Lecture-24-2006

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1 Bi 1 “Drugs and the Brain” Lecture 24 Thursday, May 18, 2006 Revised 5/21/06 Bipolar Disease Parkinson’s Disease

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2 Bipolar Disease 1. Clinical description 2. Genetics 3. Possible causes 4. Heterozygote advantage? 5. Therapeutic approaches

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3 Bipolar disorder affects 1-1.5% of the population in most modern societies. Like depression, bipolar disorder is a mood disorder . It was formerly termed manic-depressive disorder , because patients have one or more manic or nearly manic episodes, alternating with major depressive episodes. 1st episode often in mid-20’s. Bipolar disorder often leads to suicide. 1. Clinical description, based on DSM-IV.

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4 From DSM-IV Summary description of a manic episode Manic Episode is defined by a distinct period during which there is an abnormally and persistently elevated, expansive, or irritable mood. This period of abnormal mood must last at least 1 week (or less if hospitalization is required). The mood disturbance must be accompanied by at least three additional symptoms from this list: -inflated self-esteem or grandiosity, -decreased need for sleep, -pressure of speech, -flight of ideas, -distractibility, -increased involvement in goal-directed activities or psychomotor agitation, and Excessive involvement in pleasurable activities with likelihood of painful consequences If the mood is irritable (rather than elevated or expansive), at least four of the above symptoms must be present . . . . The disturbance must be sufficiently severe to cause marked impairment in social or occupational functioning or to require hospitalization, or it is characterized by the presence of psychotic features . . . . .

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5 People with bipolar disorder are often fascinating in the early stages.

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6 No single gene causes bipolar disorder. Data for concordance among twins in bipolar disorder: “narrow” definition “broad” definition monozygotic (n = 55) 79% 97% monozygotic, reared apart (n = 12) 69% dizygotic (n = 52) 24% 38% 2. Genetics

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7 From Lecture 23: Polygenic the disease occurs only if several genotypes are present together Genetically Multifactorial several distinct genes (or sets of genotypes) can independently cause the disease Partially penetrant nongenetic factors may also be required, or the disease could be inherently stochastic Polygenic Genetically Multifactorial Partially Penetrant Three concepts used in describing complex diseases

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8 “Candidate genes” are investigated thoroughly using SNPs. No overwhelming candidate, yet. from Lecture 23:

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9 Each new advance in neuroscience has been tried out on bipolar disorder--as for schizophrenia. There is no satisfactory explanation yet. As for schizophrenia, present theories invoke: circuit properties early developmental events rather than individual neurotransmitter systems. 3. Possible causes of bipolar disease

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10 Touched With Fire : Manic Depressive Illness and the Artistic Temperament by Kay Redfield Jamison "This is meant to be an illustrative rather than a comprehensive list . . .Most of the writers, composers, and artists are American, British, European, Irish, or Russian; all are deceased . . . Many if not most of these writers, artists, and composers had other major problems as well, such as medical illnesses, alcoholism or drug addiction, or exceptionally difficult life circumstances. They are listed here as having suffered from a mood disorder because their mood symptoms predated their other conditions, because the nature and course of their mood and behavior symptoms were consistent with a diagnosis of an independently existing affective illness, and/or because their family histories of depression, manic-depressive illness, and suicide--coupled with their own symptoms--were sufficiently strong to warrant their inclusion." 4. Heterozygote advantage? autobiography: An Unquiet Mind by Kay Redfield Jamison

