mutation (HLA-DQB1 * 06:02), expressed on oligodendrocytes, through microglia, presents the antigen of orexinergic neurons to CD4 + cells, which is normal for the immune system. […] However, not all cases of clinically apparent narcolepsy show a mutation in the HLA system gene. What in such cases can cause the development of this disease? Another mutation is thought to be responsible, this time located on chromosome 19 in the P2RY11 gene. […] Conclusion: The leading role in the development of narcolepsy is played by the hypothalamic peptide „orexin”, a decrease in the amount of which leads to the development of symptoms of narcolepsy.

• #46 Treatment paradigms for cataplexy in narcolepsy: past, present, and fu | NSS

  https://www.dovepress.com/treatment-paradigms-for-cataplexy-in-narcolepsy-past-present-and-futur-peer-reviewed-fulltext-article-NSS

  Overall, the currently available treatments for cataplexy act symptomatically, and there is no evidence suggesting that they target the hypocretin/orexin system. […] Sodium oxybate, which is the sodium salt of gamma-hydroxybutyrate, was observed to induce REM sleep followed by an increase in slow-wave non-REM sleep and was subsequently investigated for the treatment of narcolepsy on the hypothesis that improvement of nocturnal sleep would reduce EDS and possibly other narcolepsy symptoms, including cataplexy. […] However, a clinical comparison with the prototypical GABAB agonist baclofen showed that while sodium oxybate reduced EDS and cataplexy, baclofen had no effect on these narcolepsy symptoms. […] The autoimmune hypothesis of narcolepsy with cataplexy provides a rationale for use of immunomodulation therapy, which is exemplified by experimental use of intravenous immunoglobulin therapy, although it has only been evaluated in case studies in adults and children.

• #47 GHB as a GABA Receptor Agonist for Narcolepsy Therapy

  https://www.neurologylive.com/view/ghb-gaba-receptor-agonist-narcolepsy-therapy

  GHB acts as a GABAB receptor agonist to increase sleep efficiency; specifically, GHB binds GABAB receptors to inhibit dopamine release by modulating central cholinergic and serotonergic neurons. […] GHB has been shown to reduce the activity of patients thalamic, hippocampal, and neocortical neurons. […] Therapeutic strategies that address the underlying cause of narcolepsy, rather than simply managing symptoms, are desperately needed. […] Systematic studies of the genetic landscape of narcolepsy could inform the development of innovative treatments based on gene therapy or stem cells.

• #48 Treatment paradigms for cataplexy in narcolepsy: past, present, and fu | NSS

  https://www.dovepress.com/treatment-paradigms-for-cataplexy-in-narcolepsy-past-present-and-futur-peer-reviewed-fulltext-article-NSS

  Overall, the currently available treatments for cataplexy act symptomatically, and there is no evidence suggesting that they target the hypocretin/orexin system. […] Sodium oxybate, which is the sodium salt of gamma-hydroxybutyrate, was observed to induce REM sleep followed by an increase in slow-wave non-REM sleep and was subsequently investigated for the treatment of narcolepsy on the hypothesis that improvement of nocturnal sleep would reduce EDS and possibly other narcolepsy symptoms, including cataplexy. […] However, a clinical comparison with the prototypical GABAB agonist baclofen showed that while sodium oxybate reduced EDS and cataplexy, baclofen had no effect on these narcolepsy symptoms. […] The autoimmune hypothesis of narcolepsy with cataplexy provides a rationale for use of immunomodulation therapy, which is exemplified by experimental use of intravenous immunoglobulin therapy, although it has only been evaluated in case studies in adults and children.

• #49 Harmony Biosciences Acquires Asset With Novel Mechanism Of Action For The Potential Treatment Of Narcolepsy And Other Rare Neurological Diseases | Harmony Biosciences

  https://ir.harmonybiosciences.com/news-releases/news-release-details/harmony-biosciences-acquires-asset-novel-mechanism-action

  HBS-102 is a Melanin Concentrating Hormone Receptor 1 (MCHR1) antagonist that has the potential to offer a novel approach to the treatment of narcolepsy including the symptoms of Rapid Eye Movement (REM) sleep dysregulation, such as cataplexy, hallucinations and sleep paralysis. HBS-102 blocks the activity of melanin concentrating hormone (MCH) neurons, which scientific evidence indicates is the generator of REM sleep and its associated behaviors. Therefore, HBS-102 could potentially reduce REM intrusions into wakefulness and reduce the frequency of cataplexy, hallucinations, and sleep paralysis. […] HBS-102 is an investigational compound being developed as a potential treatment for narcolepsy and other rare neurological diseases. HBS-102 is a potential first-in-class molecule with a novel mechanism of action which targets melanin concentrating hormone (MCH) neurons in the hypothalamus, which make up the control center for REM sleep and related behaviors. In the setting of orexin deficiency (as occurs in patients with type 1 narcolepsy), there is an imbalance between orexin and MCH which could result in the control center for REM sleep going unchecked that could lead to REM sleep intruding into wakefulness. If that occurs, the clinical symptoms are experienced as cataplexy, hallucinations, and/or sleep paralysis. HBS-102, an MCHR1 antagonist, blocks the activity of the MCH neurons, which could potentially reduce REM intrusions into wakefulness and therefore reduce the debilitating symptoms of cataplexy, hallucinations and sleep paralysis.

