Monoamine Oxidase and Its Effects on the Brain

Emil Payawal

Emory University

 

Introduction
Monoamine Oxidase
Hormonal Influence
Parkinson's Disease
Free Radical Theories
Smoking
Criminality and Aggression
Conclusion
References


Introduction


Enzymes are molecules that enable many of the reactions in our body to happen at an accelerated rate. Without enzymes life on this earth would be very different. Enzymes work by lowering the activation level of a reaction. This enables cells to perform reactions like glycolysis in the narrow set of conditions in which the cells of our body have to live(Garret, 1999).
 

Of critical importance are the enzymes in the brain. Too little or too much of these neuronal enzymes can affect the health of the individual, or even affects a person’s personality. One interesting enzyme in the brain is called monoamine oxidase, or MAO. This enzyme is important in the breakdown of neurotransmitters. Regulation of this enzyme is very important. Without enough of this enzyme the brain would function improperly and possibly lead to mental retardation (Finber 1998). High levels of MAO has been linked to depression and  recently to Parkinson's disease (Hauptmann 1996). MAO has also been hypothesized to have roles in addiction (smoking, alcoholism) and criminality. MAO is also linked to depression, but that is discussed in another paper.


Neuronal Transmission


To understand how MAO interacts in the brain it is important to review the basics on neuronal transmission. When neurons transmit electrical signals to each other, a small quantity of neurotransmitter is released from a neuron’s axon terminal across what is called a synaptic gap. The neurotransmitter molecules then excite a receptor site of a nearby neuron. After exciting a neighboring neuron, the neurotransmitter molecules attach themselves to the axon terminal for use in the next impulse transmission. If this does not occur, normally spent parts of these molecules arc flushed form the nervous system by various enzymes. The process of which MAO helps to serve this flushing is known as oxidative deamination (Ellis 1991). Figure 1 depicts typical neuron transmission.


MonoamineOxidase


Monoamine oxidase is found mainly on the outer mitochondrial membrane and is found throughout the central nervous system. There are two different isozyme forms of MAO. Isozymes are multiple forms of an enzyme that differ from one another in one or more properties. The three dimensional forms of MAO A/B are unknown, but scientists have discovered several facts about each isozyme. MAO-A has 527 amino acids, and preferentially oxidizes the biogenic amine serotonin. MAO-B has 520 amino acids. Each structure preferentially oxidizes different neurotransmitters. MAO-B oxidizes phenylethylamine and benzylamine. Both MAO-A and MAO-B oxidize the neurotransmitters dopamine, epinephrine, tyramine and tryptamine.

The affectiveness of each isozyme is different. MAO-B seems to have a limited capacity to deaminate catecholamines. Individuals with a MAO-B deficiency appear to be mentally normal which has led many researchers to believe that MAO-A is the more important isozyme of the two. Deficiencies of MAO-A results in disturbed systemic amine metabolism, borderline mental retardation and possible cardiovascular and behavior abnormalities (Finber, 1998).


Hormonal Influence


MAO is under heavy genetic control (Nakatome 1998) and is influenced by sex and stress hormones (Ellis 1991). Specifically the sex hormones progesterone, estrogen, and androgen affect MAO levels. Progesterone has been shown to increase MAO activity. Estrogen and androgens both decrease MAO activity (Ellis 1991).

Symptoms of these reactions can be seen in humans. When women ovulate they produce excess levels of estrogen which will inhibit MAO activity which may be related to PMS. Responses to hormones were further confirmed with experiments with lab animals. These experiments have shown that when a male is castrated following puberty, it causes their MAO activity in the brain to rise (Ellis 1991). Then when they gave these animals an injection of exogenous testosterone causes they found it lowered the activity of the enzyme.
 

Hormones released during stress also affect MAO activity. Hormones released during stress include epinephrine and corticosterone. These hormones appear to depress MAO activity.


