Norepinephrine inactivation

Monoamine Oxidase Inhibitors. MAOIs inactivate the enzyme MAO, which is responsible for the oxidative deamination of a variety of endogenous and exogenous substances. Among the endogenous substances are the neurotransmitters, norepinephrine, dopamine, and serotonin. The prototype MAOI is iproniazid [54-92-2] (25), originally tested as an antitubercular dmg and a close chemical relative of the effective antitubercular, isoniazid [54-85-3] (26). Tubercular patients exhibited mood elevation, although no reHef of their tuberculosis, following chronic administration of iproniazid. In... 

The primary mechanism used by cholinergic synapses is enzymatic degradation. Acetylcholinesterase hydrolyzes acetylcholine to its components choline and acetate it is one of the fastest acting enzymes in the body and acetylcholine removal occurs in less than 1 msec. The most important mechanism for removal of norepinephrine from the neuroeffector junction is the reuptake of this neurotransmitter into the sympathetic neuron that released it. Norepinephrine may then be metabolized intraneuronally by monoamine oxidase (MAO). The circulating catecholamines — epinephrine and norepinephrine — are inactivated by catechol-O-methyltransferase (COMT) in the liver. 

Because duration of activity of the catecholamines is significantly longer than that of neuronally released norepinephrine, the effects on tissues are more prolonged. This difference has to do with the mechanism of inactivation of these substances. Norepinephrine is immediately removed from the neuroeffector synapse by way of reuptake into the postganglionic neuron. This rapid removal limits duration of the effect of this neurotransmitter. In... 

MAO (monoamine oxidase) two related enzymes that inactivate neurotransmitters such as serotonin, dopamine, and norepinephrine. 

A third way of promoting norepinephrine activity is to interfere with the enzyme that inactivates norepinephrine, monoamine oxidase (MAO). The monoamine oxidase inhibitors (MAOIs) work in this way. Incidentally, inhibiting monoamine oxidase also increases serotonin and dopamine activity. 

The effect of released norepinephrine wanes quickly, because approx. 90% is actively transported back into the axoplasm, then into storage vesicles (neuronal re-uptake). Small portions of norepinephrine are inactivated by the enzyme catechol-0-methyltransferase (COMT, present in the cytoplasm of postjunctional cells, to yield normeta-nephrine), and monoamine oxidase (MAO, present in mitochondria of nerve cells and postjunctional cells, to yield 3,4-dihydroxymandelic acid). 

Inhibitors of monoamine oxi-dase-B (MAOb). This isoenzyme breaks down dopamine in the corpus striatum and can be selectively inhibited by selegiline. Inactivation of norepinephrine, epinephrine, and 5-HT via MAOa is unaffected. The antiparkinsonian effects of selegiUne may result from decreased dopamine inactivation (enhanced levodopa response) or from neuroprotective mechanisms (decreased oxyradical formation or blocked bioactivation of an unknown neurotoxin). 

The coenzyme tetrahydrofolate (THF) is the main agent by which Ci fragments are transferred in the metabolism. THF can bind this type of group in various oxidation states and pass it on (see p. 108). In addition, there is activated methyl, in the form of S-adenosyl methionine (SAM). SAM is involved in many methylation reactions—e. g., in creatine synthesis (see p. 336), the conversion of norepinephrine into epinephrine (see p. 352), the inactivation of norepinephrine by methylation of a phenolic OH group (see p. 316), and in the formation of the active form of the cytostatic drug 6-mercaptopurine (see p. 402). 

Methylations. Example (2) illustrates the inactivation of the catecholamine norepinephrine by methylation of a phenolic OH group (see p. 334). 

It is believed that tricyclic antidepressants inhibit the (neuronal) reuptake of norepinephrine (noradrenaline) and/or serotonin by presynaptic nerve endings, thus blocking one of the leading mechanisms of their inactivation, and thereby increasing the concentration of the indicated amines potentiating their effects. It should be noted that, as a rule, secondary amines, which are representatives of tricyclic antidepressants, exhibit high activity, blocking the neuronal reuptake of norepinephrine, while tertiary amines act more on the neuronal reuptake of serotonin. 

Monoaminooxidase is a complex enzymatic system that is present in practically every organ that catalyzes deamination or inactivation of various natural, biogenic amines, in particular norepinephrine (noradrenaline), epinephrine (adrenaline), and serotonin. Inhibition of MAO increases the quantity of these biogenic amines in nerve endings. MAO inhibitors increase the intercellular concentration of endogenous amines by inhibiting then-deamination, which seems to be the cause of their antidepressant action. 

