Levodopa Seminar – Adi Cohen

Introduction

Dopamine is a neurotransmitter in the brain that works in

several pathways. One of those pathways is the Nigrostriatal
pathway, which is responsible for motion regulation1,2.

In this pathway, Dopamine projections start from the

substantia nigra, and from there it goes to the striatum and
other parts of the basal ganglia1,2.

Parkinson's disease is a chronic and progressive neurodegenerative disorder, in

which neurons in the Substantia nigra are degrading and lose function over time and
causing striatal dopamine deficiency. Parkinson's disease affects 2–3% of the
population ≥65 years of age3,4.

Symptoms of Parkinson's disease include tremor, Rigidity, Bradykinesia, Gait

disturbances, Dementia/cognitive impairment, Sensory symptoms, and more5.

Parkinson's disease does not have a cure. Scientists are trying, to this very day, to
find, a good treatment for the symptoms at least.

For the motor symptoms treatment, an increase of dopamine levels in the brain, and
specifically in the Nigrostriatal pathway, is required. But a problem occurs with this
idea of treatment, for dopamine is too polar and cannot cross the blood-brain
barrier (BBB)6. For that reason, peripheral injection or oral delivery of dopamine
would not be an effective treatment.
The scientific solution

Dopamine is a neurotransmitter from the catecholamines family. The

catecholamines are various naturally occurring amines
that function as neurotransmitters and hormones in
the body. They are characterized by a catechol group
attached to an amine group6,7. The molecule L-3,4-
dihydroxyphenylalanine (L-Dopa) is also a
catecholamine. Moreover, The L-Dopa is a natural
precursor for Dopamine, and the human body can
synthase dopamine from it with only one enzyme that
is available in the body and the brain6,7.

The L-Dopa molecule can cross the blood-brain barrier

and for that reason can serve as a pro-drug and
The catecholamines family
transform to Dopamine - the molecule that will help
the patient - inside the body with the help of the enzyme Aromatic l-amino acid
decarboxylase (AADC).

Why can L-Dopa cross the BBB?

The L-dopa molecule is transported inside the brain, across the blood-brain barrier,
by the large amino acid transporter (LAT1)8–11.

Physically, the L-Dopa molecule is an amino acid and can bind to LAT1 to cross the
BBB. L-Dopa is a precursor for not only dopamine but also for a number of molecules
that are necessary to the brain like Melanin12. This mechanism, of transporting the
precursor and not the relevant molecule, can prevent flooding of the brain with too
much of the needed substance and can ensure spare substance for a few needed
molecules at the time of need, and it is reserved in the same molecule.

Another possible reason is that the body mistakes L-Dopa for the amino acid
Tyrosine and is not transporting L-Dopa intentionally.
L-Type Large Amino Acid Transporter 1

The L-type amino acid transporter 1 (LAT1), or Solute

Carrier Family 7 Member 5 (SLC7A5), is a transporter in
the blood-brain barrier that is in charge of transporting
necessary amino acids from the blood to the brain. This
transporter is Na and PH independent and is Expressed in
a variety of barriers in the human body besides the BBB,
like the Blood-retina barrier, the placenta, some cancer
cells, and more. among other things, LAT1 is in charge of
transporting the amino acid tyrosine from the blood to
the brain9–11. That might be the reason that L-dopa, which differs from tyrosine by
one hydroxyl group, could be transported too.

In recent years of research, LAT1 is becoming a potential target for drug delivery to
the brain for it can transport many molecules that are similar to the essential amino
acids.10,11 This transporter is responsible for the success of other brain-delivered
drugs like Gabapentin13 for epilepsy or Melphalan14 for brain cancer treatment.

Levodopa As a Drug

L-Dopa or Levodopa was found out to be useful for controlling Parkinson's disease
symptoms in the late 1960s, and its development represents one of the most
important breakthroughs in the history of medicine15. Like all drugs, Levodopa as a
drug has pros and cons.

The most important and indisputable pro for the drug is that it crosses the BBB and
effectively treats the condition. With the drug consumption, the tremor and other
symptoms reduce dramatically, to the point that patients even forget they have the
illness and forget to take their medicine in time.

