Biochemistry of ism

8/4/2019 Biochemistry of ism

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BIOCHEMISTRY OF

PARKINSONISM

BY STUDENTS: 325-333 3RD YEAR

2010 \ 2011

Mansoura University

Faculty of pharmacy

Biochemistry department


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INDEX:

INTRODUCTION 2

BIOCHEMISTRY OF PARKINSONISM. 4

INTERACTION OF DOPAMINE AND ACH. 4

DOPAMINE BIOSYNTHESIS. 5

COENZYMES INVOLVED IN DOPAMINE BIOSYNTHESIS. 6

NEUROMELANIN. 7

CELL DAMAGE. 8

OVERVIEW OF DRUGS OF PARKINSONISM. 9

TOXIC CAUSES OF PARKINSON'S DISEASE 11

REFRENCES. 13(523-555 ) 41


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1- INTRODUCTION :

Parkinsons disease is a progressive

neurological disorder of muscle movement,

characterized by tremors, muscular rigidity,

bradykinesia (slowness in initiating and carrying

out voluntary movements), and postural and

gait abnormalities. Most cases involve people

over the age of 65, among whom the incidence

is about 1 in 100 individuals.

The cause of Parkinson's disease is unknown

for most patients. The disease is correlated with

destruction of dopaminergic neurons in the

substantianigra with a consequent reduction of

dopamine actions in the corpus striatumparts

of the brain's basal ganglia system that are

involved in motor control. The loss of dopamine

neurons in the substantianigra is evidenced bydiminished overall uptake of dopamine

precursors in this region, which can be

visualized using positron-emission tomography and the dopamine analog

fluorodopa . Genetic factors do not play a dominant role in the etiology of

Parkinson's disease, although they may exert some influence on an

individual's susceptibility to the disease. It appears increasingly likely that

an as-yet-unidentified environmental factor may play a role in the loss of

dopaminergic neurons.

Substantianigra: The substantianigra, part of the extrapyramidal

system, is the source of dopaminergic neurons that terminate in the

striatum (shown as red neurons in the Figure). Each dopaminergic

neuron makes thousands of synaptic contacts within the neostriatum

and, therefore, modulates the activity of a large number of cells.

Positron-emission tomographic scan of the

brain showing the difference in fluorodopa

(FDOPA) levels between those with and

without Parkinson's disease.


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These dopaminergic projections from the

substantianigra fire tonically rather than in

response to specific muscular movements or

sensory input. Thus, the dopaminergic system

appears to serve as a tonic, sustaininginfluence on motor activity rather than

participating in specific movements.

Neostriatum: Normally, the neostriatum is

connected to the substantianigra by neurons

that secrete the inhibitory transmitter GABA at

their termini in the substantianigra. In turn, cellsof the substantianigra send neurons back to the

neostriatum, secreting the inhibitory transmitter dopamine at their

termini. This mutual inhibitory pathway normally maintains a degree

of inhibition of the two separate areas. In Parkinson's disease,

destruction of cells in the substantianigra results in the degeneration

of the nerve terminals responsible for secreting dopamine in the

neostriatum. Thus, the normal modulating inhibitory influence of

dopamine on cholinergic neurons in the neostriatum is significantlydiminished, resulting in overproduction or a relative overactivity of

acetylcholine by the stimulatory neurons .This triggers a chain of

abnormal signaling, resulting in loss of the control of muscle

movements.

Secondary parkinsonism:Parkinsonian symptoms infrequently

follow viral encephalitis or multiple small vascular lesions. Drugs such

as the phenothiazines and haloperidol, whose major pharmacologic

action is blockade of dopamine receptors in the brain, may alsoproduce parkinsonian symptoms. These drugs should not be used in

parkinsonian patients.


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2- BIOCHEMISTRY OF PARKINSON'S DISEASE :

a- The interaction of dopamine and acetylcholine :

The primary symptoms of Parkinson's disease are due to excessive muscle

contraction.Acetylcholine controls muscle contraction via the five cholinergic receptors:

m1, m2, m3, m4, and m5. The receptors m1, m3 and m5 are stimulatory.

The receptors m2 and m4 are inhibitory. The combined stimulatory effect of

m1, m3 and m5 is more powerful in total than the combined inhibitory effect

of m2 and m4. So the overall effect of acetylcholine is to stimulate muscle

contraction.

Dopamine affects muscle contraction via the five dopamine

receptors: D1, D2, D3, D4, and D5. The receptors D2, D3

and D4 are inhibitory. The receptors D1 and D5 are

stimulatory. The combined inhibitory effect of D2, D3 and D4

is more powerful in total than the combined stimulatory

effect of D1 and D5. So the overall effect of dopamine is to inhibit muscle

contraction.