Parkinson’s Disease


Parkinson’s disease is a motor system disorder. A common feature of Parkinson’s is the masklike appearance, because of the loss of facial muscle tone. Other symptoms include stiffness in the limbs and trunk , and impaired balance and coordination. As the disease progresses, the symptoms become more severe. The disease is also chronic, meaning it lasts for many years, usually until death. The cause of the disorder is a mystery. People with Parkinson’s may have difficulty doing simple tasks such as walking and talking.
 

People who have Parkinson’s disease lose function of the dopamine neurons in an area of the brain known as the substantia nigra (Rosenweig, 1999). The dopamine which is produced in these neurons is responsible for relaying signal from the substantia nigra to the corpus striatum where it produces smooth muscle activity. When these neurons don’t produce enough dopamine, the nerves of the striatum fire out of control and victims of the disease are unable to control their movements. As previously mentioned MAO breaks down dopamine, and excesses of this enzyme have been found in individuals with Parkinson’s Disease.


Free Radical Theories


One theory about the cause of Parkinson’s Disease is that free radicals contribute to the cell death of dopaminergic neurons. This can happen when there is an increase in MAO activity as a result of aging and in neurodegenerative disorders. It has been hypothesized that when MAO oxidizes a neurotransmitter, it provides a free radical which can harm the neurons that produce dopamine. Free radicals are unstable because they lack one electron. Free radicals react with neighboring molecules to in an attempt to replace this missing electron in a process called oxidation. It was recently discovered that when MAO metabolizes tyramine, it produces an H2O2 molecule which causes oxidative damage to mitochondrial DNA of the dopamine neuron (Hauptmann, 1996). Any damage to the mitochondria of a cell would kill the cell.

A study by Nils Hauptmann et al. was conducted to determine whether the H2O2 formed during the two-electron oxidation of tyramine by the enzyme would contribute to the steady-state concentration of H2O2 which would be involved in the oxidative impairment of mitochondrial components. They examined the substrate tyramine, phenylethylamine, and benzylamine in the brains of some rats.
 

Tyramine  had the most efficient production of  H202. This was probably due to the fact that tyramine is oxidized by both isoforms of MAO which would produce a higher rate of reaction. Phenylethylamine is a preferred substrate of MAO-B and produced the second highest rate of formation. Benzylamine, which is exclusively oxidized by MAO-B, was last.

Rates of H2O2 formation during the MAO A/B-Catalyzed Oxidative Deamination of Different Amines

 

MAO isoform

v (nmol H2O2/min/mg protein)

Tyramine

A/B

1.6

Phenylethylamine

B+

1.0

Benzylamine

Benzylamine

0.4

Table 1. Hauptmann, Nils et al., “The Metabolism of Tyramine by Monoamine Oxidase A/BCausesOxidative Damage to Mitochondrial DNA.” Archives of Biochemistry andBiophysics Vol. 335, No.2, November 15, pp. 295-304, 1996. Article No. 0510

    Normally, detoxifying mechanisms are in place for the clearance of peroxide and excess Fe3+. Glutathione peroxidase will eliminate peroxide and ferritin will eliminate the excess Fe3+. However, in Parkinson’s disease, lower levels of reduced glutathione peroxidase and increased iron in the substantia nigra, suggest decreased protection against hydroxyl radical formation, leaving mitochondrial tissue vulnerable to oxidative damage. This reaction will damage the mitochondria of these dopamine producing cells, which will result in the death of the cell and reduce the production of dopamine. These discoveries have placed MAO at a special place in the pathogenesis of Parkinson’s disease.

H2O2 produces single strand breaks during the metabolism of tyramine by MAO-A/B in vitro can be considered the best evidence of oxidative damage to mitochondrial DNA, due to the diffusion of H2O2 across the mitochondiral matrix (Hauptmann 1996). HO radicals are formed in a Fenton-like reaction catalyzed by DNA-bound transition metals, which attack mainly the thymine and guanosine residues forming a primary reducing or oxidizing radical .  The radical character is transferred to the sugar moeity by HO radical leads to single strand breaks (Hauptman 1996).


