Chemical Neurotransmission (Health and Disease)
PRESENTED BY: CHE ELVIS 
ABSTRACT
The Nervous system contains millions of neurons that transmit impulses through out the body in fractions of seconds.
There are different types of neurons and a variety of neurotransmitters are produced at the pre-synaptic end of the neurons.
This neurotransmitters are released in the synapse in response to potential or stimulus.
They bind to receptors and elicit biologic responses at the post synaptic neurons.
Termination of action is by removal of neurotransmitter from synapse.
The process however seems but not necessarily occurs so easily. The slightest modification results in disease condition. A handful of them will be discoursed in this document as well as a remedy for some of them
Also, some substances are neurotoxic due to structural similarity with neurotransmitters.
In this document most chemical neurotransmitters will be touched but the major emphasis on disease will be the Glutamate transporters.
TABLE OF CONTENT
Abstract……………………………….……………………………………………………i
Table of content …………………………………………………………………………..ii
Chapter 1 General introduction
1.1 Basic definitions……………………………………………………………1
1.2 Brief review of the nervous system…………………………………………2
1.3 Neurons and their functions………………………………………………..2
1.4 Types of neurotransmitters………………………………………………….3
Chapter 2 Chemical Neurotransmission Steps
Schematic illustration of a synapse………………………………………….……4
2.1 Synthesis of neurotransmitter………………………………………….……5
2.2 Storage in synaptic vesicles………………………………………….……..5
2.3 Release of neurotransmitter………………………………………….……..5
2.4 Binding to the receptor………………………………………………….….5
2.5 Elicidation of biological response………………………………………….5
2.6 Termination of action……………………………………………………….5
Chapter 3 Neurotoxicity and disease
3.1 Alzheimer’s disease…………………………………………………………..6
3.2 Huntington’s disease…………………………………………………………6
3.3 Parkinson’s disease………………………………………………………….7
3.4 Epilepsy……………………………………………………………………..7
3.5 Cerebral ischemia……………………………………………………………8
3.6 Other neurological disorders…………………………………………………8
3.7 Neurotoxicity by other substances………………………………………….8
Chapter 4 Health
4.1 Reversal of transporter actions…………………………………………….10
4.2 Treatment of neurological disorders………………………………………..11
4.3 Treatment of poisoning with antidotes…………………………………….11
Chapter 5 Conclusion……………………………………………………….12
References
CHAPTER 1
GENERAL INTRODUCTION
1.1 BASIC DEFINITIONS
Health: Can be defined as soundness of any living organism
Disease: Disturbed or abnormal structure or physiological action in the living organism as a whole, or in any of its parts
Neurotransmission (or synaptic transmission) is communication between neurons as accomplished by the movement of chemicals or electrical signals across a synapse.
Neurones a neurone is a nerve cell; it has a cell body, a very long axon sheathed in myelin, and many tiny branches called dendrites. There are three kinds of neurones: sensory, intermediate and motor neurones.
Axons: these are long cytoplasmic tubes, they carry electric impulses from one part of the body to another. They are insulated from each other by their myelin sheathes.
Dendrites: these are tiny branches on the cell body and at the ends of all neurones. The dendrites of one cell do not actually touch the dendrites of any other cell. There are very tiny gaps between them called synapses.
Synapses: these are the gaps between the dendrites of one neurone and the cell body of another one. There is no electrical connection between nerve cells. when one neurone stimulates another it does so by secreting a chemical into the synapse. Many drugs work by interfering with these chemical transmitters
1.2 BRIEF REVIEW OF THE NERVOUS SYSTEM
The nervous system is concerned primarily with the reception of stimuli, transmission of impulse, interpretation of sensation and intergration of sensory information arising from within or out of the body.