Parkinson's disease consequently occurs when the effect of dopamine is

less than that of acetylcholine. Dopamine deficiency rather thanacetylcholine excess is normally responsible for this occurring.

Symptoms usually only begin to appear after a reduction down to about

25% of the normal activity of the dopaminergic neurons. The level of

dopamine tends to continue to fall slowly over time, with an attendant

worsening of symptoms.

DOPAMINERGIC NEURONS

Dopamine is produced in the dopaminergic neurons, one of dozens of celltypes in the brain. Dopamine formation is this cell's unique function. Nearly

all cell typesreproduce. There are only a few cell types that dont. One of

these is the dopaminergic neurons - the cells involved in Parkinsons

Disease. So there is irreversible cell loss in Parkinsons Disease. However,

no study has ever demonstrated the widely held belief that there is


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considerable, and therefore overwhelming cell loss in Parkinson s disease.

The studies previously claimed to show this have actually demonstrated

greatly reduced cell activity rather than a loss of the cells themselves. They

have used measures such as enzyme activity or the f-Dopa PET scan. Yet,

neither of these actually measure cell loss. Despite this, claims of massivecell loss in Parkinsons disease widely persist.

b- DOPAMINE BIOSYNTHESIS:

The primary fault in Parkinson's disease is that, whatever the cause, there

is insufficient dopamine. Dopamine is formed in the dopaminergic neurons

by the following pathway:

L-tyrosine L-dopa dopamine

The first step is biosynthesised by the enzyme tyrosine 3-monooxygenase

[1.14.16.2] (which is more commonly called by its former name tyrosine

hydroxylase). The following is the complete reaction:

L-tyrosine + THFA + O2+ Fe2+ L-dopa + DHFA + H2O + Fe

2+

So for L-dopa formation, L-tyrosine, THFA (tetrahydrofolic acid), and

ferrous iron are essential. The activity of this enzyme is often as low as

25% in Parkinson's disease, and in severe cases can be as low as 10%.This indicates that one or more of the elements required for the formation

of L-dopa are in insufficient quantities.

The second step in the biosynthesis of dopamine is biosynthesised by the

enzyme aromatic L-amino acid decarboxylase [4.1.1.28] (which is more

commonly called by its former name dopa decarboxylase). The following is

the complete reaction:

L-dopa + pyridoxal phosphate dopamine + pyridoxal phosphate + CO2So for dopamine biosynthesis from L-dopa, pyridoxal phosphate is

essential. The activity of the enzyme rises and falls according to how much

pyridoxal phosphate there is. The level of this enzyme in Parkinson's

disease can also be around 25% or even far less.


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c- COENZYMES INVOLVED IN DOPAMINE BIOSYNTHESIS:

Besides two enzymes being required for the formation of dopamine from L-

tyrosine (L-tyrosine >>> L-dopa >>> dopamine), three coenzymes are also

required. Enzymes are substances that will enable a specific chemicalreaction to take place in the body. Coenzymes are substances that assist

enzymes. Some enzymes (including those involved in dopamine

biosynthesis) will not function without coenzymes.

The three coenzymes involved in the formation of dopamine are : THFA

(for L-tyrosine to L-dopa), pyridoxal phosphate (for L-dopa to dopamine),

and NADH (for the formation of THFA and Pyridoxal phosphate). They are

made from vitamins via the following means :

Folic acid dihydrofolic acid tetrahydrofolic acid

Pyridoxine pyridoxal pyridoxal 5-phosphate (this requires zinc

as a cofactor)

Nicotinamide NMN NAD NADH (or NADP) NADPH

G-PROTEINS

In order to relieve Parkinson's disease, dopamine (or dopamine agonists)

must stimulate dopamine receptors, which must in turn stimulate the G

proteins :

L-tyrosine L-dopa dopamine dopamine receptors (D2, D3, D4)

> G proteins

G proteins consist of three parts : alpha - beta - gamma, that are linked to

each other. There are three types of beta unit (1, 2, 4), and seven types of

gamma unit (2, 3, 4, 5, 7, 10, 11). However, they do not matter much to

Parkinson's Disease.

What matters to Parkinson's Disease are the alpha subunits, because it is

actually these that ultimately relieve (or aggravate) Parkinson's disease.

