International Post-Baccalaureate

PharmD. Program (IPBP)

Internal Assessment (IA) Exam

STUDY GUIDE

PHARMACOLOGY- IV

© 2006

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TABLE OF CONTENTS:

I. Neuroanatomy

a. Peripheral Nervous System

b. Central Nervous System
c. Blood-brain barrier and cerebrospinal fluid

II. Neurotoxicology

a. Toxins disrupting neurotransmitter release

b. Toxins disrupting Acetylcholine neurotransmitter system
c. Toxins disrupting dopamine neurotransmitter system
d. Toxins disrupting Serotonin neurotransmitter system
e. Toxins disrupting GABA neurotransmitter system

III. Neurodegenerative disorders

a. Multiple Sclerosis (MS)

b. Amyotrophic Lateral Sclerosis (ALS)

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 I. NEUROANATOMY

Anatomical Organization of the Nervous System:

a. Peripheral Nervous System (PNS)

Somatic: Sensory nerves and cranial ganglia that innervate skin, muscles and
joints and provide sensory information to the CNS about muscle and limb
position as well as the environment.
Autonomic: Motor system for the viscera, smooth muscles, and exocrine glands.
Further subdivided to:
Sympathetic: Body response to stress.
Parasympathetic: Conserve body resources and restore homeostasis.
Enteric: Controls smooth muscles of the gut.

b. Central Nervous System (CNS):

1. Spinal cord: Simplest and most caudal region. It

receives sensory information from skin, joints, and the
muscles of the trunk & limbs. It contains motor
neurons responsible for voluntary and reflex
movements.

2. Medulla: Together with the pons,

regulates blood pressure and respiration
(breathing center). It also contains coughing
and vomiting reflexes and is a continuation of
the long tracts of the spinal cord.

3. Pons and Cerebellum: Pons contains the

neurons that relay information from the cerebral
hemispheres to the cerebellum. Cerebellum is
not part of the brain stem but is closely related to
the pons. The cerebellum Receives
somatosensory information from the spinal cord,
motor information from the cerebral cortex and
input about balance from the vestibular organs
of the inner ear. It also integrates all of the
information to coordinate planning, timing and
patterning of skeletal muscle contractions during
movement. It plays a role in the maintenance of
posture and coordination of head & eye
movements.

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4. Midbrain: Areas are involved in direct
control of eye movements, motor control
of skeletal muscles and essential nuclei
for auditory and visual systems.

5. Diencephalon: Consists of the

thalamus and the hypothalamus:
Thalamus: Processes and distributes
almost all sensory and motor information
going to the cerebral cortex. The thalamus
regulates the level of awareness and
emotions by affecting the cortex.
Hypothalamus: It has extensive
connections with the thalamus, midbrain
and the cortical areas. The hypothalamus
regulates the autonomic nervous system
and hormonal secretion by the pituitary
gland. It maintains a constant internal
environment by regulating autonomic
control centers in the brainstem and
hormone levels in the body.

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Other Cortical Areas

Basal ganglia: Composed of the

caudate nucleus, putamen, and globus
pallidus. It plays an important role in
the regulation of movement and
contributes to cognition. It receives
input from all lobes but has efferents
only to the frontal cortex via the
thalamus.

Hippocampal formation: Involved

in learning and memory.

Amygdala: Coordinates the actions of

the autonomic and endocrine systems
and is involved in emotions. It controls
defensive behaviors such as fear and
rage.

c. Blood-brain barrier and cerebrospinal fluid

The main component of the blood brain barrier (BBB) is the specialized capillary
endothelial cells which form the microvasculature of the brain. These cells have
several characteristics that differentiate them from the capillary endothelial cells
lining the vasculature in the peripheral vessels. First, brain endothelial cells are
joined by tight junctions of high electrical resistance (1000 ohm/cm2). Peripheral
endothelial cells have tight junctions of low resistance (5-10 ohm/cm 2). Second,
unlike peripheral endothelial cells, brain endothelial cells do not allow
transcellular movement of compounds. Third, in contrast to peripheral endothelial
cells, brain endothelial cells rarely have pinocytotic vesicles and contain greater
numbers of mitochondria (necessary for active transport of compounds). Another
component of the BBB is the astrocytic foot processes which further limit
penetration of substances into the brain (see figures below).

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The BBB protects the brain from the entry of potentially harmful substances that
are present in peripheral blood (Table C-1).