Despite levodopa's great effectiveness, the drug also has many cons.
One of the biggest cons of Levodopa as a drug is its severe side effects. Among the
side effects are dizziness, loss of appetite, bowel problems, change in sense of taste,
forgetfulness or confusion, nightmares, sleep disorders, headache, vomiting,
depression, and more16,17. As Parkinson's disease progress, more dopamine is
needed and the dosage of levodopa has to be increased up to the point that the side
effects are too severe and the treatment must stop; in addition, as the disease
progress, one might develop nonmotor symptoms that don't benefit from levodopa
such as balance problems or freezing of gait, which could make the medication feel
less effective18.

The molecular structure of L-Dopa and its similarity to

Tyrosine is contributing to the fact that L-Dopa can cross the
BBB, but it also has a downside. In the brain, the ribosomes
can mistake L-Dopa to be L-Tyrosine and use it to build
proteins in the brain. These proteins will not be functional
and usually be degraded by the proteosome, but sometimes it can cause plaque
accumulation and result in neuronal death19,20.

The first challenge in using oral consumption of L-dopa to treat Parkinson's is a

premature transformation of L-Dopa to Dopamine, in the body before crossing the
BBB to the brain. The solution for that problem is mixing another active
pharmaceutical ingredient (API) in the formulation that will block the AAD enzyme
and will not allow the L-dopa to transform. Most of the comitial formulation today
uses Carbidopa or Benserazide that blocks the AAD but cannot cross the BBB so it
blocks the enzymatic change in the periphery and not in the brain 21. This addition
can help reduce the dosage needed of L-Dopa and reduce the side effects of large
quantities of the drug.
Another challenge for the treatment is the usage of L-Dopa as a precursor of a
different molecule - 3-O-Methyldopa. This problem can be solved by using another
API called Entacapone that will inhibit the
enzyme COMT that transforms the L-Dopa to
3-O-Methyldopa22. The commercial
formulation called STALEVO contains all
three active ingredients – levodopa,
carbidopa, and Entacapone and is considered
a highly effective drug.

The last challenge I will discuss is the quick metabolism of dopamine in the brain. In
the healthy brain, as we previously discussed, dopamine works in several pathways.
An overexpression of dopamine to the system can result in functional disorders, this
is the reason that dopamine, like other neurotransmitters, has a very short half-life
in the brain. In sick Parkinson's brain, there is a shortage of dopamine and we would
like to make it last longer. To solve this challenge, the levodopa treatment is
combined with another drug called Selegiline. Selegiline is an inhibitor of the
monoamine oxidase enzyme group (MAO), which its members are responsible for
degrading neurotransmitters. In small dosages, it will block MAO-B enzymes that
degrade dopamine23; and in larger dosages, it can block also MAO-A enzymes that
degrade serotonin and this drug is also given in cases of depression for that reason 24.

Awakenings

Awakenings is a non-fiction book by Oliver Sacks in 1973. In his book, Sacks describe
the life histories of patients who had been victims of the 1920s encephalitis
lethargica epidemic, and his efforts in the late 1960s to help these patients. This
illness is an atypical form of encephalitis. Also known as "sleeping sickness", the
patients showed symptoms of Parkinson’s disease in the brain (EEG). The treatment
he used was the then-new drug meant for Parkinson's - L-DOPA25,26.
In 1990 a movie with the same name was
based on the book and described again the
L-Dopa treatment for the patients
described in the movie.

Robin Williams and Robert De Niro

From the movie Awakenings1990

Next Directions

Although currently, L-Dopa formulations are the most effective treatment for
Parkinson's symptoms, research is conducted all over the world to find better, more
permanent, and with fewer side effects solutions for Parkinson's patients.

The known Canadian-American actor Michael J. Fox (Back to the future) was
diagnosed with Parkinson's disease in the early 1990s. His foundation, The Michael J.
Fox Foundation, was created to contribute and advance every promising research
path to a cure for the disease. Since its establishment, the foundation raised over 1
billion dollars for research27.

A new study about stem cells therapy gives new hope for further directions in
treating the illness with cell replacement28.
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