BioChemical pathways
& Their Application in Biotechnology
Parkinson’s Disease, also short-handed as PD, is a progressive neurodegenerative disease that affects an individual’s motor function by way of a severe dopamine deficiency. [1] [2] [3]
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The Root of it All: Dopamine
The commonly known side effects of Parkinson’s - such as tremors and muscle rigidity - are caused by the depletion of a very important neurotransmitter in the brain known as Dopamine. Dopamine is not only responsible for the regulation of motor control, but helps control the pleasure and reward centers of the brain, various emotional responses, and more! [4] [5]
(Left) A diagram of the Substantia nigra. Image Citation [6] (Above) A real life photograph of the Substantia nigra. The one on the left belongs to an individual with PD and the one on the right belongs to a normal person. Image Citation [7]
The pictures from the slideshow are Image Citations [1] [2] [3] [4] [5]
So what’s the specific correlation between PD and Dopamine? How does this process occur exactly? Dopamine is actually produced in Substantia nigra - the area of the brain (located within the basal ganglia) responsible for voluntary movement, the production of dopamine, and mood regulation. [5] [6] [7]
The Basal Ganglia Image Citation [8]
Neural Pathways Image Citation [9]
So what's next?
The brain is composed of billions of neural networks where neurons transmit various messages to different sections of the brain. Dopamine is produced in the Substantia Nigra. From there, in an individual not affected by PD, the neurons send out fibers to the gray and white tissue located in the Corpus Stratia. Once the neurons reach their destination, Dopamine is released and the functions associated with the neurotransmitter are carried out. [6] [7] [8]
The Problem?
The issue with those afflicted with PD is that the Dopamine either dies in Corpus Stratia, dies along the way to its destination, or fails to be produced at all. For the Dopamine that is lost along the way, that actually results in an abnormal nerve-firing pattern that leads to the jerky symptoms associated with the disease.
For now, why these cells die, is a question that many researchers can't answer. All that is known is that it is this loss that leads the disease that affects so many people. [6] [7] [8] [9]
Image Citation [10]
The Four Dopaminergic Pathways
The neural pathways through which the neurons carrying Dopamine are formally referred to as the Dopaminergic pathways. In Parkinson's Disease, there are four main pathways that these cells travel through: Nigrostriatal Pathway, Mesolimbic Pathway, Mesocortical Pathway, and the Tuberoinfundibular Pathway. [11]
Image Citation [11]
Nigrostriatal Pathway
The Nigrostriatal pathway is not only one of the major pathways involved in PD, but one of the more important ones as it is linked to motor control. This pathway connects the Substantia nigra to the Striatum. When a significant portion of the Dopamine is depleted within this pathway, that is when the individual afflicted begins to experience the symptoms associated with the disease. [12] [13]
Mesolimbic Pathway
Image Citation [12]
Another Dopaminergic Pathway within in the brain is the Mesolimbic Pathway which is responsible for memory, reward, pleasure, addiction, emotion and various other motivating behaviors. The pathway originates from the VTA (Ventral Tegmental Area) to the Limbic System. [13] [14]
Mesocortical Pathway
Very similar to the Mesolimbic pathway, is the Mesocortical Pathway which is also responsible for memory, reward, pleasure, addiction, emotion, and various other motivating behaviors. The only significant difference between the two pathways is that this pathway begins in the VTA and leads to the Frontal Lobes of the brain. [13] [14]
Tuberoinfundibular Pathway
The final Dopaminergic Pathway associated with PD is the the Tuberoinfundibular Pathway which is primarily responsible for the regulation of hormones, sensory processes, and nurturing behavior. The pathway begins from the Hypothalamus and leads to the Pituitary gland. [13] [14]
Image Citations [13] [24]
The Medications
The basics have been covered. Now it's time to put everything together!
Levodopa/Carbidopa
The first medication in the series used for PD is the Levodopa/Carbidopa duo. The way Levodopa actually works is by transforming into Dopamine upon entry to the brain.