Unlike peripheral capillaries that allow relatively free exchange of substance

across and between cells, the BBB strictly limits transport into the brain. Thus the
BBB is often the rate-limiting factor in determining permeation of therapeutic
drugs into the brain.
The circumventricular organs (CVO's) are midline structures bordering the 3rd
and 4th ventricles of the brain. These are unique areas of the brain outside the
protection of the BBB. These barrier-deficient areas are recognized as important
sites for communicating between the brain and peripheral organs via blood-borne
products. CVO's include:
- Pineal body: Secretes melatonin and neuroactive peptides.
Associated with circadian rhythms.
- Neurohypophysis (posterior pituitary): Releases
neurohormones like oxytocin and vasopressin into the blood.
- Area postrema: Considered the "Vomiting center". When a
toxic substance enters the bloodstream, it will get into the area
postrema and cause us to throw up. In this way, we protect
ourselves by eliminating the toxic substance from our stomach
before more harm can be done.
- Subfornical organ: Important for the regulation of body fluids.
- Median eminence: Regulates anterior pituitary through release
of neurohormones.

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BBB breakdown is theorized to be a key component in central nervous system
(CNS) associated pathologies. Blood-brain barrier alteration can result from the
following:
- Opening of Tight Junctions:
Caused by: hyperosmolarity, acidic pH, multiple sclerosis, inflammation
- Increased pinocytosis:
Caused by: ischemia, seizures, tumors, mercury poisoning, tricyclic
antidepressants, meningitis
- Decreased membrane rigidity:
Caused by: sufactants and solvents (ethanol; propanol; butanol; DMSO)
- Disease / toxicant induced nutrient transport changes:
Caused by: diabetes, Alzheimer’s disease, stroke

Cerebrospinal Fluid (CSF):

CSF is a clear fluid which baths the brain. It occupies the subarachnoid space
(the space between the skull and the cerebral cortex) and the ventricles. It is
formed by the choroid plexus. The diagram below shows the production and flow
of the CSF through the ventricular system of the CNS.

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Some of the characteristics of the CSF are as following:
• Entire volume of CSF = 140 -150 ml
• Production rate: 21 ml/hr
• Turnover rate: Once every 5 hr
• It is responsible for approximately 10-20% of brain weight

Some of the functions of CSF are:

• It maintains constant external environment for neurons and glia.
• The one-way flow allows the removal of potentially harmful brain
metabolites.
• It provides a mechanical cushion to protect the brain.
• It reduces the in situ weight of the brain
• It is a conduit for peptide hormones.

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II. NEUROTOXICOLOGY

There are several toxins that disrupt the release of neurotransmitters from the
presynaptic terminal.

a. Toxins disrupting neurotransmitter release

Botulinum toxin:
Derived from bacterium clostridium botulinum, it consists of two
polypeptides (a 100 kDa heavy chain and a 50 kDa light chain). The light
chain is a zinc endopeptidase. The heavy chain binds to the
plasmalemma and facilitates the entry of the light chain into the axon
terminal. The light chain then cleaves the synaptic vesicle fusion proteins
and this result in the blockage of synaptic transmission.
Symptoms of neurotoxicity:
Food-born botulism causes symmetrical descending paralysis with cranial
nerve involvement that leads to diplopia, dysarthria and dysphagia. This
is followed by weakness of neck, arm, thorax and legs. Nausea, vomiting
and abdominal pain may occur before onset of paralysis. Other symptoms
may include dizziness, blurred vision, ptosis, dry mouth, sore throat,
severe constipation, and urinary retention.

THERAPEUTICAL USE- Intramuscular injection of small amounts of the

botulinum toxin is clinically used to treat movement disorders and
disorders of neuromuscular transmission.

Tetanus toxin
Derived from Clostridium tetani, it has similar heavy and light chains. The
heavy chain attaches to presynaptic membranes and enters the nerve
terminal. The light chain is carried by fast axonal transport to motor
neurons in the spinal cord and there it binds to the plasmalemma of
attached inhibitory neuron terminals. This blockades the inhibition of
motor neurons.
Symptoms: Causes increased motor and sympathetic activity.

α -Latrotoxin
Produced by the black widow spider, it causes massive transmitter release
at vertebrate neuromuscular junctions by increasing the probability of
vesicle fusion with the plasmalemma and inhibiting vesicle recycling.

b. Acetylcholine Disruptors:

1. Choline mustard aziridinium analogues:

Compete with choline to enter cholinergic neurons and irreversibly block
choline uptake at high concentrations. This leads to retrograde axonal
degeneration.

