Hypocretin (orexin) biology and the pathophysiology of narcolepsy with cataplexy

@article{Liblau2015HypocretinB,
  title={Hypocretin (orexin) biology and the pathophysiology of narcolepsy with cataplexy},
  author={Roland S. Liblau and Anne Vassalli and Ali Seifinejad and Mehdi Tafti},
  journal={The Lancet Neurology},
  year={2015},
  volume={14},
  pages={318-328}
}

Figures from this paper

CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice

It is demonstrated that cytotoxic CD8 T cells, but not Th1 CD4 cells, are able to target and destroy orexinergic neurons, and the potential role of CTLs as final effectors of the immunopathological process in narcolepsy is demonstrated.

Challenges in the development of therapeutics for narcolepsy

Narcolepsy — clinical spectrum, aetiopathophysiology, diagnosis and treatment

Current understanding of how genetic, environmental and immune-related factors contribute to a prominent orexin signalling deficiency in patients with NT1 are focused on, along with uncertainties concerning the ‘narcoleptic borderland’, including narcolepsy type 2 (NT2).

Recent advances in treatment for narcolepsy

Given the different clinical, biological and genetic profiles, narcolepsy may provide a nice example for developing personalized medicine in orphan diseases, that could ultimately aid in similar research and clinical efforts for other conditions.

Narcolepsy Type 1 as an Autoimmune Disorder: Evidence, and Implications for Pharmacological Treatment

Improved diagnostic tools, together with an increased understanding of the pathogenesis of NT1, may lead to new therapeutic and even preventive interventions, and Hcrt receptor agonists may be promising candidates to treat NT1.

Orexin or hypocretin?

Pharmacological management of narcolepsy with and without cataplexy

This review provides an overview of the temporal available treatment options for narcolepsy (type 1 and 2) in adults, including authorization status by regulatory agencies, as well as combination therapies.

Hypocretinergic interactions with the serotonergic system regulate REM sleep and cataplexy

It is shown that deleting the 5HT transporter in hypocretin knockout mice suppressed cataplexy while dramatically increasing REM sleep and both states and sleep need are regulated by the hypocretsinergic input into 5HT neurons.

Mapping the Hypocretin/Orexin Neuronal System: An Unexpectedly Productive Journey

This paper has had a surprisingly broad impact on neuroscience research, particularly since it was originally rejected by the Journal of Neuroscience, but the citation rate of this paper underscores the critical nature of such basic research.

CD4+ T-Cell Reactivity to Orexin/Hypocretin in Patients With Narcolepsy Type 1

A significant role of orexin/hcrt-specific T cells in narcolepsy type 1 patients could not be confirmed in this study because the heterogeneous reactivity pattern did not allow the identification of a preferential target epitope.
...

References

SHOWING 1-10 OF 138 REFERENCES

Narcolepsy: pathophysiology and pharmacology.

  • S. Nishino
  • Psychology, Medicine
    The Journal of clinical psychiatry
  • 2007
The major pathophysiology of human narcolepsy has recently been revealed by the extension of discoveries of nar colepsy genes in animal models, and hypocretin/orexin ligand deficiency has been shown in about 90% of humanNarcoleptic-cataplexy.

Elevated Tribbles homolog 2-specific antibody levels in narcolepsy patients.

Evidence is provided that reactive autoantibodies in human narcolepsy are an autoimmune disorder, provided by ELISA analysis of Serum of a patient showed specific immunoreactivity with over 86% of hypocretin neurons in the mouse hypothalamus.

Orexin neurons suppress narcolepsy via 2 distinct efferent pathways.

It is suggested that DR serotonergic and LC noradrenergic neurons play differential roles in orexin neuron-dependent regulation of sleep/wakefulness and highlight a pharmacogenetic approach for the amelioration of narcolepsy.

Hypothalamic immunopathology in anti-Ma-associated diencephalitis with narcolepsy-cataplexy.

The encephalitic process, responsible for narcolepsy-cataplexy and hypoc retin deficiency, reflects a CD8+ inflammatory-mediated response against hypocretin neurons.

Pattern of Hypocretin (Orexin) Soma and Axon Loss, and Gliosis, in Human Narcolepsy

It is reported that the percentage loss of Hcrt cells and percentage elevation of GFAP staining are variable across forebrain and brainstem nuclei, and are maximal in the posterior and tuberomammillary hypothalamic region, consistent with the hypotheses that the loss of hypocretin function in narcolepsy results from a cytotoxic or immunologically mediated attack focused on hypocrretin receptor 2.

Post-H1N1 narcolepsy-cataplexy.

The cause of narcolepsy is likely autoimmune based on the HLA association, association with T-cell receptor polymorphisms, and recently reported Tribbles 2 autoantibodies, and twin pairs are most often discordant (65% to 80%), and environmental triggers are suspected to play a critical role.

Dopaminergic regulation of sleep and cataplexy in a murine model of narcolepsy.

A role for the dopamine system in regulating sleep attacks and cataplexy in a murine model of narcolepsy is shown and it is found that catapLexy is modulated by a D2-like receptor mechanism, whereas dopamine modulates sleep attacks by aD1-like receptors mechanism.
...