1.  Relationship Between Parkinson’s Disease and Narcolepsy Eunjung Lee Jacinthe Chong Wenjia Dai Zipeng Shang PHM142 Fall 2014 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson

2. Outline  What is Parkinson’s Disease and Narcolepsy?  Symptoms and Relationship  Mechanisms of Dopamine and Hypocretin  PD Extrapyramidal System  Hypocretin synthesis and action  Demographics and Relationship  Treatment  Narcolepsy and PD drugs

3. What is Narcolepsy?  Chronic neurological disease characterized by:  Excessive Daytime Sleepiness (EDS)  Cataplexy (muscle weakness)  Abnormal REM sleep  Linked to the peptide hypocretin (orexin) deficiency in the cerebrospinal fluid

4. What is Parkinson’s Disease?  Progressive neurodegenerative disease  Most commonly known for motor symptoms  Bradykinesia, rigidity, resting tremor  Also accompanied with non-motor symptoms  Sleep disorders  Mood disorders and cognitive deficits  Can have sleep attacks that resemble narcoleptic sleep attacks

5. How are they linked?  Share symptoms of sleep disorders  Degeneration of cells that produce hypocretin in PD  Lower hypocretin levels in narcolepsy  Many patients with advanced PD also display most symptoms of narcolepsy

6.  Mechanism of Dopamine and Hypocretin

7. Parkinson’s Disease: Extrapyramidal System

8. Synthesis of Dopamine and Norepinephrine

9. Narcolepsy

10. Hypothalamus and Hypocretin

11. Autoimmunity  Suspected autoimmune response killing hypocretin-secreting neurons  Polymorphisms in HLA gene encoding for HLA proteins and MHC proteins  Antigens presented on cell surface of neurons  For narcolepsy, variant in TCRA gene as well, encoding for receptor on T-cells  Increased likelihood of T-cells producing autoimmune response  Dopaminergic neurons in substantia nigra also present MHC-1 proteins, targeted by T-cells in Parkinson’s Disease

12.  Demographics and Relationship between Narcolepsy and Parkinson’s Disease

13. Normal level of dopamine ↓ level of dopamine Age of onset usually between 35-45 Age of onset mostly between 50-60 150,000 patients in America 3 million patients worldwide 1 million patients in US 20 million patients worldwide ↑ in Japanese people (1/600) And ↓ Israel and US ↑ rate of occurrence in whites ↓ African-Americans and Asians ↓ level of hypocretin Slightly higher rate of incidence in men - Daytime sleep attacks - Nocturnal insomnia - REM sleep disorder - Hallucinations - Depression

15. Does one cause the other?  Daytime sleepiness in 76% of PD patients  75% of patients with REM sleep behavior disorder developed Parkinsonian conditions  However no direct evidence for narcolepsy causing Parkinson’s Disease

16.  Drug Therapy for Narcolepsy and Parkinson’s Disease

17. Narcolepsy: Symptoms & Treatments Excessive Daytime Sleepiness and Sleep Attacks  Amphetamines  Methylphenidate  Modafinil  Sodium oxybate Cataplexy Sodium oxybate Antidressants

18. Narcolepsy: Symptoms & Treatments Excessive Daytime Sleepiness and Sleep Attacks  Amphetamines  Methylphenidate  Modafinil  Sodium oxybate – Central nervous system stimulants – Early treatment for EDS and sleep attacks – Patients can develop tolerance – Not commonly prescribed since modafinil came onto the market

19. Narcolepsy: Symptoms & Treatments Excessive Daytime Sleepiness and Sleep Attacks  Amphetamines  Methylphenidate  Modafinil  Sodium oxybate – Central nervous system stimulants – Most commonly prescribed for EDS in narcolepsy – Side effects: headache and nausea

20. Narcolepsy: Symptoms & Treatments Excessive Daytime Sleepiness and Sleep Attacks Cataplexy Sodium oxybate Antidressants – CNS depressant – Can treat both EDS and cataplexy – Contraindicated for sedative hypnotic agents and alcohol

21. Treatment of Motor Symptoms of Parkinson’s Disease  Levodopa  Converted into dopamine in presynaptic dopaminergic neurons  Effects enhanced with DOPA decarboxylase inhibitors such as carbidopa  Most effective therapy, but associated with motor complications  Dopamine agonists  Modest efficacy in early stages of PD  E.g. pramipexole, ropininirole, pergolide (removed from market)  Anticholinergics  Not recommended due to side effects

22. Side effects of PD drugs  Sleep attacks associated with dopaminergic drugs.  Stimulating D3 receptors increases incidence of sleep attacks  Due to reduction of hypocretin levels in the CSF.  Replacing pramipexole with pergolide resolved sleep attacks and increased hypocretin levels in the CSF.

