Free Radical Theories
Criminality and Aggression
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
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.
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
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,
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.
during stress also affect MAO activity. Hormones released during
stress include epinephrine and corticosterone. These hormones appear
to depress MAO activity.
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.
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.
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
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 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).
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).
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
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).
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.
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