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2. Haloginated cholines:
Inhibit choline acetyltransferase and by doing so decrease Ach synthesis.

3. Triethylcholine:
This is a false cholinergic neurotransmitter. It is a cyclic choline analog.
Mechanism of action:
Carried to plasmalemma via choline transporter
↓
Acetylated by choline acetyltransferase
↓
Enters synaptic vesicles
↓
Released and binds to receptors
(Displays cholinoreceptor agonist activity lower than Ach
and this leads to Cholinergic hypofunction)

4. Physostigmine:
Acetylcholinesterase (AChE) inhibitor, carbamylates the enzyme and is
longer lasting.

5. Organophosphates:
Another AChE inhibitor, it interacts with the active center of the enzyme to
form stable complexes. Loss of one of the alkyl groups causes aging and
this makes the complex more stable and thus longer lasting.

c. Dopamine Disruptors

Large majority of dopamine is in the corpus striatum and the substantia nigra.
When dopaminergic neurons in the nigrostriatal pathway degenerate, this leads
to Parkinson’s disease. Neuroleptic antipsychotics decrease dopamine and
induce movement disorders.

General toxins effecting adrenergic function:

1. Methyldopa: False transmitter at adrenergic synapses.

2. Reserpine: Blocks uptake of amines.
3. Amphetamine: Increases transmitter release.

d. Serotonin Disruptors

Serotonin acts on smooth muscles in GI and cardiovascular systems and is also

a CNS neurotransmitter. Two main serotonergic pathways project to the
forebrain. They function in mood, perception, and cognition.
Fluoxetine and Sertraline

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 Inhibit serotonin uptake and serve as antidepressants. Serotonin toxicity in dogs
and rats causes tremor, apparent blindness, and tachycardia.

MDMA (ecstasy)
Damages axons derived from raphe serotonergic projections. It causes acute
reactions: Panic, paranoia, loss of reality, hallucinations, anxiety, depression,
psychosis, and memory disturbances.

e. GABA Disruptors

GABA is the major inhibitory neurotransmitter in mammalian brain.

Vigabatrin:
GABA aminotransferase inhibitor and anticonvulsant, it induces arousal and
behavioral disorders.

Benzodiazepines:
Increases GABAergic transmission and are used as sedatives and
anticonvulsants. Examples are diazepam (Valium) and Rohypnol. Neurotoxicity
is manifested by the following symptoms: drowsiness, fatigue, lethargy, muscular
incoordination, dizziness, and somnolence.

Anticonvulsant barbiturates:
CNS-depressant drugs, they activate GABA receptors at high concentrations.
They cause mild sedation to general anesthesia while in some subjects,
paradoxical excitement may occur. Toxicity results in: distortion of mood,
judgment, and motor skills, coma, reduced breathing, loss of blood pressure,
shock, hypothermia and death.

Picrotoxin: GABA antagonist. It is a polycyclic lactone isolated from a climbing

shrub indigenous to Indonesia. It powerfully stimulates the CNS and elicits
widespread seizure activity.

Organochlorine insecticides:
Exert convulsant effects by antagonizing GABA (examples are: lindane, dieldrin,
and endrin). Clinical effects of intoxication are tremors and seizures.

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III. NEURODEGENERATION
Brain development in a fetus is first concentrated on making neurons. After birth
however, the rate of neuron creation slows down. It is normal for each neuron to
become connected to between 10,000 and 100,000 other neurons. Over time,
neuron creation stops altogether then actually goes into reverse as nerve cells
gradually die. This is a natural aging process. However, in extreme cases, the
loss can be extensive and leads to neurodegenerative diseases. In the next two
sections we shall review the autoimmune disorder, multiple sclerosis (MS), and
the motor neuron disease, Amyotrophic Lateral Sclerosis (ALS).
a. Multiple Sclerosis
Introduction

Multiple sclerosis (MS) is a chronic, long-term condition that affects the central
nervous system, including the brain and spinal cord. MS is an autoimmune
disease, which means that the body's immune system mistakenly attacks itself,
targeting the cells, tissues, and organs. In people with MS, patches of
inflammation occur in the brain and spinal cord. This causes myelin coating
around the nerve fibers to deteriorate (See figure below). Eventually, the axons
of nerve fibers themselves may be damaged or destroyed. These processes are
never the same in any two people with MS. When they occur, how quickly, and
to what extent can vary a great deal.