• #50 Harmony Biosciences Acquires Asset With Novel Mechanism Of Action For The Potential Treatment Of Narcolepsy And Other Rare Neurological Diseases | Harmony Biosciences

  https://ir.harmonybiosciences.com/news-releases/news-release-details/harmony-biosciences-acquires-asset-novel-mechanism-action

  HBS-102 is a Melanin Concentrating Hormone Receptor 1 (MCHR1) antagonist that has the potential to offer a novel approach to the treatment of narcolepsy including the symptoms of Rapid Eye Movement (REM) sleep dysregulation, such as cataplexy, hallucinations and sleep paralysis. HBS-102 blocks the activity of melanin concentrating hormone (MCH) neurons, which scientific evidence indicates is the generator of REM sleep and its associated behaviors. Therefore, HBS-102 could potentially reduce REM intrusions into wakefulness and reduce the frequency of cataplexy, hallucinations, and sleep paralysis. […] HBS-102 is an investigational compound being developed as a potential treatment for narcolepsy and other rare neurological diseases. HBS-102 is a potential first-in-class molecule with a novel mechanism of action which targets melanin concentrating hormone (MCH) neurons in the hypothalamus, which make up the control center for REM sleep and related behaviors. In the setting of orexin deficiency (as occurs in patients with type 1 narcolepsy), there is an imbalance between orexin and MCH which could result in the control center for REM sleep going unchecked that could lead to REM sleep intruding into wakefulness. If that occurs, the clinical symptoms are experienced as cataplexy, hallucinations, and/or sleep paralysis. HBS-102, an MCHR1 antagonist, blocks the activity of the MCH neurons, which could potentially reduce REM intrusions into wakefulness and therefore reduce the debilitating symptoms of cataplexy, hallucinations and sleep paralysis.

• #51 Therapeutic Advances: Narcolepsy-Associated Excessive Daytime Sleepiness With Histamine Modulation – Pulmonology Advisor

  https://www.pulmonologyadvisor.com/cch/narcolepsy-excessive-daytime-sleepiness-histamine-pitolisant-modafinil-armodafinil/

  Histamine modulation has sparked significant interest in narcolepsy management due to its pivotal role in promoting wakefulness and its interaction with the hypocretin system. Pitolisant is the first H3R antagonist/inverse agonist not based on imidazole to advance into clinical development. […] […] Pitolisant is believed to work by inhibiting the auto-inhibitory actions of histamine and H3R agonists on endogenous histamine release, leading to elevated histamine levels and increased acetylcholine release in brain regions associated with arousal. Additionally, pitolisant selectively enhances dopamine levels in the prefrontal cortex, which sets it apart from other medications. This selective action may help mitigate psychomotor effects and reduce the risk of drug abuse compared to medications that increase dopamine levels less selectively. […] […] In clinical trials focused on patients with narcolepsy, pitolisant has been extensively evaluated and demonstrated efficacy in managing both EDS and cataplexy. […]

• #52 WAKIX Increases Histamine Levels in the Brain

  https://wakixhcp.com/why-wakix/mechanism-of-action/

  The mechanism of action (MOA) of WAKIX in EDS in patients 6 years and older with narcolepsy or cataplexy in adult patients with narcolepsy is unclear; however, its efficacy could be mediated through its activity as an antagonist/inverse agonist at H3 receptors. […] WAKIX Binding to H3 Receptors Increases Histamine Synthesis and Release. […] H3 receptors help regulate histamine synthesis and release. Normally, when synaptic histamine levels are high, histamine binds to H3 autoreceptors to inhibit further synthesis and release of histamine in the brain.

