January 27, 2004
Transmitter Cases – Parkinson’s and Others
Transmitters – Bridges to Neuro Functioning
Transmitters, Synapse & Receptors
Drug Targets? - 5 Options in Transmitter Control
Case Studies:
Jet Lag and Seasonal Affective Disorder
Food Allergies?
Depression
Erectile Dysfunction
Parkinson’s Disease
Lecture Notes:
..........Synaptic Transmission of an Impulse - When analyzing how the nervous system functions (in healthy as well as in disease states), we tend to focus most of our attention on the cells which make up this system – the neurons (or for that matter, we focus on the CNS and the PNS and subdivisions within). However, this is really only part of the story of how our nervous system actually functions and gets things done in our body. As you know our neurons have the capacity of conducting impulses along their processes (viz, axons) and eventually target other cells in the body (e.g., other neurons, three types of muscle, and selected glands). The successful targeting (activation) of these target cells by the neuron is only made possible through the cell-to-cell communication vehicle known as the synapse (or synaptic junction).
..........Transmitters and Receptors - Neurons are not in direct contact with their target cells, but rather there is a fluid-filled space (or gap) between the end of a neuron (presynaptic membrane of the axon) and the target cell (postsynaptic membrane). Taken together this configuration is referred to as a synapse (or synaptic junction). So if there isn’t direct cell-to-cell contact between the neuron and the target cell, how are target tissues like muscle activated by our nerves? Once a nerve impulse reaches the end of the axon (presynaptic membrane), chemicals called transmitters are released into the synaptic space or gap; in turn the transmitter is free to diffuse across the gap in search of its receptor on the target cell. Located on the postsynaptic membrane of the target cell are protein receptors which are capable of specifically binding with the transmitter; once a transmitter-receptor complex is formed [T*R] the target cell responds in some manner, depending upon what type of cell it is. For example, if the target cell is another neuron, the target response is the generation of another nerve impulse within the target neuron. If the target cell is muscle, the target response is for the muscle to contract or relax. And if the target cell is a gland, the target response is the secretion of a hormone. Hence, the synapse provides a mechanism by which nerves activate and control key parts of our body (i.e., sustaining nerve-to-nerve communication such as seen in our PNS and CNS; stimulating heart, skeletal and smooth muscles; as well as causing the release of particular hormones).
..........Inactivation of the Transmitter - With regard to the [T*R] complex, once the [T*R] complex has done its job in activating the target cell, the [T*R] complex disassociates itself freeing up the transmitter again. However, there is an enzyme located on the postsynaptic membrane of the target cell which destroys the transmitter. Hence, once the transmitter has done its job, it is prevented from functioning as a transmitter substance again. If this were not the case, think about the following scenario for a second. Let’s say you are at your PC keyboard busy typing up a lab report. In this instance motor nerves of your CNS/PNS are stimulating and controlling muscles of your hands and arms as you search out and type letters from the keyboard. The transmitter which is released by your motor axons is a chemical called acetylcholine; once within the synapse a [T*R] complex is formed which consequently causes the contraction of your typing muscles. However once you have typed a particular letter on the keyboard (for example, the letter M) you are now free to type another letter (say the letter P). This is made possible because the acetylcholine released in the formation of the letter ‘M’ has been destroyed by the enzyme acetylcolinesterase, and a new round of transmitter is needed from the axon to form the letter ‘P’. If this were not the case and the transmitter was allowed to remain free within the synapse, there would be no way to turn the target tissue ‘off”; that is, muscles needed to type the letter ‘M’ would stay contracted and there would be no way to continue typing.
..........Actions of Drugs upon the Synapse - By understanding the synapse, and the interplay of transmitter and receptor, you will be a position now to appreciate how a growing list of drugs called neuro-pharmaceuticals actually function. Today most people can rattle off the names of popular drugs like Prozac, Viagra and L-Dopa; but how many of you know how these drugs function to achieve the desired effects of relief from depression, erectile dysfunction, and Parkinson’s respectively? Answers to these questions rely on your ability (and the ability of drug companies) to identify susceptible ‘drug targets’; that is, what do you want to do and how are you going to do it?