In MS, errant T cells somehow leak out of the blood vessels and cause swelling
and damage in the surrounding white tissue. When the damage becomes
significant, persons with MS experience the characteristic symptoms of poor
muscle coordination, numbness or tingling, weakness and fatigue. Once the
inflammation has subsided, special cells within the nervous system begin to
repair the myelin that was damaged by the inflammation. This process is called
"remyelination”.

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This cycle of damage and recovery occurs over and over in the white matter,
often unnoticed, especially in early stages of the disease. When and to what
extent problems become symptomatic depends on the location, the extent, and
the severity of the inflammation. If the inflammation occurs repeatedly in the
same place and the repair processes are not able to keep up, permanent
damage to the axons may occur. When the inflammation covers a large area, it
can often leave a scar in the nervous system, known as a "plaque," which can be
identified through an MRI scan.
Forms of MS
The first signs of MS often appear between the ages of 20 and 40. Sometimes
MS can start in children or in elderly people, too. The progression of the disease
is variable, depending on the severity or location of inflammation or how quickly
the myelin breaks down (See figure below).
Relapsing-remitting (RR) MS: this type shows clearly defined relapses with
some amount of recovery. It is the most common form of MS. Around 75% of all
people with MS are diagnosed with relapsing-remitting MS at the time of
diagnosis. However, over a 10-year period, 50% of RR-MS patients without
therapy will likely progress to secondary progressive MS. For this reason,
treatment at diagnosis with MS therapies that have been proven to slow the
progression of disability may be important in combating the long-term path of the
disease.
Secondary progressive (SP) MS: while technically a form of progressive MS, this
type acts like a relapsing form of MS in its early-to-mid stage, with relapses and
remissions being quite common. But then a more gradual loss of physical and
cognitive functions starts to take over and relapses become less common. It is
estimated that about one-third of people with MS have this form of the disease.
Roughly two-thirds of people with secondary progressive MS have relapses, and
thus also fall within the definition of relapsing MS.
Primary progressive MS: this type shows no relapses, but over a period of years,
there is gradual loss of physical and cognitive functions. This form of MS affects
about 10% of all people with MS.
Dividing MS into groups according to the progress of the disease is often a
question of looking back over a longer period. However, because MS is such a
variable disease, it is nearly impossible to predict how MS will affect a person in
the future. Symptoms are one way to mark the progression of disease in MS.
However, MS can also progress silently through axonal loss. The brain can adapt
to and compensate for some level of damage and symptoms are highly
dependent on the location of the damage since different parts of the brain are
responsible for different activities. A person with MS can look and feel fine, yet
his or her disease may be active.

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Symptoms
Patients with MS experience a wide range of symptoms. Some problems occur
often, and some are seldom seen. They all depend on where the inflammation
and demyelination is situated in the CNS. The course of illness is different for
each individual. Even when there are no symptoms, there is progression of
damage to the central nervous system over time. Some of the symptoms that
may occur with MS are as follows:
Optic Neuritis: This is an inflammation of the optic nerve. Over a period of days,
the patient may develop blurred vision. Sometimes there is pain behind the eye.
After initial symptoms, there is gradual improvement, sometimes after several
weeks. But recovery is not always complete. During periods of stress, fatigue or
fever, the blurred vision in the eye may return. This does not necessarily mean
that the MS is active again. Rather, it may be the result of permanent disability
that has accumulated over time.
Loss of Muscle Strength in Arms and Legs: Often, MS is active on the nerve
fibers that control muscle movement. Many people with MS lose muscular
strength in the arms and legs as the disease progresses. The loss can range
from reduced dexterity to paralysis of an arm or leg.
Loss of sense of Touch: When sensory fibers are damaged, the sense of touch
may be replaced by feelings of numbness or tingling. Parts of the body may feel
burning or cold, even though there is no heat or chill present. Symptoms can be
temporary (relapses) or more progressive, and can occur in various parts of the
body.