It is organized into the central nervous system (CNS) and the Peripheral nervous system (PNS)
CNS consists of the brain and spinal cord. It contains millions of neurons and has white and gray matter
PNS consists of all the sensory nerves containing sensory neurons (this feed information into the spinal cord and brain) and motor nerves ( these carry messages to other parts of the body from the brain and spinal cord)
1.3 STRUCTURE AND FUNCTION OF NEURONES
The function of a neuron is to receive INPUT “information” from other neurons, to process that information, then to send “information” as OUTPUT to other neurons.
A “typical” neuron has four distinct parts (or regions). The first part is the cell body (or soma). This is not only the metabolic “control center” of the neuron, it is also its “manufacturing and recycling plant.” (For instance, it is within the cell body that neuronal proteins are synthesized.) The second and third parts are processes — structures that extend away from the cell body. Generally speaking, the function of a process is to be a conduit through which signals flow to or away from the cell body. Incoming signals from other neurons are (typically) received through its dendrites. The outgoing signal to other neurons flows along its axon. A neuron may have many thousands of dendrites, but it will have only one axon. The fourth distinct part of a neuron lies at the end of the axon, the axon terminals.
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1.4 TYPES OF NEUROTRANSMITTERS
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Acetylecholine |
Choline |
CNS, parasympathetic nerves |
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Serotonin 5-hydroxyphane (5-HT) |
Tryptophane |
CNS, chromatin cells of the gut, enteric cells |
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GABA |
Glutamine |
CNS |
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Glutamate |
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CNS |
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Aspartate |
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CNS |
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Glycine |
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Spinal cord |
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Histamine |
Histidine |
Hypothalamus |
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Epinephrine Synthesis pathway |
Tyrosine |
Adrenal medulla, some CNS cells |
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Norepinephrine Synthesis pathway |
Tyrosine |
CNS, sympatheic nerves |
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Dopamine |
Tyrosine |
CNS |
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Adenosine |
ATP |
CNS, peripheral nerves |
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ATP |
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Sympathetic, sensory, enteric nerves |
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Nitric oxide,NO |
Arginine |
CNS, gastrointestinal tract |
CHAPTER 2
STEPS OF CHEMICAL NEUROTRANSMISSION
Schematic illustration of a synapse.
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Step 1. The neurotransmitter is manufactured by the neuron and stored in vesicles at the axon terminal. |
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Step 2. When the action potential reaches the axon terminal, it causes the vesicles to release the neurotransmitter molecules into the synaptic cleft. |
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Step 3. The neurotransmitter diffuses across the cleft and binds to receptors on the post-synaptic cell. Step 4. The activated receptors cause changes in the activity of the post-synaptic neuron. |
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Step 5. The neurotransmitter molecules are released from the receptors and diffuse back into the synaptic cleft. |
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Step 6. The Neurotransmitter is re-absorbed by the post synaptic neuron. This process is known as Reuptake. |
CHAPTER 3
NEUROTOXICITY AND DISEASE
The general point of focus in this section will be the role of Glutamate transporters in neurodegenerative Diseases. How ever it is worth nothing that all transporters have diseases
3.1 ALZHEMER’S DISEASE (AD)
Glutamate toxicity plays a role in neurodegeneration in AD. Reduced glutamate transporter expression and uptake are associated with (AD). Experiments reveal the uptake is reduced in patients with AD.
3.2 HUNTINGTONS’ DISEASE (HD)
HG is a genetic disease arising from expansion of CAG codons for glutamine, resulting in a polyglutamine (PolyQ) of at least 30 residues in the protein Huntington. This mutation leads to deep cortical layers and degeneration of the striatum. The hippocampus and hypothalamus are also affected.
There are a variety of ways the mutant Huntington could result in neurodegeneration such as formation of protein aggregates, effects on endocytosis and exocytosis and interaction with other proteins.