• #53 What is the mechanism of Pitolisant Hydrochloride?

  https://synapse.patsnap.com/article/what-is-the-mechanism-of-pitolisant-hydrochloride

  Pitolisant hydrochloride is a novel therapeutic agent used primarily for the treatment of narcolepsy, a chronic sleep disorder characterized by excessive daytime sleepiness, cataplexy, and other symptoms related to the dysregulation of sleep-wake cycles. Understanding the mechanism of action of pitolisant hydrochloride requires delving into its pharmacological properties and the neurobiological pathways it influences. Pitolisant hydrochloride is classified as a histamine H3 receptor antagonist/inverse agonist. The histamine H3 receptor is predominantly expressed in the central nervous system (CNS) and plays a crucial role in modulating the release of histamine and other neurotransmitters such as dopamine, norepinephrine, and acetylcholine. Histamine itself is a critical neurotransmitter involved in the regulation of the sleep-wake cycle and cognitive functions. When pitolisant hydrochloride binds to the histamine H3 receptor, it prevents the receptor from inhibiting the release of histamine. In effect, this leads to an increase in histaminergic neurotransmission in the brain. By acting as an inverse agonist, pitolisant hydrochloride not only blocks the inhibitory effects of the H3 receptor but also promotes its active conformation, thereby enhancing the release of histamine. The elevation of histamine levels in the CNS has several downstream effects. First, it promotes wakefulness by stimulating histamine receptors in various brain regions, including the cortex and the hypothalamus. These regions are integral to maintaining alertness and cognitive function. Second, increased histamine release can indirectly boost the levels of other neurotransmitters like dopamine and norepinephrine. Dopamine is essential for motivation, reward, and attention, while norepinephrine is crucial for arousal and vigilance. In the context of narcolepsy, pitolisant hydrochlorides ability to enhance histaminergic activity helps mitigate excessive daytime sleepiness and reduce the frequency and severity of cataplexy attacks. By stabilizing the histamine-mediated arousal system, patients experience improved wakefulness and a better overall quality of life. Moreover, pitolisant hydrochloride’s influence on cognitive functions extends beyond wakefulness. Histamine is known to play a role in learning and memory processes. Therefore, by modulating histamine levels, pitolisant hydrochloride may also offer cognitive benefits, which are particularly valuable for narcolepsy patients who often suffer from cognitive impairments due to their condition. In summary, pitolisant hydrochloride operates through a well-defined mechanism involving the antagonism/inverse agonism of the histamine H3 receptor. By enhancing histaminergic neurotransmission, it promotes wakefulness, reduces cataplexy, and potentially improves cognitive function in narcolepsy patients. This unique mechanism of action distinguishes pitolisant hydrochloride from other treatments and highlights its therapeutic potential in managing sleep disorders.

• #54 Therapeutic Advances: Narcolepsy-Associated Excessive Daytime Sleepiness With Histamine Modulation – Pulmonology Advisor

  https://www.pulmonologyadvisor.com/cch/narcolepsy-excessive-daytime-sleepiness-histamine-pitolisant-modafinil-armodafinil/

  Histamine modulation has sparked significant interest in narcolepsy management due to its pivotal role in promoting wakefulness and its interaction with the hypocretin system. Pitolisant is the first H3R antagonist/inverse agonist not based on imidazole to advance into clinical development. […] […] Pitolisant is believed to work by inhibiting the auto-inhibitory actions of histamine and H3R agonists on endogenous histamine release, leading to elevated histamine levels and increased acetylcholine release in brain regions associated with arousal. Additionally, pitolisant selectively enhances dopamine levels in the prefrontal cortex, which sets it apart from other medications. This selective action may help mitigate psychomotor effects and reduce the risk of drug abuse compared to medications that increase dopamine levels less selectively. […] […] In clinical trials focused on patients with narcolepsy, pitolisant has been extensively evaluated and demonstrated efficacy in managing both EDS and cataplexy. […]

• #55 Therapeutic Advances: Narcolepsy-Associated Excessive Daytime Sleepiness With Histamine Modulation – Pulmonology Advisor

  https://www.pulmonologyadvisor.com/cch/narcolepsy-excessive-daytime-sleepiness-histamine-pitolisant-modafinil-armodafinil/

  Histamine modulation has sparked significant interest in narcolepsy management due to its pivotal role in promoting wakefulness and its interaction with the hypocretin system. Pitolisant is the first H3R antagonist/inverse agonist not based on imidazole to advance into clinical development. […] […] Pitolisant is believed to work by inhibiting the auto-inhibitory actions of histamine and H3R agonists on endogenous histamine release, leading to elevated histamine levels and increased acetylcholine release in brain regions associated with arousal. Additionally, pitolisant selectively enhances dopamine levels in the prefrontal cortex, which sets it apart from other medications. This selective action may help mitigate psychomotor effects and reduce the risk of drug abuse compared to medications that increase dopamine levels less selectively. […] […] In clinical trials focused on patients with narcolepsy, pitolisant has been extensively evaluated and demonstrated efficacy in managing both EDS and cataplexy. […]

• #56 Genetics of narcolepsy | Human Genome Variation

  https://www.nature.com/articles/s41439-018-0033-7

  In 1999, two independent groups revealed the pathogenesis of narcolepsy in animals. Orexin A and orexin B (also known as hypocretin 1 and hypocretin 2, respectively) are neuropeptides that regulate arousal, wakefulness, and appetite and are produced exclusively by neurons in the lateral hypothalamic area. […] In humans, the orexin A level is severely reduced or undetectable in the cerebrospinal fluid (CSF) of approximately 90% of patients with NT1. NT1 is characterized by a low orexin A level (110pg/ml) and cataplexy. […] Thus, measurement of orexin A in the CSF is an important diagnostic tool. […] The strong association with HLA indicates immunological pathogenesis of NT1. […] The strong association between NT1 and HLA suggests an autoimmune etiology. […] The strong association between NT1 and HLA suggests an autoimmune etiology. […] These reports suggest that NT1 results from inflammation or autoimmune processes in the central nervous system.