MAO Inhibitors-brief history


MAO was discovered to have an important function in neurotransmission when tuberculosis patients were given the drug iproniazid. These patients experienced an "elightening effect" which is the result of increased levels of neurotransmitters. Zeller et al. demonstrated iproniazids MAO inhibitory action. Furthur studies also showed that MAO inhibition led to higher levels of serotonin and noradrenaline. The "enlightening effect" that the patients experienced and the increased levels of neurotransmitters provided the basis of introduction of MAO inhibitors in treating psychological disorders suchas depression and hopes of curing other CNS disorders. The MAO inhibitors that were developed suffered tremendous setbacks when side effects of these inhigitory drugs became apparent. MAO inhibitors caused hypertension in an effect dubbed the "cheese effect." Tyramine, and other amines found in cheeses, causes the hypertension when MAO is inhibited. This led to the discontinuation of MAO inhibitors ( Youdim, 1991)
 
During 1962 through 1972, the enzyme was purified and separated into its two forms, MAO-A and MAO-B. This discovery enabled scientists to develop drugs which would inhibit MAO without the "cheese effect" such as L-deprenyl, which only inhibits MAO-B.  The "cheese effect" was soon demonstrated to be a side effect of the inhibition of MAO-A. Early initiation of L-deprenyl and levodopa therapy has been show to retard the advancement of Parkinson’s. L-deprenyl inhibits MAO-B which increases the amount of levodopa for neurotransmission (Youdim, 1991).


Smoking


There are some interesting relationships between MAO and smoking as well. A study done by J.S. Fowler et al. Have discovered that cigarette smokers show a 40% decrease in the level of MAO-B (Fowler, 1996). As mentioned before, decrease in MAO will lead to an increase in neurotransmitter, especially dopamine. This suggests that MAO inhibition is linked with the addictive properties of cigarettes (Glassman, 1996).The mechanism of this inhibition is not known. It is believed that cyanomethylation of the reactive amino groups in the MAO protein may reduce its catalytic activity, leaving more neurotransmitters available in the synaptic gap which leads to the smokers high.

The ability of smoking to inhibit MAO-B has Fowler et al. to suspect that MAO plays a role in addiction of many drugs. Therefore smoking, or the inhibition of MAO-B, can act as a gateway to other drugs. The increased levels of dopamine plays a key role in reward signalling and addiction (Glassman, 1996). Drugs such as cocaine, amphetamine and heroin all tap into the same mesolimbic  dopamine system that smoking taps into.

L-deprenyl therapy has been reported to reduce the rate of progression in people with Parkinson’s disease, and has led some scientists to believe that cigarette smoking may actually protect smokers from contracting this disease. Increased levels of dopamine has other benefits as well, such as increased alertness and cognitive performance (Glassman, 1996).


Criminality andAggression



MAO has been shown to affect individuals behaviors. Scientists discovered that  behavior varies with different levels of the enzyme. For example, they have found that rhesus monkeys with low platelet MAO are more active, playful, gregarious, and slept less than normal monkeys (Ellis, 1991). Studies were also done on human neonates using extracted blood from their umbilical cords. Infants who tended to be fussier and who exhibited more motor acitivites had low levels of MAO. Other studies were conducted which shows that  the levels of platelet MAO in infants were inversely proportional to behavioral and emotional activity. Babies with low levels of MAO also sucked their thumbs, and bit their nails more than other babies. Overall these studies showed patterns of behavior which suggested less inhibited behavior, or even lack of self control.

These studies led scientists to theorize a relationship between MAO and its role in criminality. In fact, several studies have since found that low platelet MAO has been associated with high probabilities of criminal behavior. These studies have shown that low MAO activity  results in an individual's decreased ability or motivation for self control. Individuals with low MAO activity would then exhibit impulsive responses to the environment which would potentiate a person's likelyhood for criminality (Ellis 1991). Lack of self control and the need for immediate gratification could lead these people into the state peneteniary. Higher levels of aggression often attributed to criminals has also been attributed to MAO. Higher levels of aggression have long been associated with high levels of serotonin,  a neurotransmitter which MAO breaks down (Ellis 1991). Low levels would result in increased aggression.