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11 from Jamison KEY: H= Asylum or psychiatric hospital; S= Suicide; SA = Suicide Attempt Writers Hans Christian Andersen, Honore de Balzac, James Barrie, William Faulkner (H), F. Scott Fitzgerald (H), Ernest Hemingway (H, S), Hermann Hesse (H, SA), Henrik Ibsen, Henry James, William James, Samuel Clemens (Mark Twain), Joseph Conrad (SA), Charles Dickens, Isak Dinesen (SA), Ralph Waldo Emerson, Herman Melville, Eugene O'Neill (H, SA), Mary Shelley, Robert Louis Stevenson, Leo Tolstoy, Tennessee Williams (H), Mary Wollstonecraft (SA), Virginia Woolf (H, S) Composers Hector Berlioz (SA), Anton Bruckner (H), George Frederic Handel, Gustav Holst, Charles Ives, Gustav Mahler, Modest Mussorgsky, Sergey Rachmaninoff, Giocchino Rossini, Robert Schumann (H, SA), Alexander Scriabin, Peter Tchaikovsky Nonclassical composers and musicians Irving Berlin (H), Noel Coward, Stephen Foster, Charles Mingus (H), Charles Parker (H, SA), Cole Porter (H) Poets William Blake, Robert Burns, George Gordon, Lord Byron, Samuel Taylor Coleridge, Hart Crane (S) , Emily Dickinson, T.S. Eliot (H), Oliver Goldsmith, Gerard Manley Hopkins, Victor Hugo, Samuel Johnson, John Keats, Vachel Lindsay (S), James Russell Lowell, Robert Lowell (H), Edna St. Vincent Millay (H), Boris Pasternak (H), Sylvia Plath (H, S), Edgar Allan Poe (SA), Ezra Pound (H), Anne Sexton (H, S), Percy Bysshe Shelley (SA), Alfred, Lord Tennyson, Dylan Thomas, Walt Whitman Artists Richard Dadd (H), Thomas Eakins, Paul Gauguin (SA), Vincent van Gogh (H, S), Ernst Ludwig Kirchner (H, S), Edward Lear, Michelangelo, Edvard Meunch (H), Georgia O'Keeffe (H), George Romney, Dante Gabriel Rossetti (SA)

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12 1887 1887-88 Vincent Van Gogh 1853-1890 750 paintings; 1600 drawings; 700 letters Life history: born and raised in the Netherlands Paris 1886-88 Arles 1888 (1st episode; cut off his own ear) hospitalized 1888-1890 Auvers-sur-Oise 3 months. Shot himself 7/27/1890 1886

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13 I should like to do portraits which will appear as revelations to people in a hundred years' time. -- Letter to his sister Wil, 3 June 1890 Early 1889 Dr. Gachet June 1890

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14 July 1890

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15

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16

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17 Surgery to remove large portions of the brain (1950’s-60’s) Electroconvulsive shock therapy (ECT). Now administered under anesthesia. Various electrode placements, pulse widths, and frequencies “In situations where medication, psychotherapy, and the combination of these interventions prove ineffective, or work too slowly to relieve severe symptoms such as psychosis (e.g., hallucinations, delusional thinking) or suicidality, electroconvulsive therapy (ECT) may be considered. ECT is a highly effective treatment for severe depressive episodes.“ -- National Institute of Mental Health Over a hundred theories have been offered to account for the efficacy of ECT. http://www.acnp.org/G4/GN401000108/CH106.html 5. Therapeutic approaches to bipolar disorder Surgical and electrical intervention

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18 Li + ion (Nestler Pp. 35--353) Therapeutic effects begin in ~ 5 d, require several wk. Li + is quite poisonous at higher doses. Valproic acid and other anticonvulsants These also require several wk for full effects. Therapeutic approaches to bipolar disorder Drugs (upper left-hand region of the periodic table, Little Alberts 2-7) The usual ionic suspects in Bi 1

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19 1. We don’t know, but there are now some good guesses. All ideas about Li + assume an intracellular target. Li + enters cells freely through several channels and ion-coupled transporters that normally serve for Na + . Intracellular concentrations of Li + are probably several mM. Most ideas about Li + involve enzyme inhibition. Most of the suspected enzymes manipulate high-energy phosphate bonds. How does Li + act? Three exemplar patients in the early days of Li +

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20 Two enzymes inhibited by Li + , explaining some pathological effects of Li + on development, and suggested to explain therapy for bipolar disease. kinase phosphorylated protein cAMP Ca 2+ intracellular messenger receptor t s q i G protein enzyme channel effector from Lecture 14: new theory of Li action Nucleus kinase phosphorylated transcription factor from Lecture 12: old theory of Li action Enzyme Ca 2+ in cytosol Ca 2+ in vesicles (not synaptic vesicles) Gq

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21 Parkinson’s Disease 1. Clinical description 2. Genetics 3. Possible causes; animal models 4. Heterozygote advantage (none known)? 5. Therapeutic approaches

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22 Neurodegenerative diseases: Parkinson’s (Nestler p 312: tremor at rest 3-5 Hz, “pill-rolling” slow movements, particularly when starting, short, rapid steps) but most Parkinson patients are either medicated or stimulated Alzheimer’s Amyotrophic lateral sclerosis “Lou Gehrig’s disease” various cerebellar ataxias, including polyglutamine proteins no muscle atrophy (no wasting) Michael J. Fox Poor movement

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23 Nestler Figure 8-6 from several previous lectures dopamine-producing neurons die in PD