So how does this work?
Chemical structure of Levodopa. Image Citation [16]
Chemical structure of Dopamine. Image Citation [17]
Image Citations [14] [15]
Levodopa is actually a chemical precursor to Dopamine - meaning that they have similar chemical properties. When Levodopa is ingested, it is absorbed into the GI tract and then transported to the brain. Now here's where Levodopa's magic begins to work.
Unlike Dopamine, Levodopa is actually able to cross the Blood-brain barrier - short-handed as BBB. The BBB is actually semi-permeable, meaning what can cross and what can not cross is very selective. Among the things not allowed to enter the brain are foreign substances and neurotransmitters - which is why Dopamine isn’t allowed to cross. But because Levodopa can, it transforms into Dopamine and follows Dopamine regular path of motion. [15] [16] [17] [18] [19]
What about Carbidopa?
A diagram depicting how Levodopa crosses the BBB and turns into Dopamine. Image Citation [18]
Carbidopa, the second medication in this duo, is actually there to make sure Levodopa remains effective. If Levodopa was taken by itself, it would disintegrate before even reaching the brain. This disintegration is actually caused by blood enzymes known as “amino acid decarboxylases”. So in order to prevent this, Carbidopa actually prevents these blood enzymes from breaking down Levodopa. This in turn allows Levodopa to not only last longer, but be more effective. [15] [16] [19]
Dopamine Agonists
Image Citations [19]
Dopamine Agonists are another type of medication used for patients associated for PD. The way that Dopamine Agonists have been constructed is that they have a similar structure to Dopamine - different from Levodopa which was constructed to have similar chemical structure to Dopamine.
It's about Lock and Key!
The way Dopamine Agonists work is not by being changed into Dopamine like how Levodopa did, but by mimicking the action of Dopamine. It’s like lock and key. There are Dopamine receptors located within the pathway between the Substantia nigra and the Corpus Striatum. These receptors would ideally be the lock and the Dopamine would be the key. With the key in the lock, signals would normally be sent out - thus allowing fluid movement to occur.
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Because Dopamine Agonists have been created to have a similar structure to Dopamine, then they are able to take on this role as well. Thus the brain is stimulated in an identical manner - as though Dopamine was actually present.
(Far Left) A diagram depicting the lock and key method of how Dopamine Agonists work. Image Citation [20] (Left) A MRI image of the Corpus Striatum Image Citation [21]
Mao-B Inhibitor
The third commonly used medication is known as Mao-B inhibitor. In the brain, normally an enzyme called MAO-B would break down various chemicals including Dopamine. Ideally, this medication would be taken with Levodopa because it would break down these enzymes, thus allowing more Dopamine to be absorbed through the pathways. [15] [22] [23] [24] [25]
A diagram depicting how MAO-B Inhibitors work. In the diagram, "Azilect" is actually one of the pharmaceutical names for the in inhibitors. Image Citation [22]
COMT Inhibitor
The final medication used commonly for individuals with PD are COMT Inhibitors, and they are typically taken with Levodopa. Normally in the brain, Dopamine would be broken down by an enzyme known as Catechol-o-methyltransferase. This enzyme doesn’t just break down Dopamine, but several other neurotransmitters. For patients with PD, it is essential for them to take COMT inhibitors - which stop the enzyme from breaking down Dopamine - as they already have a very small reserve of the valuable neurotransmitter.
Image Citation [23]
Neurodegenerative Page
Carbidopa Image Citation [25]
Disease 1: Parkinson's Disease
What is Parkinson's Disease?
Fact!
Fact!
Tip!
Click on the blue text under "The Four Dopaminergic Pathways" to be taken to the section of the page pertaining to that word's information.
PD occurs when individuals lose up to 60-80% of their Dopamine carrying cells!
Over 1 million people in the US are affected with PD; and over 5 million people in the world are currently living with the disease!