..........Drug Targets? - What is a ‘drug
target’? In the case of clinical depression, studies have
shown that the neurotransmitter serotonin is reduced in
regions of the brain of depressed patients. So in this
instance what is our therapeutic end-game? Increase serotonin
levels in the brain – right? How can we do this? What do we
want a drug to do? In the case of depression, let’s look at 5
options involving controlling elements of the synapse
(i.e., neuron-to-neuron communications within the brain which
involves serotonin as the transmitter substance):
..........Option One – A drug can be
designed to increase (or decrease) the synthesis
of serotonin within the neuron, hence regulating the amount of
transmitter available for release. This strategy is
behind the use of using melatonin to treat ‘jet lag’ or
‘seasonal affective disorders where there is an imbalance in
brain serotonin levels due to disruptions in our day-night
light-cycles. In the first instance, jet lag creates a
situation where day is night, and night is day which in effect
disrupts one of our biological cycles or rhythms; in the second
instance, our biological rhythm is disrupted in the winter time
when the nights are long and the days are much shorter. In both
cases, the amount of daylight influences the amount of serotonin
synthesized in the brains which in turn can have an effect on our
behavior. Normally, dark conditions (at night) cause a
small gland in the brain called the pineal gland to release a
chemical called melatonin; in turn the increased levels of
melatonin inhibit serotonin synthesis which subsequently causes
us to be ‘drowsy’ or ‘sleepy’ (later with the
arrival of morning light, the pineal gland is inhibited and
serotonin synthesis can resume to its normal levels and we awaken
to a new day). The alternation of melatonin- and
serotonin–driven activities form a major basis of our normal
day-night rhythms of sleep and awakefullness. In the cases of
disorientation, sleepiness, and sometimes the depression
associated with seasonal affected disorders (and jet lag), there
is usually a positive association of the aforementioned symptoms
with levels of serotonin in the brain.
..........Option Two – There are chemicals
which serve as a precursors (or building blocks) of
serotonin; on one hand, there are dietary, naturally-occurring
chemicals such as the amino acid tryptophan which is used to
synthesize serotonin, and on the other hand there are drugs which
pharmacologically enhance the neuronal synthesis of serotonin. In
both instances serotonin levels increase thereby affecting
behavior. With regard to the former case, many people are
sensitive to certain foods which contain tryptophan and in turn
increases brain serotonin (for example, bananas are high in
tryptophan and eating them can cause behavioral side-effects in
some people; the side-effects are related to increases in newly
synthesized serotonin stemming from the dietary intake of
tryptophan).
..........Option Three – To increase
serotonin, certain drugs act to increase (or decrease)
the release of serotonin into the synapse by the
presynaptic membrane of the neuron; hence, the level of
transmitter within the synapse can be regulated by controlling
the rate of transmitter release by the neuron.
..........Option Four – There is a range of
drugs which act to control transmitter activity by blocking
the serotonin receptor; in this manner the formation of
the serotonin-receptor complex [T*R] is prevented and subsequent
activation of the target neuron is thereby blocked. There are
many clinical disorders affecting behavior where this treatment
strategy is used.
..........Option Five – More recently, drugs
have been developed which act to block the destruction of
the transmitter AFTER the [T*R] complex has been formed;
in these situations, more serotonin is available within the
synapse because it has not been destroyed by enzymatic
degradation. A drug like Prozac falls into this category where
levels of transmitter can be sustained, with the effect of
relieving depression caused by serotonin depletion. Because
Prozac inhibits the enzyme which normally destroys serotonin, the
transmitter is permitted to remain longer within the synapse. For
more information on the action of Prozac as well as the clinical
manifestations of depression see, www.prozac.com .
..........Viagra Story (Another Option 5 Mechanism Where a Drug Inhibits the Breakdown of a Transmitter - As most of you know from various commercial endorsements on TV, or from word of mouth, one of the most popular drugs today is Viagra; a drug used to treat impotence or erectile dysfunction in men. To understand how viagra works, it is useful here to briefly review the components of male erection. The initiation of an erection comes from various sensory stimuli involved in fore-play; these sensory signals are transmitted to the hypothalamus where motor nerve impulses are subsequently generated through the autonomic system targeting blood vessels of the penis. In the unstimulated state blood vessels entering the penis are relatively constricted with the net effect of preventing blood from entering storage regions within the shaft of the penis; however autonomic motor nerve stimulation of these blood vessels causes relaxation or dilation, and in turn permitting blood to enter the storage regions of the penis thereby inflating the shaft of the penis (viz., erection).
..........How does viagra work? To cause the smooth muscle of the penile blood vessels to relax, the motor nerve first causes the muscle to release a chemical called nitrous oxide; this chemical in turn activates an enzyme called guanylate cyclase which converts GTP (guanosine triphosphate) to cGMP (cyclic guanosine monophosphate). Acting as a second messenger within the smooth muscle the cGMP then acts on the muscle and causes it to relax (consequently allowing blood to enter the penis and erection takes place). However once cGMP has done its job, it is destroyed by an esterase enzyme, and its action upon the muscle is removed. What sustains the erection during the sex act if cGMP is destroyed? In simple terms the answer is in repeated sensory stimulation; the repetition will re-activate the sensorimotor reflex or cascade of events leading up to the renewal of cGMP formation and sustained erection. On the other hand, the action of viagra is to sustain cGMP by inhibiting the esterase enzyme; if esterase is inhibited, the destruction of cGMP is prevented with the net effect of sustaining an erection. Hence like the action of Prozac on inhibiting serotonin breakdown, viagra is also a drug which acts by inhibiting the breakdown of a chemical messenger (cGMP) needed to sustain a body function. More information on the action of viagra, as well as safety issues of this drug can be found at: www.viagra-helps.com .
