Treatments and Disease Management – Parkinson's

Since the exact cause of Parkinson’s disease remains elusive to the scientific community, there is no specific treatment that will cure the disease. However, significant advances in the field of medicine and drug therapies have made progress towards effectively manages the symptoms of the disease. Parkinson’s is, at it’s most basic, caused by a deficiency of dopamine because the cells that make it are dying. In order to correct for this problem, there are several methods of managing the symptoms and mimizing the negative affects of the disease. (Michael J Fox Foundation)

Dopamine Agonists

The first method by utilizing a dopamine agonist to stimulate the dopamine receptors, therefore compensating for the dopamine deficiency caused by the disease. Dopamine agonists are made up of two categories, ergoline and non-ergoline agonists. Both target the D2-type dopamine receptors. D2-type dopamine receptors are a class of receptor found on the membrane of neurons that when stimulated initate a signal transduction pathway that allows for coordinated movements as well as other important roles in other organ systems of the body. An ergoline agonist is a type of compound that is derived from ergoline, a compound naturally found in ergot fungi. A few of these types of agonists are Parlodel (bromocriptine) and Permax (pergolide).The other class of D2-like agonists used to treat Parkinson’s disease are non-ergoline agonists. These are not derived from ergoline and have been shown through clinical studies to be more effective and better tolerated than the ergoline agonists. A few common medications prescribed are Requip (ropoinirole) and Mirapex (pramipexole) which are also capable of binding to the dopamine receptor and initiating the same signal transduction pathways as dopamine. This doesn’t correct the underlying cause of the disease but one the pathways caused by the binding of dopamine that is affected is the regulation of calcium, which is involved in movement. This disruption is why patients with Parkinson’s disease suffer from tremors and abnormal muscle movement. (Michael J Fox Foundation)

Structure of Ergoline, found on google images
Structure of Ergoline, found on google images
Structure of  bromocriptine, found on google images
Structure of bromocriptine, found on google images
Structure of Pergolide, found on google images
Structure of Pergolide, found on google images

Anticholinergic Treatment

The second method used to treat Parkinson’s disease is with anticholinergic compounds. In the brain, dopamine is used in conjunction with acetylcholine, a different neurotransmitter, to create smooth body movements. When the dopaminergic neurons undergo apoptosis and dopamine levels fall, the balance between the dopamine and acetylcholine is disrupted. By treating with an anticholingeric substance, the amount of acetylcholine in the brain will also be reduced, therefore restoring the balance between dopamine and acetylcholine. This restoration reduces tremor and muscle stiffness in Parkinson’s patients, but not without side effects. Acetylcholine is also involved in other pathways in the brain besides movement. It plays a critical role in decision making as well as memory. When Parkinson’s patients are treated with anticholingeric medications such as Artane or Cogentin, they tend to suffer from memory impairment. Due to these side effects, this is not a common treatment option. (Michael J Fox Foundation)

Artane
Artane, found on google images
Cogentin, found on google images
Cogentin, found on google images

L-DOPA Therapy

A third way doctors treat Parkinson’s is through inhibiting the enzyme that converts levodopa to dopamine. This enzyme is called DOPA carboxylase and uses a pyridoxal phosphate (PLP or commonly known as vitman B6) cofactor. Levodopa, otherwise known as L-DOPA, binds to PLP at the amino terminus, allowing for the decarboyxlation through resonance and extensive delocalization of electrons into the PLP ring. By inhibiting this enzyme, less L-DOPA is converted to dopamine. This seems backwards as a way to treat a disease caused by a pre-exisiting deficiency of dopamine however, the carboxylase inhibitor is unable to cross the blood brain barrier. Since L-DOPA can cross the blood brain barrier, the inhibitor creates a higher concentration of L-DOPA in the blood which reaches the brain. This higher blood concentration of L-DOPA increases the amount of dopamine produced in the brain, thereby minimizing the effects of the dopamine shortage caused by the disease. Due to the large number of decarboxylase enzymes found in the body, it has been, until recently, difficult to target the specific DOPA decarboxylase. A team of researchers has isolated a compound from a plant species  Euonymus glabra that has been shown to selectively bind to the DOPA carboxylase, eliminating side effects from unwanted interactions with out decarboxylases. (Michael J Fox Foundation)

Levodopa, google images
Levodopa (L-DOPA), google images
Pyridoxal phosphate (PLP), google images
Pyridoxal phosphate (PLP), google images

Catechol-O-Methyl Transferase Inhibition

The last common method by which Parkinson’s disease is controlled is by targeting the degradation pathway of neurotransmitters. Dopamine is broken down by catechol-O-methyl transferase (COMT) which uses S-adenosylmethionine (SAM) to methylate catecholamines like dopamine. After the neurotransmitter has been methylated, it begins to be degraded by other enzymes. This methylation process is a target for Parkinson’s treatment because by inhibiting COMT, less dopamine is methylated and consequently degraded. Since not as much dopamine is being produced naturally, reducing the amount that is degraded in the brain helps keep the levels of cerebral dopamine closer to normal levels. (Michael J Fox Foundation)

Swiss PDB view of active site of COMT inhibitor with SAM and Mg2+ cofactor, SAM = yellow, Mg2+ = red, substrates = green
Swiss PDB view of active site of COMT inhibitor with SAM and Mg2+ cofactor, SAM: yellow, Mg2+: red, substrate: green
Tasmar (tolcapone), example of COMT inhibitor, google images
Tasmar (tolcapone), example of COMT inhibitor, google images

 

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History and Metabolic Context

Molecular Bases of the Disease State

Conclusions and Proposals for Future Work