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Pain: MS can be accompanied by various kinds of pain. Damage to the sensory
tracts in the spinal cord can result in burning pain in the arms and legs. MS can
often result in damage to the nerves of the face, a painful condition known as
"trigeminal neuralgia". If MS has impaired the ability to walk, the extra strain in
the muscles of back and legs can become painful.
Loss of Bladder and Bowel control: Many people with MS will develop trouble
controlling the urge to urinate or will be unable to completely empty the bladder.
Less frequently, they will also experience problems with bowel control.
Fatigue: People with MS experience fatigue or tiredness. But since fatigue can
be a sign of so many other diseases, it is not often immediately identified as
being caused by MS. Fatigue occurs in both relapsing MS and in the more
progressive types of the disease.
Cognitive Function: At some point in the course of MS, one may notice changes
in cognitive function, such as memory and speed of thinking. One may also have
difficulty concentrating.
Mood Changes: Many people with MS experience periods of depression.
Sometimes it is linked directly to physical changes in the brain caused by MS.
Understandably, it may also be an emotional reaction to having the illness and
learning to cope with the symptoms and the challenges they represent.
Diagnosis
Early diagnosis of multiple sclerosis is very important because it is best to begin
therapy soon, rather than waiting until the disease progresses. Early treatment
of MS has been shown to help slow progression of the disease, which may lead
to a better quality of life. A diagnosis of MS usually begins with a thorough
neurological examination and a discussion of full medical history. However, to
confirm the presence of MS, advanced diagnostic procedures are used. These
include:
Magnetic Resonance Imaging (MRI): The MRI scan shows any defects in the
white matter. There is an association between the amount of disease activity
shown on the MRI scan and the progress of the disease, but the link is not very
clear and is difficult to interpret.
Lumbar Puncture (spinal tap): In this examination, a long, hollow needle is
inserted into the spinal column to take a sample of the CSF. The CSF in people
with MS has slightly more inflammatory cells and an increase in inflammatory
proteins.
Evoked Potentials: By measuring what are known as evoked potentials or
evoked responses, certain nerve fibers can be checked. The more
demyelination, the slower the transmission of impulses measured.

Drug Therapy:

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There is at present no cure for MS. Many patients do well with no therapy
because many medications have serious side effects. However, for patients who
need intervention, the following drugs are in use:

- Three forms of beta interferon (Avonex, Betaseron, and Rebif) have

now been approved by the Food and Drug Administration for treatment of
relapsing-remitting MS. Beta interferon reduces the number of
exacerbations and may slow the progression of physical disability. Also,
when attacks occur, they tend to be shorter and less severe.

- The FDA also approved a synthetic form of myelin basic protein,

called copolymer I (Copaxone), for the treatment of relapsing-remitting
MS. Copolymer I has few side effects, and studies indicate that the agent
can reduce the relapse rate by almost one third.

- An immunosuppressant treatment, Novantrone (mitoxantrone),

is approved by the FDA for the treatment of advanced or chronic MS.

- While steroids do not affect the course of MS, they can reduce the
duration and severity of attacks in some patients. Spasticity, which can
occur either as a sustained stiffness caused by increased muscle tone or
as spasms is treated with muscle relaxants and tranquilizers such as
baclofen, tizanidine, diazepam, clonazepam, and dantrolene.

Physical therapy and exercise can help preserve remaining function, and patients
may find that braces, canes, and walkers can help them remain independent and
mobile. Avoiding excessive activity is important measures patients can take to
counter physiological fatigue. If psychological symptom of fatigue such as
depression is evident, antidepressant medications may help.

Causes
Scientists now believe that MS results from an abnormal response to an infection
or an environmental factor. In general it is thought that MS is caused by a
combination of factors.

Climate
MS does not occur as frequently in every country throughout the world. MS most
commonly affects Caucasians, particularly in North America, Europe, and
Australia. The differences are not as great as we used to think. We do know,
however, that in both the northern and southern hemisphere, MS is more
frequent the farther away a country is from the equator. This applies to regions
within a country itself. For example, in the US, the incidence of MS is much
higher in northern states with temperate climates (seasonal changes) than in
warmer southern states.

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Some studies suggest that there may be a connection between where a person
lived for about the first 15 years of his or her life and the incidence of MS. For
example, children up to age 15 who move to another area where there is a
higher or lower risk for MS become as likely to get MS as people who have
always lived in that area. But people older than 15 who move remain as likely to
get MS as if they had not moved.

Viruses
A great deal of research has investigated the links between MS and all kinds of
viruses. As yet there has been no reliable proof of any specific virus being
responsible for MS. A likely possibility is that MS is the result of a response to
several outside factors, such as viral infections, in a person who may be
susceptible to MS based on his or her genetic makeup.

b. Amyotrophic Lateral Sclerosis

Introduction

Amyotrophic lateral sclerosis (ALS) is a motor neuron disease first described in

1869 by the noted French neurologist Jean-Martin Charcot. As many as 20,000
Americans have ALS and people of all races and ethnic backgrounds are
affected. The disease is more prevalent in men and most cases occur between
the ages of 40-60. ALS is sometimes called Lou Gehrig’s disease after the
famous ball player who was diagnosed with the condition in 1939.