..........Parkinson’s Disease Caused by Loss of Dopamine-Producing Cells – Parkinson’s is a neuro-degenerative disease characterized by tremors, weakness, loss of balance, difficulties in swallowing and speech, and possible immobilization, double-vision, and depression. The cause of the disease seems to be related to the loss of dopamine-producing neurons within regions of the brain; dopamine is another one of the neurotransmitters functioning within specific pathways of the CNS. For whatever reason, if dopamine-producing neurons are degenerating within the brain, specific motor functions under the brain’s control will be negatively affected.
..........Treatments? - Management of the disease have focused on two major areas: controlling the tremors, and treatment with the drug L-dopa. Controlling the tremors involves a range of approaches including, drugs to inhibit tremors, electrical stimulations, and the surgical destruction of ‘over active’ pathways within the brain. On the other hand, L-dopa is a drug which is structurally similar to naturally-occurring dopamine and has the net effect of sustaining transmitter levels within the Parkinson’s patient; typically L-dopa provides 4 to 10 years of relief from disabling symptoms. However, because the loss of dopamine-sensitive neurons is continuous and relentless, drug therapy eventually becomes ineffective. For more information on Parkinson’s disease and its treatment, see the following private organizations: www.parkinson.org , www.parkinsonsinfo.com and www.neuroguide.com . In addition, extensive information on the research of Parkinson’s disease as well as other neurological disorders where neurotransmitters are affected (e.g., myasthenia gravis and the loss of acetylcholine receptors) can be found at: www.nih.gov and www.fda.gov.
..........Parkinson’s Disease and Potential Treatment
with Stem Cells? – As you learned last semester in
Bio 129 (www.biology.buffalo.edu/courses/bio129) stem cell research may hold the promise of treating
many currently untreatable disorders (including
Parkinson’s). Stem cell research centers upon pluripotential
germ cells found within the human embryo which over time will
ultimately differentiate into functional adult tissues. For
example it may be possible in the future to implant stem cells
into a diabetic patient as a means of establishing
insulin-secreting cells within the patient. Heart patients may
someday benefit by having degenerated parts of their hearts
repaired by implanted stem cells. Moreover, individuals with
compromised immune systems may reap the potential benefits of
stem cell implantation. There is a growing list of clinical
disorders which may be effectively treated with stem cells as an
approach to restore lost function (regardless of the cause).
..........However as you know stem cell research is a
controversial subject; since the source of stem cells is likely
to be early human embryos, there are many ethical, moral and
political factors involved in future decisions of whether or not
government-funding will be available to support stem cell
research. Alternatively, stem cells from adult tissues (e.g.,
bone marrow cells) offer a less controversial, but likely a less
productive route of treatment. With regard to Parkinson’s
disease, the end-game of treatment by stem cells would be to
establish dopamine-producing cells within the brain, thereby
restoring the dopamine transmitter lost in the disease (and of
course restoring health to the patient).
..........Parkinson’s Disease Case Study -
In order to give you an appreciation of the scientific as well as
personal factors involved in deciding whether or not to proceed
with stem cell treatment of Parkinson’s disease, a real-life
case study is available at the University at Buffalo’s
National Center for Case Studies in Science ( http://ublib.buffalo.edu/libraries/projects/cases/case.html ). The case is entitled – ‘A Search
for the Right Answer: Fetal Tissue Research and Parkinson’s
Disease’ and is authored by Anne Fourtner, Charles Fourtner,
and Clyde Herreid (latter two authors are Professors
within the Department of Biological Sciences, University at
Buffalo); the specific case study and attending discussions of
the science and personal factors involved are found at: http://ublib.buffalo.edu/libraries/projects/cases/fetal_tissue.html .
..........The underlying therapeutic approach in the proposed case
study involves surgically implanting dopamine-producing neurons
of fetal origin; the patient in the case is a 62 year old mother
called Gretchen who is affected with Parkinson’s disease.
However, there are several questions raised by her and her family
as they consider the scientific as well as ethical merits of
fetal cell treatment in her case. Some examples of
questions raised and debated:
What will be the source of the fetal cells? Presumably from aborted fetuses.
Will prior approval be needed to undergo the procedure? Patient? Researchers? Institutional authorities? Medical committees? Government agencies?
What will be the age of the donor cells? Is this a factor?
How long will the fetal cells be stored prior to use? Is this a factor?
Should tissues or cells be used? Is there a difference?
Should immune suppressive therapy be employed? Guard against rejection?
Who would qualify for this treatment? What would be the basis of patient selection procedures?
End