Download CNS_Part2

Introduction to the CNS
• http://biosingularity.wordpress.com/2007/0
5/07/neurons-and-how-they-workanimation
• Link
• Link
• Link
• Link
• http://www.healthscout.com/animation/68/
10/main.html
Neurotransmitters found in the
CNS
HO
O
Me
Me
HO
NH2
HO
NH2
(Small Peptides)
N
H3C
O
Me
HO
HO
Acetylcholine
Endorphins
Dopamine
Noradrenaline
O
NH2
HO
HN
HO
NH2
N
H
Serotonin
(5-Hydroxytryptamine)
5-HT
N
Histamine
O
NH2
O
gamma-aminobutyric acid
(GABA)
HO
OH
NH2
Glutamate
•
•
•
•
Link: Acetycholine
Link: Noradrenaline
Link: Noradrenaline
Link: Glutamate
It’s a balancing act!!
• Current models of CNS diseases often
attribute the physiological cause of the
disease to an imbalance of
neurotransmitters.
Acetylcholine
O
Me
Me
N
H3C
O
Me
• All ACh receptors in the CNS are nicotinergic. The
stimulating effect of nicotine is due to the
influence of these receptors.
Nicotine
Acetylcholine
O
Me
Me
N
H3C
O
Me
• Acetylcholine is transmitted within cholinergic
pathways that are concentrated mainly in specific
regions of the brainstem and are thought to be
involved in cognitive functions, especially
memory. Severe damage to these pathways is
the probable cause of Alzheimer’s disease.
Acetylcholine
O
Me
Me
N
H3C
O
Me
• http://highered.mcgrawhill.com/sites/0072495855/student_view
0/chapter14/animation__chemical_syna
pse__quiz_1_.html
• See Patrick Chapter 19, pt. 1
Alzheimer’s Disease
• Alzheimer’s Disease (AD) is characterized
by an increasing impairment of cognitive
abilities.
• AD is the most common cause of senile
dementia (dementia = decline in cognitive
abilities beyond what is expected by
normal aging)
Stages of Alzheimer’s
Disease
•
•
•
•
Predementia
Early dementia
Moderate dementia
Advanced
Stages of Alzheimer’s Disease
• Predementia: Short term memory loss and
inability to acquire new information
Stages of Alzheimer’s Disease
• Early dementia: Shrinking vocabulary and
increased problems with complex tasks
Stages of Alzheimer’s Disease
• Moderate dementia: Extreme difficulty finding words.
Long term memory is affected.
Stages of Alzheimer’s Disease
• Advanced: Human behavior becomes automatic.
Nearly all language is lost. Patients cannot perform
even the most simple tasks, including feeding
oneself. Death frequently results from pneumonia
or infection (approx. 6-12 yrs after onset).
Causes?
• Little is known about the causes of AD
• There has been some success in linking AD
to certain genes.
Cures?
• There is no cure for AD
• There are a few drugs available that can
help moderate some of the symptoms
• There is no evidence that these drugs
slow the progression of the disease
• http://www.healthscout.com/animation/68/
7/main.html
Physiology of AD
• Amyloid plaques interfere with the normal transmission
of nerve impulses within the brain and destroy other
brain cells located in their same vicinity.
• Neurofibrillary tangles “cause a collapse of the
molecular skeletons that neurons rely on not just for
structure but also for the transport of nutrients from the
body of the cell to the…axons. This process not only
disrupts the ability of neurons to communicate with one
another but also eventually causes them to ‘starve’ to
death as vital nutrients cease to get distributed
throughout the entire cell.”
• Amyloid precursor protein (APP) is a large nerve-protecting
protein that is the source of beta amyloid.
• In Alzheimer's certain enzymes, particularly those called
gamma-secretases, snip APP into beta amyloid pieces. This
process is controlled by factors called presenilin proteins.
(Genetic abnormalities that affect either APP or presenilin
proteins occur in some inherited cases of early-onset
Alzheimer's.)
• High levels of beta amyloid are associated with
reduced levels of the neurotransmitter acetylcholine.
(Neurotransmitters are chemical messengers in the
brain.) Acetylcholine is part of the cholinergic system,
which is essential for memory and learning and is
progressively destroyed in Alzheimer's disease.
Acetylcholine and
Acetylcholinesterase
• Link
• Link
• Link
Drugs to Treat AD:
Inhibitors of Acetylcholinesterase
O
N
MeO
Donepezil
(Aricept)
MeO
Galantamine
(Razadyne, Razadyne ER,
Reminyl, Nivalin)
O
N
O
N
Rivastigmine
(Exelon)
Donepezil
Donepezil is a reversible inhibitor of acetylcholinesterase
Has an oral bioavailability of 100% and easily crosses the blood brain barrier
Studies show modest benefits in cognition and behavior.
Galantamine
Galantamine is a reversible inhibitor of acetylcholinesterase
Has an oral bioavailability of 80 - 100% and easily crosses the blood brain barrier
Rivastigmine
Rivastigmine is a ‘pseudo-irreversible’ inhibitor of acetycholinesterase
Upon reaction with the active site serine, a carbamate (urethane) is formed
that is chemically more resilient toward hydrolysis than an ester linkage.
Drugs to Treat AD:
NMDA receptor antagonist
Memantine
(Axura® and Akatinol® Namenda® Ebixa® and Abixa®
Memox®)
NMDA = N-methyl-D-aspartate
This drug interferes with the action of the neurotransmitter glutamate in the
CNS
Memantidine
Link
Link
H3C
NH2
O
OH
NH
O
O
OH
HO
O
L-Glutamic Acid
HO
N-Methyl-D-aspartate
Memantine
(NMDA)
• Memantine is a low affinity uncompetitive antagonist of the glutaminergic
NMDA receptors.