ALS is uncommon. It begins in middle age and proceeds to death in several

years. There is a loss of motor neurons in the brain, brainstem and spinal cord
that control the voluntary muscles of the body. Messages from motor neurons in
the brain (called upper motor neurons) are transmitted to motor neurons in the
spinal cord (called lower motor neurons) and from them to particular muscles. In
ALS there is a loss in both upper and lower motor neurons. The latter leads to
the loss of anterior horn cells (see below), so patients have progressive
weakness that proceeds to paralysis from neurogenic muscular atrophy. Because
of the loss of anterior horn cells, the anterior (ventral) spinal motor nerve roots
demonstrate atrophy in comparison with a normal spinal cord.

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Thus, ALS causes weakness with a wide range of disabilities. Eventually all
muscles under voluntary control are effected and patients lose their strength and
ability to move their arms, legs and body. Most people with ALS die from
respiratory failure. In 90-95% of ALS cases, the cause is unknown.
Approximately 5-10% of the cases are inherited (familial forms of ALS). Studies
show that in about 20% of these familial forms, there is a mutation in an enzyme
known as superoxide dismutase 1 (SOD1) SOD plays an important role in
detoxifying superoxide (a reactive oxygen intermediate which can damage cells).
Symptoms
The onset of ALS may be subtle and the symptoms are frequently overlooked.
Earliest symptoms are twitching, cramping, stiffness of muscles, slurred speech,
or difficulty chewing. The part of the body affected by the early symptoms of the
disease depends on which muscles are damaged first. The obvious weakness
and atrophy of muscles will cause a physician to suspect ALS. The disease is
progressive and other muscles will begin to atrophy causing increasing problems
in moving, swallowing, and speaking. Although the sequence of symptoms and
rate of disease progression varies among individuals, eventually the patient will
not be able to stand, walk or use their hands and arms. When muscles in the
diaphragm and chest wall fail, patients lose the ability to breathe without
ventilator support.

Diagnosis:

No one test can provide a definitive diagnosis of ALS. Instead, the diagnosis is
based on the symptoms and signs observed by the physician.

Drug Therapy:

No cure has yet been found for ALS. However, the FDA has approved the first
drug treatment for the disease. Riluzole is believed to reduce damage to motor

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neurons by decreasing the release of glutamate. Clinical trials with ALS patients
showed that riluzole prolongs survival by several months, mainly in those with
difficulty swallowing. The drug also extends the time before a patient needs
ventilation support. Riluzole does not reverse the damage already done to motor
neurons, and patients taking the drug must be monitored for liver damage and
other possible side effects. However, this first disease-specific therapy offers
hope that the progression of ALS may one day be slowed by new medications or
combinations of drugs.
Other treatments for ALS are designed to relieve symptoms and improve the
quality of life for patients. Physicians prescribe medications to help reduce
fatigue, ease muscle cramps, and reduce excess saliva. Drugs also are available
to help patients with pain, depression, sleep disturbances, and constipation.
Pharmacists can give advice on the proper use of medications and monitor a
patient's prescriptions to avoid risks of drug interactions. Physical therapy and
special equipment can enhance independence throughout the course of ALS.
One of the most exciting areas of research into ALS is stem cell therapy. Stem
cells, which are immature cells that can differentiate into specialized adult cells,
could represent the next great advance for ALS therapy.
Causes
The cause of most cases of ALS is unknown. However, it is thought that the
following factors may play a role in the disease process:
Free Radicals - In ALS, the antioxidant stores are depleted and free
radicals build to toxic levels leading to oxidative stress.
Excess Glutamate- Glutamate is an excitatory neurotransmitter. In ALS,
there is an overabundance of glutamate in the nervous system. This may
result from inadequate reuptake of glutamate. Experiments suggest that
there may also be a defect in the production or release of glutamate.
Defects in Mitochondria- Mitochondria have their own DNA. Because of
oxidative phosphorylation, free radical production is high in these
organelles. As a result, mitochondrial DNA can be damaged. A certain
amount of damage occurs as part of the aging process, but in ALS, there
appears to be more damage to mitochondria than the average aging cell
sustains.
Immune System Abnormalities- Autoimmunity could play a role in ALS, but
so far, conclusive studies are lacking, and none of the treatments used for
other autoimmune diseases has been effective against ALS.

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