Mutant Huntington with the poly Q expansion displays decreased binding to post synaptic density protein 95(PSD-95) , freeing PSD-95 to bind NMDA receptors to the cell surface, thereby stabilizing NMDA receptors and increasing receptor activation
In summary, mutant Huntington may decrease glutamate transporter levels, resulting in decreased glutamate uptake and exacerbating excitotoxicity
3.3 PARKINSON’S DISEASE (PD)
The hallmarks of PD are striking degeneration of dopaminergic nigrostriatal neurons and the presence of lewey bodies; the loss of nigrostriatal neurons leads to motor dysfunction including tremor rigidity and bradykinesia
One hypothesis is that the over activation of glutamate receptors on nigrostriatal neurons may contribute to excitotoxic death.
Drugs that increase glutamate uptake have beneficial effects in models of PD. NMDA antagonists provide short term protection after N-methyl-1,4-phenylpyridium administration in rat.
3.4 EPILEPSY
Epilepsy is a common neurologic disorder; by 20years of age, 1% of the population will have developed epilepsy, and the incidence increases to 3% by 75years of age.
In addition to perturbations to the GABA-ergic system, alterations in the glutamatergic system have been hypothesized to play a role in the development of seizures and epilepsy.
Studies have shown results suggesting that impaired glutamate homeostasis maybe a factor contributing to patient’s epilepsy (JEN, et al 2005)
In contrast to decreased levels of glutamate transporters, increased levels of glutamate transporters have also been described in animal models of epilepsy. Given that glutamate transporter knockout or knockdown leads to seizures, it seems likely that increases in glutamate transporters might represent a compensatory neuroprotective mechanism, rather than contribute to epileptogenesis.
3.5 CEREBRAL ISCHEMIA
Stroke is the third leading cause of death in the U.S, and the predominant type of stroke is cerebral ischema. There is reasonable evidence that glutamate-mediated excitotoxicity, imflammation, and cell death contribute to the neurodegeneration observed after death.
In humans that experience stroke, the concentration of glutamate in the plasma and cerebrospinal fluid is significantly elevated in patients with a large cerebral infarct. However, glutamate concentrations do no necessarily correlate with initial stroke severity, suggesting that there may be some glutamate susceptibility that is unique among individuals.
3.6 GLUTAMATE TRANPORTERS AND OTHER DISORDERS
Decreased levels of glutamate transporters seem to be a common observation in many neurodegenerative diseases. Nieman-Pick disease symptoms range from ataxia and dystomia to dementia, and are due to mutations in genes for proteins that affect intracellular transport of cholesterol leading to accumulation of cholesterol in the lysosomes, neural swelling and neural death.
Glutamate transporter dysfunction may also contribute to HIV-associated dementia (HAD). Transporter alterations have also been implicated in different models of CNS injury, psychiatric illnesses, including schizophrenia.
3.7 NEUROTOXICITY BY OTHER SUBSTANCES
Chronic dosing of isoniazid in experimental animals causes degeneration of the peripheral nerves. Peripheral neuropathy in man due to isoniazid in ma n is influenced by acetylator phenotype being predominantly found in slow acetylators.
6-Hdroxydopamine is a selectively neurotoxic compound which damages the sympathetic nerve endings this is due to structural similarity to dopamine and noradrenaline. It is thus actively taken up into the synaptic system along with other catecholamines. Once localized in the synapse it destroys the nerve terminal.
Neurotoxicity is also caused by neurotransmitter inhibition. For example the inhibition of cholinesterase, the enzyme responsible for hydrolyzing acetylcholine results in accumulation. The toxic effects can be divided into three types as the accumulation of acetylcholine leads to symptoms which mimic the muscarinic, nicotinic CNS actions of acetylcholine.
CHAPTER 4
HEALTH
4.1 REVERSAL OF TRANSPORTER ACTIONS
Studies have been carried out to investigate if treatment targeted towards up regulating glutamate transporters offer neuroprotection and if there are any possible deleterious side effects of over expression of glutamate transporters.