• #57 Narcolepsy—A Neuropathological Obscure Sleep Disorder: A Narrative Review of Current Literature

  https://www.mdpi.com/2076-3425/12/11/1473

  The exact cause and pathophysiology of narcolepsy pathology are unknown, but it has been classified into three major types based on research and clinical experience: (1) narcolepsy accompanied by cataplexy; (2) narcolepsy without cataplexy, characterized by daytime sleepiness; and (3) secondary narcolepsy, caused by hypothalamic injury and an imbalance in neuronal transmission. […] The strong link between the HLADQB1*06:02 allele and polymorphisms in other immune-related genes and the immunological-autoimmune response in narcolepsy patients with cataplexy support the autoimmune hypothesis. […] The removal of hypocretin neurons is very selective, sparing the melanin-concentrating hormone-releasing neurons found in the lateral hypothalamus, supporting the popular autoimmune hypothesis for narcolepsy disease pathogenesis.

• #58 Narcolepsy: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1188433-overview

  Hypocretin deficiency is theorized to produce instability of sleep and wake states, thereby preventing the person from sustaining more continuous sleep or wakefulness. […] A large majority of patients with narcolepsy without cataplexy have normal CSF hypocretin levels. […] Investigators have identified low levels of histamine (a neurotransmitter that may help maintain wakefulness) in the CSF of patients with hypocretin-deficient narcolepsy. […] Hypocretin neurons, thought to be autoexcitatory, project from the lateral hypothalamus into these regions and serve to maintain wakefulness. A deficiency of hypocretin neurons may decrease the threshold for transitioning between wakefulness and sleep (so-called sleep state instability). This is a proposed explanation for the sleepiness and REM intrusion into wakefulness found in narcolepsy. […] Destruction of hypocretin-producing neurons appears to be an autoimmune process. […] A study in a mouse model found that the serum of narcolepsy patients was reactive with over 86% of hypocretin neurons from the mouse hypothalamus.

• #59 SciELO Brazil – Narcolepsy: an interface among neurology, immunology, sleep, and genetics Narcolepsy: an interface among neurology, immunology, sleep, and genetics

  https://www.scielo.br/j/anp/a/5NJMPDWsWcXCh7V5QRdbxmq/?lang=en

  Narcolepsy is a primary disorder of the central nervous system resulting from genetic, environmental, and immunological interactions defined as excessive daytime sleepiness plus cataplexy, hallucinations, sleep paralysis, and sleep fragmentation. […] The pathophysiology is not entirely known, but the interaction among genetic predisposition, environmental exposition, and immune component with consequent hypocretin-1 deficiency is the model to explain narcolepsy type I. […] The mechanism of narcolepsy type II is less understood. […] A new finding is the reduction in hypocretin-1 levels observed in patients with narcolepsy and cataplexy, attributed to the disappearance of producer cells in the hypothalamus. […] A higher prevalence of the HLA-DQB1*0602 allele and a low hypocretin concentration in the central nervous system characterize individuals with narcolepsy and cataplexy.

• #60 Narcolepsy—A Neuropathological Obscure Sleep Disorder: A Narrative Review of Current Literature

  https://www.mdpi.com/2076-3425/12/11/1473

  The exact pathological mechanism that causes the death of hypocretin neurons in most narcolepsy patients with cataplexy is unknown. […] The main common pathogenesis for narcolepsy, diabetes and stroke is hypocretin deficiency with a great number of pathophysiological mechanisms that are associated with those diseases.

• #61 A novel hypothesis for narcolepsy type 1 pathogenesis. | The Lundbeck Foundation

  https://lundbeckfonden.com/en/a-novel-hypothesis-narcolepsy-type-1-pathogenesis

  Narcolepsy type 1 is a sleep disorder hypothesised to be driven by an autoimmune destruction of hypocretin/orexin (HCRT) neurons in the lateral hypothalamus. […] This project explores the hypothesis that local processes in the hypothalamus induces a susceptible state allowing the autoimmune attack to happen. […] we hypothesise that the hypothalamic response to a peripheral infection initiates processes causing the HCRT neurons to become more vulnerable.

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