• By binding and inhibiting these receptors, Memantine is believed to
alleviate a process known as excitotoxicity, which is believed to be
involved in Alzheimer’s Disease.
Norepinephrine
HO
HO
NH2
HO
• Most cell bodies of noradrenergic neurons are in
the locus coeruleus, a center in the brain stem.
These neurons send their axons to the limbic
system (appetite inhibition), the subcortical
centers and the cerebral cortex (arousal).
Norepinephrine
HO
HO
NH2
HO
• Noradrenaline is classed as a monoamine
neurotransmitter and noradrenergic neuron are
found in the locus coeruleus, the pons and the
reticular formation in the brain. These neurons
provide projections to the cortex, hippocampus,
thalamus and midbrain.
Norepinephrine
HO
HO
NH2
HO
• The release of noradrenaline tends to
increase the level of excitatory activity within
the brain, and noradrenergic pathways are
thought to be particularly involved in the
control of functions such as attention and
arousal.
Norepinephrine
• Link
Attention Deficit Hyperactivity
Disorder (ADHD)
Attention-Deficit/Hyperactivity Disorder (ADHD) (sometimes
referred to as ADD when only inattentiveness and
distractibility are problematic) is a neurological disorder initially
appearing in childhood which manifests itself with symptoms
such as hyperactivity, forgetfulness, poor impulse control, and
distractibility.
Research suggests that ADHD arises from a combination of
various genes, many of which affect dopamine transporters.
Additionally, SPECT scans found people with ADHD to have
reduced blood circulation, and a significantly higher
concentration of dopamine transporters in the striatum which
is in charge of planning ahead.
Analogs of noradrenaline are
used to treat ADHD
• Norepinephrine is believed to play a big
role in attention and focus
• Individuals with ADHD are often
prescribed stimulants which resemble
norepinephrine structurally
• Alternatively, ADHD patients may be
prescribed norepinephrine reuptake
inhibitors
Treatment of ADHD
Noradrenaline
(natural neurotransmitter)
Amphetamine
(Adderall)
Atomoxetine (Strattera)
norepinephrine reuptake inhibitor
Methylphenidate
(Ritalin)
Locus ceruleus
• The Locus ceruleus, also spelled locus caeruleus or
locus coeruleus (Latin for 'the blue spot'), is a
nucleus in the brain stem responsible for
physiological responses to stress and panic.
• The locus ceruleus (or "LC") is located within the dorsal
wall of the upper pons, under the cerebellum in the
caudal midbrain, surrounded by the fourth ventricle.
• This nucleus is one of the main sources of
norepinephrine in the brain, and is composed of mostly
medium-sized neurons.
• Melanin granules inside the LC contribute to its blue
color; it is thereby also known as the nucleus
pigmentosus pontis, meaning "heavily pigmented
nucleus of the pons".
Locus ceruleus
hippocampus
Thalamus
HO
NH2
HO
Dopamine
• Dopamine is also classed as a monoamine
neurotransmitter and is concentrated in very specific
groups of neurons collectively called the basal
ganglia. Dopaminergic neurons are widely
distributed throughout the brain in three important
dopamine systems (pathways): the nigrostriatal,
mesocorticolimbic, and the tuberohypophyseal
pathways. A decreased brain dopamine
concentration is a contributing factor in Parkinsonﾕs
disease, while an increase in dopamine
concentration has a role in the development of
schizophrenia.
Biosynthesis of Epinephrine
CO2H
HO
HO
Tyrosine
NH2
hydroxylase
HO
L-Tyrosine
NH2
CO2H
HO
Dopa
Decarboxylase
OH
OH
HO
-hydroxylase
HO
Norepinephrine
(Noradrenaline)
HO
Dopamine
Levodopa
(L-DOPA)
Dopamine
NH2
NH2
HO
NHMe
N-methyl transferase
(in Adrenal medulla)
HO
Epinephrine
(Adrenaline)
HO
NH2
HO
Dopamine
•
•
•
•
•
Although dopamine is synthesized by only several hundred thousand cells, it fulfils
an exceedingly important role in the higher parts of the CNS.
These dopaminergic neurons can be divided into three subgroups with different
functions.
The first group regulates movements: a deficit of dopamine in this (nigrostriatal)
system causes Parkinson's disease which is characterized by trembling, stiffness
and other motor disorders, while in the later phases dementia can also set in.
The second group, the mesolimbic, has a function in regulating emotional
behavior.
The third group, the mesocortical, projects only to the prefrontal cortex. This area
of cortex is involved with various cognitive functions, memory, behavioral planning
and abstract thinking, as well as in emotional aspects, especially in relation to
stress. The earlier mentioned reward system is part of this last system. The
nucleus accumbens is an important intermediate station here. Disorders in the
latter two systems are associated with schizophrenia.
Dopamine and Parkinson’s Disease
• In patients with Parkinson’s disease, there
is disease or degeneration of the so-called
basal ganglia in the deeper grey matter of
the brain, particularly of that part known as
the substantia nigra.
Parkinson’s Disease
• The substantia nigra, which connects with the striatum (caudate
nucleus and globus pallidus), contains black pigmented cells and, in
normal individuals, produces a number of chemical transmitters, the
most important of which is dopamine.
• Transmitters are chemicals that transmit, that is, pass on, a
message from one cell to the next, either stimulating or inhibiting the
function concerned; it is like electricity being the transmitter of sound
waves in the radio. Other transmitters include serotonin,
somatostatin and noradrenaline.
• In Parkinson’s disease, the basal ganglia cells produce less
dopamine, which is needed to transmit vital messages to other parts
of the brain, and to the spinal cord, nerves and muscles.
In Parkinson’s disease, there is degeneration of the substantia nigra which produces the chemical dopamine deep inside the brain