Transcript Lecture-24-2006

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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Bipolar Disease
1. Clinical description
2. Genetics
3. Possible causes
4. Heterozygote advantage?
5. Therapeutic approaches
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1. Clinical description, based on DSM-IV.
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.
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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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People with bipolar disorder are often fascinating in the early stages.
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2. Genetics
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%
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From Lecture 23:
Three concepts used in describing complex diseases
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
Genetically
Multifactorial
Polygenic
Partially
Penetrant
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“Candidate genes” are investigated thoroughly using SNPs.
No overwhelming candidate, yet.
Hunting for Genes with SNPs
from Lecture 23:
Controls
sequence A1 20%
Schizophrenics
20%
sequence A1
Locus A
Chomosome 12
sequence A2
no linkage to
schizophrenia
sequence A2
80%
80%
40%
70%
Locus B
Chomosome 1
sequence B1
sequence B1
may be near a gene
that helps to cause
schizophrenia
sequence B2
sequence B2
60%
30%
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3. Possible causes of bipolar disease
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.
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4. Heterozygote advantage?
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."
autobiography:
An Unquiet Mind
by Kay Redfield Jamison
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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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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
1887
1887-88
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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
Dr. Gachet
June 1890
Early 1889
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July 1890
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5. Therapeutic approaches to bipolar disorder
Surgical and electrical intervention
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
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Therapeutic approaches to bipolar disorder
Drugs
(upper left-hand region
of the periodic table,
Little Alberts 2-7)
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.
The usual ionic suspects in Bi 1
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Three exemplar patients in the early days of Li+
How does Li+ act?
1. We don’t know, but there are now some good guesses.
2.
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.
3.
Most ideas about Li+ involve enzyme inhibition.
Most of the suspected enzymes manipulate high-energy phosphate bonds.
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from Lecture 12: old theory of Li action
Two enzymes inhibited by Li+,
explaining some pathological
effects of Li+ on development,
and suggested to explain
therapy for bipolar disease.
Gq
Enzyme
Ca2+
in vesicles
(not synaptic vesicles)
receptor
Ca2+
in cytosol
G protein
i q s t
effector
channel enzyme
from Lecture 14: new theory of Li action
kinase
intracellular
messenger
Ca2+ cAMP
kinase
phosphorylated
transcription factor
Nucleus
phosphorylated
protein
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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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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
no muscle atrophy (no wasting)
Amyotrophic lateral sclerosis
“Lou Gehrig’s disease”
Poor movement
various cerebellar ataxias, including
polyglutamine proteins
Michael J. Fox
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from several previous lectures
dopamine-producing
neurons die in PD
Nestler Figure 8-6
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like several previous Lectures
Only dopaminergic neurons express the cell membrane dopamine transporter.
Antidepressants
(“SSRIs” = serotoninselective
reuptake inhibitors):
Prozac
Zoloft
Paxil
Attention-deficit
disorder medications:
Ritalin
Dexedrine
Drugs of abuse:
Cocaine
Amphetamine
Drugs of abuse:
MDMA
Na+-coupled
cell membrane
serotonin
transporter
Na+-coupled
cell membrane
dopamine
transporter
cytosol
NH 3+
HO
N
H
synaptic
cleft
HO
HO
H2
C
C
H2
NH 3+
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dopamine
Parkinsonism in people
HO
H2
C
C
H2
NH 3+
HO
1. Most cases are unexplained
reactive:
oxidative damage?
2.
The “frozen addict”. An impurity in synthetic heroin.
Taken up by the dopamine transporter (expressed only in dopaminergic cells).
Kills cells.
3.
The influenza pandemic (worldwide epidemic) of 1918, which killed 20 million
people.
The flu specifically killed dopaminergic neurons in many people (“Awakenings”).
4.
Genetics: see next topic
5.
Smoking protects against PD.
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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
AD
(Unknown function)
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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a-synuclein has an unknown function;
Mutant a-synuclein forms fibrils;
But it does not contain triplet repeats
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Parkin is a ubiquitin protein ligase;
UCH-L1 removes ubiquitin
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PINK1 is PTEN-Induced Putative Kinase 1
LRRK2 is Leucine-Rich Repeat Kinase 2
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DJ-1 has an unknown function
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3. Animal Models for Parkinson’s Disease:
Drosophila that overexpress synuclein
1. The 4 dopaminergic neurons
die preferentially!
We don’t know why.
(2. The cells show dense structures
like Lewy bodies)
3. The flies show a
“movement disorder”
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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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Excitotoxicity
from Lecture 5:
Cells have evolved elaborate processes for pumping out intracellular Na+ and
Ca2+.
These gradients can be used in two ways:
1. The gradients are used for uphill “exchange” to control the concentrations of
other small molecules.
2.
Transient, local increases in intracellular Ca2+ and Na+ concentrations can
now be used for signaling inside cells!
………………..
But sustained increases in Ca2+ 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.
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Therapeutic Approaches
from Lecture 2
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
HO
H2
C
NH 3
CO 2
HO
levodopa, “L-dopa”
zwitterionic
permeates into brain
+
enzyme:
decarboxylase
HO
-
H2
C
C
H2
NH 3+
HO
dopamine
does not enter brain
. . . but L-dopa therapy eventually causes dyskinesia,
a good example that GPCR pathways lead to gene activation.
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Deep brain stimulation for Parkinson’s Disease
Courtesy of Visiting Professor Johannes Schwarz (Leipzig)
Tremor arises in a
malfunctioning
feedback loop:
substantia nigra,
striatum, and other
structures.
dopamine-producing
neurons die in PD
Implanted stimulating
electrodes retune this
loop.
Nestler Figure 8-6
(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
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started.
Summary of Mechanisms that may account
for Neuroscience Diseases
Classes of mutation:
Triplet repeats (huntingtin)
Nonsense mutation (stops the protein, “amber” codon,
some CFTR mutants)
Missense mutation (doesn’t stop the protein)
(CFTR-DF508)
Cell death:
Protein trafficking and degradation
Oxidative damage
Excitotoxicity
Deficits in development
Migration
Specification
(Not taught in Bi 1)
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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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