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24 Only dopaminergic neurons express the cell membrane dopamine transporter. Antidepressants (“SSRIs” = serotonin- selective reuptake inhibitors): Prozac Zoloft Paxil Drugs of abuse: MDMA Attention-deficit disorder medications: Ritalin Dexedrine Drugs of abuse: Cocaine Amphetamine like several previous Lectures Na + -coupled cell membrane serotonin transporter Na + -coupled cell membrane dopamine transporter cytosol synaptic cleft

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25 1. Most cases are unexplained The “frozen addict”. An impurity in synthetic heroin. Taken up by the dopamine transporter (expressed only in dopaminergic cells). Kills cells. The influenza pandemic (worldwide epidemic) of 1918, which killed 20 million people. The flu specifically killed dopaminergic neurons in many people (“Awakenings”). Genetics: see next topic Smoking protects against PD. dopamine reactive: oxidative damage? Parkinsonism in people

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26 Familial Parkinson’s Disease Provides a Good Review of Bi 1 (~ 10% of patients) See next 4 slides Locus Chromosome location Gene or protein name Inheritance pattern PARK1 & PARK4 4q21 –q23 a -synuclein (Unknown function) AD PARK2 6q25.2-q27 parkin AR PARK3 2p13 Unknown AD, IP PARK5 4p14 UCH-L1 unclear PARK6 1p35-p36 PINK1 AR PARK7 1p36 DJ-1 AR PARK8 12p11.2 –q13.1 LRRK2 AD AD, autosomal dominant; AR, autosomal recessive; IP, incomplete penetrance

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27 a -synuclein has an unknown function; Mutant a -synuclein forms fibrils; But it does not contain triplet repeats

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28 Parkin is a ubiquitin protein ligase; UCH-L1 removes ubiquitin

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29 PINK1 is PTEN-Induced Putative Kinase 1 LRRK2 is Leucine-Rich Repeat Kinase 2

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30 DJ-1 has an unknown function

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31 3. Animal Models for Parkinson’s Disease: Drosophila that overexpress synuclein 1. The 4 dopaminergic neurons die preferentially! We don’t know why. 3. The flies show a “movement disorder” (2. The cells show dense structures like Lewy bodies)

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32 3. Animal Models for Parkinson’s Disease: Mice with hypersensitive nicotinic acetylcholine receptors an example of “Excitotoxicity” (next 6 slides, many reviewing previous Bi 1 material, Omitted to avoid duplicating P Patterson’s Watson Lecture 5/17/06))

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33 from Lecture 13 Primary Target Details (dates: ) morphine-heroin GPCR (G protein-coupled receptor) (Gi) m -opioid receptor 1985-1993 THC GPCR (Gi) cannabinoid receptor 1988 nicotine agonist-activated channel a 4 nicotinic acetylcholine receptor 1905-1995 cocaine cell membrane neurotransmitter transporter dopamine transporter 1980-1991 amphetamine vesicular & cell membrane neurotransmitter transporter vesicular monoamine transporter 1990 - 1995 ethanol ? K channel ? G protein-gated inward rectifier GIRK1/2 1993 - 1999 LSD GPCR (Gq) 5-HT2a receptor 1985-1990 caffeine enzyme cyclic AMP phosphodiesterase 1965 phencyclidine ligand-activated channel NMDA glutamate receptor 1965

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34 Knockout mice in Drugs and the Brain (Behavioral observations) 1. The m -opioid receptor m -opioid receptor knockouts specifically lack responses to certain types of pain. 2. The a 4 nicotinic receptor a 4 nicotinic receptor knockouts: (1) respond less to nicotine in pain tests (2) fail to self-administer nicotine. 3. The dopamine transporter Dopamine transporter knockout mice: (1) are hyperactive, (2) show less response to cocaine, (3) self-administer cocaine less 4. Cannabinoid receptors Cannabinoid receptor knockouts have little overt differences to normal mice. They don’t show these effects of THC and anandamide: (1) decreased pain responses and (2) decreased heart rate. --------------------------------------------------- 5. But NMDA receptor knockouts die at birth: an uninformative result from Lecture 13

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35 Labarca and colleagues (2001) hoped to make a strain of mice that were hypersensitive to nicotine. (This would also be useful for research on nicotine addiction). They knew, from site-directed mutagenesis in frog eggs, that mutating a single amino acid in the a 4 nicotinic receptor produced a “hypersensitive” receptor whose channel opened at lower concentrations of acetylcholine. from Lecture 7

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36 “Knock-in” mice: site-directed mutagenesis in an animal Gene (DNA) Hypothesis: Your favorite behavior event requires your favorite protein . . . Mutate just one amino acid in the gene of interest Replace the mouse gene with the altered gene Breed many identical mice study the animals . . . and a subtle change in the protein’s function will change that behavior.