Tyramine, the only indirect-acting compound, exhibits sympathomimetic effects by causing the release of endogenic norepinephrine, and it has only found practical use in experiments. It inactivates monoaminooxidase very quickly. It has no practical clinical use. 

Transport back into the noradrenergic neuron (reup-take), followed by either vesicular storage or by enzymatic inactivation by mitochondrial MAO. The transport of norepinephrine into the neurons is a sodium-facilitated process similar to that for choline transport. 

The enzyme, monoamine oxidase, exists in two forms MAO-A (intestinal mucosa and intraneuronally in the brain) and MAO-B (platelets and mainly extraneuronally in the brain). Serotonin is preferentially metabolised by MAO-A and noradrenaline (NA norepinephrine), and dopamine and lyramine by both forms. The first generation MAOI antidepressants (phenelzine, tranylcypromine, and isocarboxazid) inhibit both MAO-A and MAO-B and are thought to work by increasing the availability of 5-HT and NA in the synapse—with longer-term adaptive effects occurring as for the TCAs. These MAOls are irreversible, i.e. they permanently inactivate MAO. Thus, recovery of activity occurs slowly, over days, as new MAO molecules are synthesised. 

Newer MAOI drugs are selective for the MAO-A subtype of the enzyme, and are less likely to interact with foods or other drugs. Monoamine oxidase (MAO) inactivates monoamine substances, many of which are, or are related to, neurotransmitters. The central nervous system mainly contains MAO-A, whose substrates are adrenaline (epinephrine), noradrenaline (norepinephrine), metanephrine, and 5-hydroxyti7ptamine (5-HT), whereas extra-neuronal tissues, such as the liver, lung, and kidney, contain mainly MAO-B which metabolises p-phenylethylamine, phenylethanolamine, o-tyramine, and benzylamine. 

Monoamine oxidase inhibitors MAO is found in neural and other tissues, such as the gut and liver. In the neuron, this enzyme functions as a "safety valve" to oxidatively deaminate and inacti vate any excess neurotransmitter molecules (norepinephrine, dopamine, or serotonin) that may leak out of synaptic vesicles when the neuron is at rest. The MAO inhibitors2 may irreversibly or reversibly inactivate the enzyme, permitting neurotransmitter molecules to escape degradation and, therefore, to both accumu late within the presynaptic neuron and to leak into the synaptic space. This causes activation of norepinephrine and serotonin receptors, and may be responsible for the antidepressant action of these drugs. 

Amphetamines not only mimic the action of norepinephrine and dopamine they also boost the levels of these neurotransmitters in a synaptic cleft by blocking their removal. Normally, neurotransmitters are reabsorbed by presynaptic neurons after they have exerted their effect on postsynaptic receptor sites. This process, commonly called neurotransmitter reuptake and illustrated in Figure 14.24, is the body s way of recycling neurotransmitters, molecules that are difficult to synthesize. Special membrane-embedded proteins are required to pull once-used neurotransmitter molecules back into a presynaptic neuron. Amphetamines inactivate norepinephrine and dopamine reuptake proteins by binding to them. As a consequence, the concentration of these stimulating neurotransmitters in the synaptic cleft is maintained at a higher-than-normal level. 

THE AMPHETAMINES AND ECSTASY The stimulant drug amphetamine dramatically and rapidly induces the release of norepinephrine and dopamine (and serotonin) into the synapse and greatly slows their inactivation by blocking reuptake back into the neuron. The increased and prolonged presence of these neurotransmitters within the synapse produces heightened alertness, euphoria, lowered fatigue, decreased boredom, depressed appetite, and insomnia. Once amphetamine leaves the brain, the rebound symptoms are extreme fatigue and depression. 

Regardless of the untested merits of the above work, methylation as a first step in the deactivation of noradrenaline in the body is just as plausible as is the evidence that methylation is the final step in the synthesis of adrenaline. The evidence for and against this route of synthesis has been discussed previously in this review. Tainter etal. (155) reported that in dogs under phenobarbital anesthesia Z-arterenol had a pressor activity 1.7 times that of Z-epinephrine. In this sense then, methylation might be considered a process of inactivation. However, they found in contrast that the acute toxicity of Z-epinephrine (LDso) was about four times that of Z-norepinephrine (114) 155). 