23. Narcolepsy Drugs for the Treatment of Sleep Disorders in PD?  Modafinil  3 studies, conflicting results  Insufficient evidence for efficacy in treatment of EDS in PD patients.  Sodium oxybate  One study showed promising results.  Insufficient evidence

24. Possible Future Therapies?  Hypocretin  BBB is impermeable  Hypocretin agonists  None reported yet  Hypocretin systems have been used to treat sleep disorders  Hypocretin receptor antagonist for treatment of insomnia

25. References  Asai, H., Hirano, M., Furiya, Y., Udaka, F., Morikawa, M., Kanbayashi, T., Shimizu, T., and Ueno, S. (2009). Clin Neurol Neurosurg, 111(4), 341-344. doi: 10.1016/j.clineuro.2008.11.007.  Billiard, M. (2008). Narcolepsy: current treatment options and future approaches. Neuropsychiatr Dis Treat, 4(3), 557-566.  Cebrián C, Zucca FA, Mauri P, Steinbeck JA, Studer L, Scherzer CR, Kanter E, Budhu S, Mandelbaum J, Vonsattel JP, Zecca L, Loike JD, Sulzer D (2014) MHC-I expression renders catecholaminergic neurons susceptible to T-cell-mediated degeneration. Nat Comms 5:3633. DOI: 10.1038/ncomms4633 http://dx.doi.org/10.1038/ncomms4633  e-CPS [Internet]. Ottawa (ON): Canadian Pharmacists Association; c2014 [cited 2014 Oct 9]. Available from: http://www.e- cps.ca. Also available in paper copy from the publisher.  Gray Jean, editor. e-Therapeutics + [Internet]. Ottawa (ON): Canadian Pharmacists Association; c2014 [cited 2014 Oct 9]. Available from: http://www.e-therapeutics.ca.myaccess.library.utoronto.ca Also available in paper copy from the publisher.  Haq, I.Z.; Naidu, Y.; Reddy, P. & Chaudhuri, K.R. (2010). Narcolepsy in Parkinson’s disease. Expert Review of Neurotherapeutics, 10 (6), 879-884. doi: 10.1586/ern.10.5610.1586/ern.10.5  Hungs, M. & Mignot, E. (2001). Hypocretin/orexin, sleep and narcolepsy. BioEssays : news and reviews in molecular, cellular and developmental biology, 23 (5), 379-408. doi: 10.1002/bies.105810.1002/bies.1058  Jankovic, J., & Aguilar L.G. (2008). Current approaches to the treatment of Parkinson’s disease. Neuropsychiatr Dis Treat, 4(4): 743-757.  Kobayashi, K. (2001). Role of catecholamine signaling in brain and nervous system functions: new insights from mouse molecular genetic study. Journal of Investigative Dermatology Symposium Proceedings, 6 (1), 115-121. doi: 10.1046/j.0022- 202x.2001.00011.x10.1046/j.0022- 202x.2001.00011.x

26.  Kornum, B. R., Faraco, J., & Mignot, E. (2011). Narcolepsy with hypocretin/orexin deficiency, infections and autoimmunity of the brain. Current Opinion in Neurobiology, 21 (6), 897-903.  Mieda, M., and Sakurai, T. (2013). Orexin (hypocretin) receptor agonists and antagonists for treatment of sleep disorders. CNS Drugs, 27(2), 83-90. doi: 10.1007/s40263-012-0036-8.  National Sleep Foundation. (2014). Parkinson's Disease and Sleep. Retrieved October 18, 2014 from http://sleepfoundation.org/sleep-topics/parkinsons-disease-and-sleep http://sleepfoundation.org/sleep-topics/parkinsons-disease-and-sleep  Nishino, S. (2007). Clinical And Neurobiological Aspects Of Narcolepsy. Sleep Medicine, 8 (4), 373-399.  Ondo, W.G., Perkins, T., Swick, T., Hull, K.L., Jimenez, J.E., Garris, T.S., and Pardi, D. (2008). Sodium oxybate for excessive daytime sleepiness in parkinson disease. Arch Neurol, 65(10), 1337-1340. doi: 10.1001/archneur.65.10.1337.  Seppi, K., Weintraub, D., Coelho, M., Perez-Lloret, S., Fox, S. H., Katzenschlager, R., Hametner, E.-M., Poewe, W., Rascol, O., Goetz, C. G. and Sampaio, C. (2011). The Movement Disorder Society Evidence- Based Medicine Review Update: Treatments for the non-motor symptoms of Parkinson's disease. Mov Disord, 26: S42–S80. doi: 10.1002/mds.23884  Swick, T. J. (2012). Parkinson's Disease and Sleep/Wake Disturbances. Parkinson's Disease, 2012, 1-14.  UCLA. (2007, May 4). Link Between Parkinson's And Narcolepsy Discovered. ScienceDaily. Retrieved October 20, 2014 from www.sciencedaily.com/releases/2007/05/070504122134.htmwww.sciencedaily.com/releases/2007/05/070504122134.htm

27. Summary Overview:  Parkinson’s Disease: progressive neurodegenerative disease well known for motor symptoms but also include non-motor symptoms like sleep disorders  Narcolepsy: chronic neurological disease characterized by excessive daytime sleepiness, cataplexy, and abnormal REM sleep behavior Relationship:  Both diseases have a decrease in hypocretin levels (or neurons secreting hypocretin) – believed to be responsible for sleep symptoms in both diseases  Polymorphisms in HLA gene lead to antigen presenting neurons in the brain, becoming a target for T-cells to attack and destroy neurons that regulate the sleep-wake cycle  No evidence to show one causing the other but share common sleep disorder symptoms that can potentially be treated with same classes of drugs Function of Hypocretin:  To integrate information from different systems in the body (i.e. the circadian cycle) in order to determine or promote wakefulness  Stimulates catecholaminergic (dopamine, norepinephrine and epinephrine) pathways in the brain stabilizing wakefulness or sleep Drugs:  Modafinil and Sodium oxybate are used to treat narcolepsy while Levodopa and dopamine agonists are used to treat PD  Hypocretin agonists are a possible future therapy for narcolepsy and sleep disorder symptoms in PD