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37 Neurons that make dopamine: “pleasure-reward” system highlighted Neurons that make dopamine express a 4 nicotinic acetylchioline receptors Nestler Figure 8-6 Rich in nicotinic receptors

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38 Some strains of these a 4 nicotinic receptor hypersensitive “knock-in” mice died, because they were born with very few dopaminergic neurons. The reason: The hypersensitive nicotinic receptor channels in the dopaminergic neurons were opened by the small circulating amounts of acetylcholine-like molecules in the body. This constant activation short-circuited the membrane potential; the cells could not pump ions quickly enough, and they died. Ser Immunostaining for the enzyme that makes dopamine from tyrosine WT mutant

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39 A better excitotoxic model for Parkinson’s disease: Activate the excitotoxic a 4 gene in the adult. This was accomplished by injecting a virus that eliminates an attenuating sequence from the excitotoxic a 4 gene in the adult mouse (Sigrid Schwarz, Johannes Schwarz, Oliver Dorigo, Arnie Berk). Fraction of Mutant Receptors Fraction of Hypersensitive Subunits a*/(a*+a) Viable adenovirus (HDA) cre lethal

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40 L9‘S, HDA-control 0 100 200 WT, HDA- control WT, HAD-cre L9‘S; HDA-cre Dopaminergic positive cells * WT-HDA-ctr L9‘S-HDA-cre Amphetamine Counts per 5 min 3 d 20-33 d post surgery min Tests of movement Important controls An adult mouse model for dopaminergic degeneration

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41 Cells have evolved elaborate processes for pumping out intracellular Na + and Ca 2+ . These gradients can be used in two ways: 1. The gradients are used for uphill “exchange” to control the concentrations of other small molecules. Transient, local increases in intracellular Ca 2+ and Na + concentrations can now be used for signaling inside cells! ……………….. But sustained increases in Ca 2+ and Na + permeability place a metabolic strain on cells and kill them. Another human example: stroke. 1. Cells release glutamate because the Na-coupled transporter loses its gradient. 2. Glutamate activates receptors, causes further depolarization. from Lecture 5: Excitotoxicity

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42 levodopa, “L-dopa” zwitterionic permeates into brain dopamine does not enter brain enzyme: decarboxylase Therapeutic Approaches from Lecture 2 . . . but L-dopa therapy eventually causes dyskinesia, a good example that GPCR pathways lead to gene activation. Another example of neutral drug permeation. In Parkinson’s Disease: most neurons that make dopamine die (Lecture 25) The challenge: replace the dopamine in the brain

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43 dopamine-producing neurons die in PD (Videos are restricted to Caltech: http://www.its.caltech.edu/~lester/Bi-1/Lecture-images/CIT-only/Anders.avi http://www.its.caltech.edu/~lester/Bi-1/Lecture-images/CIT-only/Walther.avi ). http://www.ninds.nih.gov/disorders/deep_brain_stimulation/deep_brain_stimulation.htm http://www.medtronic.com/activa/physician/implantable.html Before the videos were shot, stimulating electrodes were implanted surgically. Midway through each video, the stimulators were programmed via magnetic pulses, and stimulation started. Deep brain stimulation for Parkinson’s Disease Courtesy of Visiting Professor Johannes Schwarz (Leipzig) Nestler Figure 8-6 Tremor arises in a malfunctioning feedback loop: substantia nigra, striatum, and other structures. Implanted stimulating electrodes retune this loop.

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44 Classes of mutation: Triplet repeats (huntingtin) Nonsense mutation (stops the protein, “amber” codon, some CFTR mutants) Missense mutation (doesn’t stop the protein) (CFTR- D F508) Cell death: Protein trafficking and degradation Oxidative damage Excitotoxicity Deficits in development Migration Specification Summary of Mechanisms that may account for Neuroscience Diseases (Not taught in Bi 1)

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45 All I really need to know about life I learned in Bi 1 1. If you want a job done right, get a protein 2. Electrical circuits explain many processes 3. Most processes follow an exponential time course 4. Most processes end with a Gaussian distribution 5. Optics can show lots of details 6. Some drugs produce quasi-permanent changes in gene activation 7. Osmosis explains many processes 8. Many diseases are inherited , but some are polygenic. 9. Faulty protein degradation and excitotoxicity cause diseases.

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