Regulation The concentration of free fatty acids in the blood is controlled by the rate at which hormone-sensitive triacylglycerol lipase hydrolyzes the triacylglycerols stored in adipose tissue. Glucagon, epinephrine and norepinephrine cause an increase in the intracellular level of cAMP which allosterically activates cAMP-dependent protein kinase. The kinase in turn phosphorylates hormone-sensitive lipase, activating it, and leading to the release of fatty acids into the blood. Insulin has the opposite effect it decreases the level of cAMP which leads to the dephosphorylation and inactivation of hormone-sensitive lipase. 

An example of a class of drugs that interrupt neurotransmitter degradation is the monoamine oxidase (MAO) inhibitors. MAO is a mitochondrial enzyme that exists in two forms (A and B). Its major role is to oxidize monoamines such as norepinephrine, serotonin, and dopamine by removing the amine grouping from the neurotransmitters. Under normal circumstances, MAO acts as a safety valve to degrade any excess transmitter molecules that may spill out of synaptic vesicles when the neuron is in a resting state. MAO inhibitors prevent this inactivation. In their presence, any neurotransmitter molecules that leak out of the synaptic vesicles survive to enter the synapse intact. Receptors are thus exposed to a greater amount of the neurotransmitter. 

MAO inhibitors were the first widely used antidepressants, but because of various undesirable side effects they are employed today in only a more limited number of cases. People who are treated with MAO inhibitors, for example, must be careful of their diet. They should not eat food rich in tyramine or other biologically active amines. These foods include cheese, beer, and red wine. Individuals on MAO inhibitors are unable to inactivate tyramine present in the food. Because tyramine causes the release of endogenous norepinephrine, patients are susceptible to increased blood pressure (e.g., potential lethal cerebral hemorrhages) and cardiac arrhythmias. 

Early formulations of the monoamine theory of depression cited two strands of evidence. One was the effects of antidepressant drugs and the other was the effects of reserpine. Skildkraut believed that studies have shown a fairly consistent relationship between drug effects on catechloamines, especially norepinephrine, and affective or behavioural states (Schildkraut 1965, p. 509). He went on to describe how drugs that cause depletion and inactivation of norepinephrine centrally produce sedation or depression, while drugs which increase or potentiate brain norepinephrine are associated with behavioural stimulation or excitement and generally exert an antidepressant effect in man (p. 509). 

Primary amines are oxidized in the body by monoamine oxidase (MAO). MAO converts the amine to an imine, which is hydrolyzed to yield an aldehyde and ammonia. One function of MAO is to regulate the levels of the neurotransmitters serotonin and norepinephrine. Monoamine oxidase inhibitors prevent the oxidation (and inactivation) of these neurotransmitters, thereby elevating mood. MAO inhibitors were the first antidepressants, but they are used sparingly now because of numerous side effects. 

Inhibitors of monoamine oxidase A (thy-meretics). Moclobemide is the only representative of this group. It produces a reversible inhibition of MAOa, which is responsible for inactivation of the amines norepinephrine, dopamine, and serotonin (A). Enzyme inhibition results in an increased concentration of these neurotransmitters in the synaptic cleft. Moclobemide is less effective as an antidepressant than as a psychomotor stimulant. It is indicated only in depressions with extreme psychomotor slowing and is contraindicated in patients at risk of suicide. 

Q6 In comparison with the sympathetic transmitter norepinephrine, the inactivation of acetylcholine by cholinesterases is rapid so that normally the activity of acetylcholine at the synapse is relatively short-lived. The choline component is taken up into the presynaptic terminal and acetylcholine is resynthesized and stored in the synaptic vesicles. Anticholinesterases function as cholinergic stimulants in the parasympathetic nervous system since they greatly prolong and so increase the actions of endogenous acetylcholine at muscarinic receptors on the effector tissue. 

Catechol O-methyltransferase plays an important role in the catabolism of catecholamine neurotransmitters such as dopamine, norepinephrine, and epinephrine, and inactivation of catechol estrogens and catechol xenobiotics. Several different methods have been developed. 

There are two types of MAO MAO-A, found mainly in the liver and gastrointestinal tract, and MAO-B, found mainly in the brain and platelets. MAO-A in the liver is involved in the elimination of ingested monoamines (e.g. tyramine) and inactivates circulating monoamines (e.g. epinephrine, norepinephrine and dopamine) when they pass through the liver. Co-ingestion of these monoamines with MAO inhibitors leads to their unopposed action, which causes severe hypertension, so the former should be avoided. 

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