Transcript Orexin Autoimmunity

PHM142 Fall 2016
Coordinator: Dr. Jeffrey Henderson
Instructor: Dr. David Hampson
Narcolepsy and
Orexin
Autoimmunity
Kunal Bhatt, Bao Thi Nguyen, Roshni Patel, Mamun
Patwary
November 8, 2016
Outline
● Orexin?
○ What is it?
○ Where is it?
○ What are the receptors?
● Narcolepsy and how it is related to orexin
● Orexin autoimmunity
● Treatment for Narcolepsy
Orexin: What is it?
● Also known as Hypocretin (HCRT)
● Excitatory neuropeptide hormone produced in the
hypothalamus
● Involved in:
○ Food consumption
■Prominent in LHA
○ Energy homeostasis
○ Arousal
Orexin: Where is it?
Orexin: Receptors
Two orexin receptors have been identified to date (OX1R and OX2R)
● G protein with a proposed seven transmembrane
● Receptors display distinct pattern of interaction with orexins
● Orexin-A high affinity for BOTH receptors; Orexin-B 10-fold higher affinity at
OX2R than OX1R
● OX1R is 100-fold selective for OX-A, OX2R has equal affinity for BOTH
Orexin: Receptors
●
Two subtypes of receptors account for different functions of Orexin
●
OX2R deficient mice - fragmented wakefulness characteristic of narcolepsy
●
OX1R knockout mice - only show mild sleep disorder
●
Double knockout mice - severe deficit in sleep wake cycle
Narcolepsy: Chronic Sleep Disorder
High tendency to fall asleep during the daytime
Nocturnal sleep fragmentation
Rapid Eye Movement (REM) sleep
Cataplexy
Narcolepsy: Other Potential Symptoms
Hypnagogic hallucinations - realistic dreams you experience as you are about to
fall asleep
Sleep paralysis - inability to move immediately upon awakening
Narcolepsy: Causes
● Loss of orexin (hypocretin)-producing neurons in the hypothalamus
● Mutations/Deletions in the HCRT (Orexin A and B), HCRTR1 (OX1R) or
HCRTR2 (OX2R) genes (not common in narcoleptics)
● Autoimmune Basis
Narcolepsy: Autoimmunity
Hypothesized that narcolepsy caused by autoimmune destruction of orexin
neurons and receptors
Has not been proven despite vast amounts of research since the 80’s
Some correlations that maintain idea of autoimmune involvement
Specific orexin cell loss in CSF of postmortem analysis of narcolepsy patients but other cells
were still intact
Ongoing research and proposed mechanisms in hopes to find a target to treat
Narcolepsy: Autoimmunity Proposed Mechanism
HLA genes code for MHC I and II
MCH present antigens to T cells for targeting
and destruction
Autoimmune disease: host antigens presented
to T cells
Orexin tissue seen as foreign, and
therefore targeted
(Kornum et al., 2011)
99% of patients carry specific HLA
genes associated with narcolepsy
(HLA DQB1*06:02 and HLA
DQA1*01:02)
Narcolepsy: Treatment
No treatment of cause, only treatment of symptoms
Sleepiness
Modinafil and amphetamine-like drug to promote wakefulness
Cataplexy
Tricyclic antidepressants and selective serotonin reuptake inhibitors
Suppress REM sleep during the day
Example: Imipramine
Summary Page
Orexin?
Excitatory neuropeptide hormone produced in the hypothalamus
Involved in:
Food consumption
Sleep
Energy homeostasis
Arousal
Orexin has two forms (Orexin A and Orexin B) and two receptors (OX1R and OX2R)
Orexin-A higher affinity for BOTH receptors; Orexin-B higher affinity for OX2R
OX2R deficiency results in narcoleptic phenotype
Summary Page
Narcolepsy and how related to orexin
Narcolepsy - characterized by excessive sleepiness during the daytime, fragmented sleep, REM
sleep, and cataplexy
Caused by damage to orexin-producing neurons in the hypothalamus, mutations in the orexin
genes and of their receptors, or potentially an autoimmune response to the peptides and
receptors
Orexin autoimmunity
Nothing proven yet despite a plethora of studies
Drugs for Narcolepsy and how they work
Sleepiness promotes wakefulness
References
Boss, C., & Roch, C. (2015, May 15). Recent trends in orexin research—2010 to 2015. Bioorganic & Medicinal Chemistry Letters, 25(15), 28752887. doi:10.1016/j.bmcl.2015.05.012
Ebrahim, I. O., Howard, R. S., Kopelman, M. D., & Sharief, K. M. (2002, May). The hypocretin/orexin system. J R Soc Med, 95(5), 227-230. Retrieved
November 7, 2016.
Kornum, B. R., Faraco, J., & Mignot, E. (2011, December). Narcolepsy with hypocretin/orexin deficiency, infections and autoimmunity of the brain.
Current Opinion in Neurobiology, 21(6), 897-903. doi:10.1016/j.conb.2011.09.003
Lecea, L. D., & Huerta, R. (2014, February 12). Hypocretin (orexin) regulation of sleep-to-wake transitions. Frontiers in Pharmacology Front.
Pharmacol., 5. doi:10.3389/fphar.2014.00016
Liblau, R. S., Vassalli, A., Seifinejad, A., & Tafti, M. (2015, March). Hypocretin (orexin) biology and the pathophysiology of narcolepsy with cataplexy.
The Lancet Neurology, 14(3), 318-328. doi:10.1016/s1474-4422(14)70218-2
Medications: Narcolepsy Network. Retrieved November 08, 2016, from http://narcolepsynetwork.org/about-narcolepsy/treatment/narcolepsymedications/
Tsujino, N., & Sakurai, T. (2009). Orexin/hypocretin: a neuropeptide at the interface of sleep, energy homeostasis, and reward system.
Pharmacological reviews, 61(2), 162-176.