Excitatory neurotransmission at many CNS synapses depends upon AMPA-type glutamate receptors. Derangements in AMPA receptor-mediated synaptic transmission may be a contributing factor in neurological and neurodegenerative diseases and could be a target for therapeutic intervention. Drugs that positively modulate AMPA receptors by reducing AMPA receptor desensitization and/or slowing AMPA receptor deactivation, such as thiazide derivatives (cyclothiazide, diazoxide, IDRA 21) and benzoylpiperidine derivatives (1-BCP, CX516, aniracetam), facilitate AMPA receptor-mediated processes and may have beneficial therapeutic effects. For example, AMPA modulators facilitate long-term potentiation, which may be important for memory storage, and facilitate memory encoding in behavioral experiments. Thus, AMPA modulators might ameliorate memory deficits that occur in dementia, such as Alzheimer’s disease. However, AMPA receptor-mediated excitotoxicity may occur with excessive AMPA receptor activation such as in seizures or ischemia, and positive AMPA modulators would promote neuronal injury under those conditions. Regardless of the ultimate clinical utility of positive AMPA modulators, their discovery and study have already provided significant insight into the physiology and structural determinants of important AMPA receptor properties.
4.2 TREATMENT OF NEUROLOGICAL DISORDERS
Manipulations of glutamate transporters may have pharmacologic effects but it is very likely to t have some unwanted non specific side effects
Although treatment for AD designed to target glutamate glutamate for upregulation are not currently in use, one treatment option acts to decrease glutamergic activation of NMDA receptors. Memantine is an NMDA receptor partial antagonist and protects against glutamate-induced neurotoxicity without physiological activation of NMDA receptors, and has been shown to significantly reduce functional and cognitive decline in patients with AD.
It is therefore conceivable that treatment aimed at upregulating glutamate transporters could also have beneficial effects for AD patients by decreasing excitotoxicity
The major treatment of Parkinsons disease is L-3,4-Hydroxyphenyla mine (L-DOPA), to replace the progressive loss of dopamine; however repeated L- DOPA treatment leads to motor complications.
4.2 TREATMENT OF POISONING
Poisoning by organophosphorus compounds can be treated, and although the acute symptoms can be alleviated, the delayed neuropathy cannot.
1) The compound pralidoxine is administered in order to degenerate the acetycholinesterase. This forms a complex with the organophosphorus moiety.
Pralidoxime must be administered quickly as if the phosphorylated enzyme is allowed to age then it will no longer be an effective antidote.
2) The physiological effects of the accumulation of acetylcholine can be antagonized by the administration of atropine and the symptoms alleviated.
Atropine and pralidoxime have a synergistic effect and are usually taken together.
CHAPTER 5
CONCLUSION
So many conclusions can be drawn;
The neurotransmission process does not always occur so easily as expected.
The slightest change in a step leads to a disease condition.
Also there are many substances that are neurotoxic amd influence chemical neurotransmission either directly or indirectly.
REFERENCES
Richard S. Snell Clinical neuroanatomy for medical students 3rd edition
J.A. Timbrell Principles Of Biochemical toxicity 2nd edition
Donald Voet and Judith G. A Textbook of Biochemistry with clinical Relations
3rd ed
Neil A Campbell, Biology 4th edition year 1996 pg 994 to 996
PCH 362 notes of 2007/08 academic year in UB by Prof Efange
Neurobiology of Disease
Volume 5, Issue 2, August 1998, Pages 67-80
Neurotransmitters Dr. C. George Boere
Neurons, Synapses, Action Potentials, and Neurotransmission Neurons, synapse Action Potentials, and Neurotransmission by Robert Stufflebeam
Carlos G. Finlay and Michael R. Markham, Synaptic transmission in diagrams
Molecular and chemical neuroscience, vol 17 issue 5 Watanabe, Hiroshi Takeshima, Toshiya Manabe Masahiko
Standard dictionary of the English language volume one
Google image results for neurons
PRESENTED BY CHE ELVIS NKWENTI (ELVIZY)
