Parkinson’s Disease Drug Therapy: The Role of Levodopa and Carbidopa in Treating Disease Symptoms By: Nicole Hume

Overview of Parkinson’s Disease: Common Symptoms and Manifestations Parkinson’s Disease is a nervous system disease that affects movement. The symptoms of this disease are progressive, possibly beginning with a small tremor of the hand, slowing of movements, or stiffness. Slurred speech is another symptom of the disease, and symptoms become worse as the disease progresses. Although these symptoms seem like a problem with muscle, the root cause of the disease is in the nervous system. The nervous system is the network of neurons in our body responsible for transmitting nerve impulses so we can carry out actions such as muscle movement and contraction. Unfortunately, there is no cure today for Parkinson’s Disease, but the symptoms can be treated with drugs Levodopa (L-Dopa) and carbidopa. Figure 1 shows the common symptoms of Parkinson’s Disease. Figure 1: Common symptoms of Parkinson’s Disease

Development of Parkinson’s Disease through Loss of Dopaminergic Signaling Parkinson’s Disease arises as a result of nerve cells called neurons gradually breaking down or dying in the brain. These nerve cells are located in the substantia nigra region of the midbrain. The substantia nigra is a part of the brain that plays a role in movement and requires the neurotransmitter dopamine, a chemical responsible for signaling connections in the brain that lead to outward changes such as movement. In patients with Parkinson’s Disease, these dopaminergic neurons (neurons that produce dopamine and transmit dopamine signals) are destroyed. Therefore dopamine is no longer produced in this area of the brain and cannot signal to control body movements. Figure 2 compares a normal neuron and a Parkinson’s affected neuron. It is estimated that 70% of neurons in the substantia nigra are destroyed at the time of first symptoms. As more neurons die, the symptoms become worse. It is not understood how these neurons die, but Parkinson’s Disease drug therapy involves promoting an increase in dopamine levels in the brain to promote dopaminergic signaling in the substantia nigra, ultimately leading to body movements. Figure 2: Comparison dopamine signaling in a normal neuron compared to a Parkinson’s Disease affected neuron

Figure 1 image from http://spinalstenosis.org/blog/pain-parkinsons-disease/ Figure 2 image from http://healthlifemedia.com/healthy/what-is-parkinsons-disease/

Mechanism of Parkinson’s Disease Drug Therapy The most common therapy involves levodopa (L-Dopa), which is taken in combination with carbidopa. Both drugs work together to decrease the symptoms of Parkinson’s disease.

L-Dopa L-Dopa has been the most effective treatment for Parkinson’s for the last thirty years. This drug is a dopamine precursor; it is a molecule that is converted to dopamine by an enzymatic reaction once it is inside the body. L-Dopa is taken orally, absorbed in the blood stream, and crosses the blood-brain barrier. The blood-brain barrier (BBB) is a filter that selectively allows the passage of certain substances from the periphery into the brain and vice versa. L-Dopa can cross the blood-brain barrier while dopamine cannot, which is why L-Dopa is given as the drug instead of dopamine. Once L- Dopa crosses the blood-brain barrier, it is converted to dopamine by an enzyme called DOPA Decarboxylase (DDC). This enzymatic reaction increases dopamine levels in the brain so signaling for movement in the substantia nigra can occur. Figure 3 depicts the action of L-Dopa once is has entered the neuron. L-Dopa is converted to dopamine inside the neuron, where it is packaged into a vesicle. The vesicle travels to the end of the neuron and enters the synapse, where it releases dopamine. The dopamine can then bind to a receptor on the receiving cell to pass on the message. These messages consist of electrical signals that ultimately lead to muscle movement. Figure 3: The Mechanism of L-Dopa Inside the Neuron to promote dopaminergic signaling Carbidopa Only 1-3% of oral L-Dopa reaches the brain before it is metabolized to another substance that is neither a dopamine precursor nor cross the blood-brain barrier, which means that when taking L-Dopa alone, only a small percentage of the drug taken is effectively alleviating symptoms of Parkinson’s Disease. This problem arises because DDC exists in the peripheral tissues as well and converts L-Dopa to dopamine before it is able to cross the blood-brain barrier. When this reaction occurs, no dopamine is able to reach the brain and produce dopaminergic signaling needed for movement. To avoid this problem, carbidopa is given with L-Dopa. The mechanism of action of carbidopa involves the inhibition of DDC. The drug binds to the enzyme outside of the BBB and prevents it from Figure 4: General Overview of Levodopa/Carbidopa interacting with L-Dopa, therefore no conversion to Therapy in the Peripheral and Central Nervous System dopamine occurs. Carbidopa is effective because it is not able to cross the blood-brain barrier and only inhibits DDC in the periphery. By inhibiting DDC in the periphery, absorbed L-Dopa can cross the blood-brain barrier and enter the brain where it is converted to dopamine by the DDC enzymes in the brain that are not inhibited. Figure 4 depicts this process, showing that the conversion of L-Dopa to dopamine is inhibited by carbidopa, then L-Dopa can cross the BBB, enter the brain, and be converted to Dopamine by the enzyme DDC.

Figure 3 image from http://www.nobelprize.org/nobel_prizes/medicine/laureates/2000/press.html Figure 4 image from http://m.blog.daum.net/ni-co2/15005700

Conclusion Parkinson’s Disease is a nervous system disease that leads to tremors, slowed movement, and slurred speech. These symptoms occur as a result of dopaminergic neuron degeneration in the substantia nigra region of the brain. This region of the brain is responsible for movement and relies on dopamine to send these movement signals. Drug therapy for Parkinson’s Disease is aimed at alleviating symptoms by increasing the amount of dopamine in the brain. To do so, Levodopa (L-Dopa) is administered along with carbidopa. L-Dopa is taken orally, is absorbed into the blood stream, and crosses the blood brain barrier. Once the drug is inside the brain, DOPA Decarboxylase converts L-Dopa to dopamine to increase the amount of dopamine for signaling in the substantia nigra. As a result, the physical symptoms of Parkinson’s Disease are alleviated. However, only a small percentage of L-Dopa can reach the site of action in the brain because it is metabolized in the periphery. Carbidopa is used to inhibit the conversion of L-Dopa to dopamine before it reaches its site of action. This inhibition allows L-Dopa therapy to be more effective and allow people with Parkinson’s Disease to control their muscle movements. In the future, an ideal drug therapy would be to target the degenerated neurons in the substantia nigra. However, alleviating the symptoms is the most effective treatment today.