Another study was done on a Dutch family who were prone to periodic violent outbursts for many generations. The men in the family lacked a gene for the production of MAO. Among these group of men, who were at times shy and non-threatening, one raped his sister , and later in a mental institution , stabbed a warden in the chest with a pitchfork. Another tried to run over his boss with a car, and two were arsonists (Goldberg,1995).

The theory behind these Jekyll-and-Hyde changes in behavior proposed by genetecist Han Brunner is that the surge of excess chemical messengers floods the victims brains causing erratic reactions to the environment. Abnormal levels of serotonin have been found in violent criminal offenders and arsonists. Scientists contend that malfunctions in genes for the production of serotonin could be the cause of the chemical imbalance (Goldberg, 1995). In addition to these studies, a French researcher used cloning techniques to create an overly aggressive mouse. Rene Hen did this by manipulating mouse fetal cells, knocking out gene coding for the production fo  14 known serotonin receptors. Then he inbreeded generations of the offspring. The result was a killer mouse, that when cornered would attack impulsivley, without the sniffing and approaching behavior that normal mice demonstrate (Goldberg 1995).


Conclusion

Hormone and enzyme activity in the brain is a fascinating topic, especially the activity of MAO. MAO is important in the oxidation of neurotransmitters in the nervous systemn and regulation of this enzyme is very important. If the enzyme is not regulated properly, many different things can happen to your central nervous system which will affect your behavior and health. Scientists still don't know many things about MAO, such as its three dimensional structures and much about its regulation, but current research has led to the discoveries of safe MAO inhibitors which are being used to treat people with diseases like Parkinson's and depression. More research into its regulation would benefit those who are afflicted with abnormal levels of this enzyme.


References


1)Ellis, Lee. "Monoamine Oxidase and Criminality: Identifying an Apparent Biological  Marker for Antisocial Behavior." Journal of Crime and Delinquency, v28, n2;May  1991

2)Finber, et al., "MAO- The Mother of all Amine Oxidases." (New York: Springer,  1998).

3)Fowler, J. S. “Inhibition of Monoamine Oxidase B in the Brains of Smokers.” Nature.Vol. 379. February 1996 pp. 733-736

4)Glassman, Alexander H, and Koob, George F. “Psychoactive Smoke.” Nature. Vol.379,February 22 1996. Pp. 677-678

5)Garret, Reginald H. and Grisham, Charles M. “Biochemistry.”, (Philadelphia: Saunders College Publishing:1999)

6)Goldberg, Jeff. "The Bad Seed: Amid Controversy, Scientists Hunt for the Aggression Gene." Omni, v17, n5, p. 16 February 1995

7)Hauptmann, Nils et al., “The Metabolism of Tyramine by Monoamine Oxidase A/BCausesOxidative Damage to Mitochondrial DNA.” Archives of Biochemistry andBiophysics Vol. 335, No.2, November 15, pp. 295-304, 1996. Article No. 0510

8)Nakatome, Masato, “Detection and Analysis of Four Polymorphic Markers at the HumanMonoamine Oxidase (MAO) Gene in Japanese Controls and Patients with Parkinson’s Disease.” Biochemical and Biophysical Research Communication, v247, n 2, June 18, 1998, p452-456 (IDRC988812)

9)Pons, C. et al. “Human Anti- Mitochondria Autoantibodies Appearing in IproniazidInduced Immunoallerguc Hepatitis Recognize Human Liver Monoamine Oxidase B.” Biochemical and Biophysical Research Communications 218, pp.118-124,  1996

10)Rosenweig, Mark R. “Biological Psychology.” (Sunderland : Sinauer Associates, Inc.,1999)

11)www.mediconsult.com/parkinsons/shareware/parkinsons/causes/ht

12)Youdim, Moussa B., “New Directions in Monoamine Oxidase A and B Selective Inhibitors” and Substrates. Biochemical Pharmacology, Vol. 41, No.2 (Pergamon  Press:London, 1991 )pp. 155-162,

13)Zubay, Geoffrey L. "Biochemistry." (Wm. C. Brown Publishers: Boston , 1998)     pp. 711