Introduction to the CNS

• http://biosingularity.wordpress.com/2007/05/07/neurons-and-how-they-work-animation

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• http://www.healthscout.com/animation/68/10/main.html

Neurotransmitters found in the CNS

H3C ON

O

Me

MeMe

Acetylcholine

HO

HO

HO

NH2

Noradrenaline

HO

HO

NH2

DopamineEndorphins

(Small Peptides)

Serotonin(5-Hydroxytryptamine)

5-HT

NH

HO NH2NH2

HO

O

gamma-aminobutyric acid(GABA)

HO

O

NH2

OH

O

Glutamate

HN

N NH2

Histamine

• 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

• All ACh receptors in the CNS are nicotinergic. The stimulating effect of nicotine is due to the influence of these receptors.

Nicotine

Acetylcholine

• 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

• http://highered.mcgraw-hill.com/sites/0072495855/student_view0/chapter14/animation__chemical_synapse__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

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Drugs to Treat AD:Inhibitors of Acetylcholinesterase

N

O

MeO

MeO Donepezil(Aricept)

Galantamine

(Razadyne, Razadyne ER, Reminyl, Nivalin)

O

O

NN

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

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L-Glutamic Acid N-Methyl-D-aspartate

(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.

NH2

O

HO

OH

O

NH

O

HO

OH

H3CO

Memantine

Norepinephrine

• 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).

HO

HO

HO

NH2

Norepinephrine

• 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.

HO

HO

HO

NH2

Norepinephrine

• 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.

HO

HO

HO

NH2

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)

Atomoxetine (Strattera) norepinephrine reuptake inhibitor

Amphetamine(Adderall) 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

• 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.

HO

HO

NH2

Dopamine

Biosynthesis of Epinephrine

HO

NH2

CO2H

L-Tyrosine

Tyrosine

hydroxylase HO

NH2

CO2H

Levodopa(L-DOPA)

HO

HO

NH2

Dopamine

HODopa

Decarboxylase

Dopamine

β-hydroxylase

HO

HO

NH2

OH

Norepinephrine(Noradrenaline)

HO

HO

NHMe

OH

Epinephrine(Adrenaline)

N-methyl transferase

(in Adrenal medulla)

• 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.

HO

HO

NH2

Dopamine

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