There are five types:

G proteins that aggravate Parkinson's disease : Gs 1 alpha


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G proteins that relieve Parkinson's disease : Gi 1 alpha, Gi 2 alpha,

Gi 3 alpha

G proteins that have little effect on Parkinson's disease : Go alpha

The sole purpose of dopamine (or dopamine agonists) stimulatingdopamine receptors is to cause the alpha subunits (the active part of G

proteins) to break away from the rest of the G protein. Without this

occurring almost everybody would have Parkinson's disease. Once the

alpha part of G proteins is released, via cyclic AMP, it takes the final action

in the series of event that leads to the ridding of Parkinson's Disease,

which is to inhibit the cells it has effect on.

NEUROMELANIN

In the cells involved in Parkinson's disease (the dopaminergic neurons) the

function is to produce dopamine. In the melanocytes, which are in the skin,

the function is to produce the pigment melanin. Melanin is what causes

people to suntan. Although they end up with different substances

(dopamine and melanin), both of these cells start off with L-tyrosine, and

both of them form L-dopa as well:

dopaminergic neurons : L-tyrosine > L-dopa > dopamine

melanocytes : L-tyrosine > L-dopa > melanin

In the dopaminergic neurons, when somebody can not form

dopamine, they can accidentally form melanin instead. In the

brain it is called neuromelanin because of the different amino

acids it is attached to. However, this is not a normal

mechanism, and it occurs via a different mechanism from that

found in the skin. The formation of neuromelanin in the brain

is often claimed to be what happens in healthy brains. Healthy brains aresupposed to be darker in the part of the brain called the substantianigra.

However, it is actually due to the biochemical mechanisms not working

properly. As not much L-dopa is formed in Parkinson's disease, there isn't

much capacity for that L-dopa to accidentally form melanin in the brain. So

people with Parkinson's disease can tend to have not much pigment in the


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part of the brain called the substantianigra. However, that does not cause a

medical problem because melanin is not supposed to be in the brain.

CELL DAMAGE

The primary natural means via which cell damage can occur in Parkinson'sdisease is due to the reaction from L-tyrosine to L-dopa not taking place.

The following is what should happen :

L-tyrosine + THFA + O2 + Fe2+ L-dopa + DHFA + H2O + Fe2+

However, if for example, the THFA in the above reaction is lacking, the

following can happen instead :

L-tyrosine + Fe2+ + O2 L-tyrosine + Fe3+ + O-2 (superoxide anion)

As can be seen there is no L-dopa formed in the faulty reaction, and the

superoxide anion is formed instead. The superoxide anion is one of the

most highly destructive elements in cells. The formation of L-dopa can also

fail to take place if L-tyrosine is deficient.

So the simplest means of preventing cell damage from taking place is to

ensure that you have those substances required for the formation of L-

dopa, which are L-tyrosine, THFA (which is made from the vitamin folic acid

using nicotinamide), and ferrous iron.

Vitamin C and vitamin E have been used to try to help to prevent cell

damage in Parkinson's Disease. This is because they are claimed to assist

in two enzyme reactions in the brain that get rid of the superoxide anion

once it has been formed :

Superoxide dismutase [1.15.1.1] : 2O-2 + 2H+ H2O2+ O2

Catalase [1.11.16] : H2O2 H2O + 1/2 O2

However, the problem with the use of vitamin C and vitamin E in trying to

prevent cell damage is that they do nothing at all to prevent the original

source of the problem, which is the formation of superoxide anion.


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3-an overview of the medication forParkinsons disease :

Most symptoms of Parkinsons disease are attributable to the lack ofdopamine within the striatum of the brain. Thus, the majority ofantiparkinson drugs are aimed at temporarily replenishing, mimickingor enhancing dopamine. Drugs that alter dopamine levels are oftencalled dopaminergic drugs. These compounds are intended toalleviate muscle rigidity, improve speed and coordination ofmovement, and lessen tremor. Levodopa and dopamine agonists arethe key dopaminergic medications used to treat PD. Both drugsincrease dopamine levels in the brain, but they do so by differentmeans. Levodopa, given in combination with carbidopa, is convertedby brain cells into dopamine. Dopamine agonists, by contrast, do nothave to be converted into dopamine; rather, they mimic dopamine

and act directly on dopamine receptors in the brain. Levodopa anddopaminergic drugs are considered first-line treatments, meaningthey are usually the first medications to be prescribed for PD. Otherdrugs such as and COMT inhibitors MAO-B inhibitors alter dopaminelevels by preventing the breakdown of levodopa. These medicationsare usually prescribed in addition to levodopa and / or a dopamineagonist, so are considered second line and third line treatments.information on these medications.In PD, low dopamine levels mayupset the balance of dopamine and another chemical In the brain,

acetylcholine. Anticholinergic medications are sometimes prescribedin an effort to restore this balance. These drugs may be helpful fortremor that does not respond to other medications, and areconsidered a third line treatment. Chapter 3 provides additionalinformation on anticholinergic drugs.

Parkinsons medications, including common dosages, side effects,and indications are summarized in the table next page.


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4-TOXIC CAUSES OF PARKINSON'S DISEASE

Paraquat

Paraquat is a quaternary ammonium herbicide. Other members of this

class include diquat, cyperquat, diethamquat, difenzoquat andmorfamquat. Pesticides are known to be associated with anincreased rate of Parkinson's Disease. Paraquat structurallyresembles MPTP and its metabolite MPP+. MPTP and MPP+ areneurotoxic chemicals, that induce Parkinson's Disease inexposed humans. Paraquat might therefore might, as do MPTPand MPP+ inhibit tyrosine hydroxylation, which is essential for theformation of dopamine.

ROTENONE

Rotenone is an insecticide that has the potential to cause Parkinson'sdisease. Insecticides are also known to affect well water. Rotenone iscommonly used in powdered form to treat parasitic mites on chickens andother fowl, and so can be found in poultry. Rotenone isproduced by extraction from the roots, seeds, and leavesof certain tropical legumes. Rotenone inhibits tyrosinehydroxylation, which is essential for the formation ofdopamine. So rotenone could cause Parkinson's diseaseby lowering dopamine levels. When given intravenouslyto mice, rotenone has been demonstrated to cause amodel of Parkinson's disease. Rotenone toxicity is alsocaused by complex I inhibition, depletion of cellular and oxidative damage.These processes cause loss of midbrain dopaminergic neurons, leading todepletion of dopamine in the brain.

MANGANESE

Manganese can cause manganism, an irreversible neurological disordersimilar to Parkinson's disease. Occupational exposures occur mainly in

welding, mining as miners are surrounded by manganese dustand airborne manganese particles, alloy production, processing,ferro-manganese operations especially in which manganese oreor manganese compounds are turned into steel, and work withagrochemicals. The towns and communities surrounding theareas of manganese heavy industry could also become affectedby toxic exposure to manganese. It is also hypothesized that


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long-term exposure to the naturally-occurring manganese in shower wateralso puts people at risk. Manganese inhibits tyrosine hydroxylation, whichis essential for the formation of dopamine. So manganese may causeParkinson's disease by lowering dopamine levels.

TOLUENE

Toluene is a solvent that has been shown to cause Parkinson's Disease, or

that has been associated with people with Parkinson's disease.

Toluene is used as an octane booster in fuel, as a solvent in

paints, paint thinners, chemical reactions, rubber, printing,

adhesives, lacquers, leather tanning, disinfectants, and to

produce phenol and TNT (a component of explosives). It is also

used as a raw material for toluene di-isocyanate, which is used in

the manufacture of polyurethane foams. The precise means of toxicity of

toluene is not known.

MERCURY

Mercury toxicity is a known cause of symptoms that mimic Parkinson's

disease, especially tremor. One of the chief targets of the toxin is the

enzyme pyruvate dehydrogenase (PDH). The enzyme is

irreversibly inhibited by several mercury compounds, the lipoic

acid component of the multienzyme complex binds mercurycompounds tightly and thus inhibits PDH. However, the cause

of the symptoms o f Parkinson's disease is likely to be due to

the fact that mercury potently causes the release of dopamine, thereby

lowering dopamine levels. Mercury is found in a wide variety of sources:

dietary fish intake, ethnic over-the-counter medications, occupational

exposures to mercury vapour, possession of dental amalgam fillings, gold

production, skin ointment, some soaps.


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References:

1-BOOKS:

LIPPINCOTTS ILLUSTRATED REVIEWS PHARMACOLOGY 4THEDITION.

Parkinson Disease: Medications 3rd Edition by Jill Marjama-Lyons,M.D.

LIPPINCOTTS ILLUSTRATED REVIEWS BIOCHEMISTRY 5THEDITION

2- WEBSITES:

WWW.WIKIPEDIA.ORG

http://www.viartis.net/parkinsons.disease/toxic.causes.htm
http://www.wikipedia.org/http://www.wikipedia.org/http://www.viartis.net/parkinsons.disease/toxic.causes.htmhttp://www.viartis.net/parkinsons.disease/toxic.causes.htmhttp://www.viartis.net/parkinsons.disease/toxic.causes.htmhttp://www.wikipedia.org/


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