Hypothesis, Theories, and Drugs for Treating Parkinson's Disease

This is my first post in 2023, and I will surely enjoy it. Before I continue, let me wish everyone a Happy New Year and a Happy Holiday. That said, I will be continuing with my post on Parkinson's disease. I wrote on the pathophysiology of Parkinson's disease, and in today's post, I will be writing on the Hypothetical or Theoretical part of this disease, then I will go on with the drugs to treat Parkinson's disease. Let's Begin.

It is important to know that currently when diagnosing Parkinson's disease, there isn't a special test to diagnose it. Usually, when a person looks like they have Parkinson's, the Doctors just do a simple evaluation looking at signs and symptoms, and then place them on L-Dopa (also known as levodopa, which is a medication used to treat the symptoms of Parkinson's disease and other conditions that involve dopamine deficiency), and then wait to see how the patient reacts to the treatment. There is a belief that it is a result of a mutation in the gene, basically, the Leucine-rich repeat kinase 2 (LRRK-2) which is a protein that is believed to be associated with an increased risk of Parkinson's disease. Whenever the gene mutates, it disrupts the Endosome and lysosome degradation pathway (which it normally controls when not mutated), it also alters specific proteins which are signal transducers such as RAS, MAP-Kinase, decreasing the partway, the vesicular transport process, and decrease in dopaminergic output, and the mutation can cause the phosphorylation of TAU protein leading to Neurofibullary tangles. .

The endosome-lysosome pathway functions by degrading α-Synuclein molecule but when there is a mutation in the endosome-lysosome pathway, α-Synuclein molecule increases, forming Lewy bodies which is believed to have an effect on the dopaminergic output. ,.

Another gene known as PARK-2 is a gene for encoding E3-Ubiquitin Ligase which allows proteasome to break α-Synuclein peptide. When there is a mutation in the PARK-2, deterring the gene from encoding proteasome which would break α-Synuclein, then α-Synuclein would increase in concentration, increasing Lewy body formation. ,

Deglycase (DJ-1) is another gene linked to Parkinson's disease. DJ-1 affects the proteins of oxidative stress (antioxidant proteins), as well as affects mitochondrial function. A mutation in this gene would lead to a reduction in the ability to control oxidative stress, causing an increase in reactive Oxygen Species, and also leading to an increased mitochondrial dysfunction, which will result in the death of the dopaminergic neurons. , . Similar to the reaction of the DJ-1 gene is the PINK-1 gene..

Another hypothetical belief of Parkinson's disease is Insecticides. it is believed that insecticide that contains rotenone, DDT, 2,4-dichloro phenoxy-acetic acid, dieldrin, diethyldithiocarbamate, paraquat, maneb, trifluralin, parathion, and imidazoldinethione could cause neuron death, leading to Parkinson's disease. ,.

1-methyl-4-phenyl-1,2,3,6,tetrahydropyridine (MPTP) can also cause destruction of the dopaminergic neuron, causing less dopamine release which could cause Parkinson's disease..

To synthesize Dopamine, we can start with the GI tract where Tyrosine molecule is being absorbed into the blood, moving into the axon neuron, acted by Tyrosine hydroxylase converting tyrosine into DOPA which is then acted by DOPA Decarboxylate after which decarboxylation occurs converting it to Dopamine. ,,. With an increase in action potential, causing an influx of calcium, causing the synaptic protein in the axons binds to one another. Also, the lipid bilayers fuse forming a bubble where it exocytoses Dopamine into the synaptic cleft where it binds to the dopaminergic receptors. ,. It goes back to the synaptic bulb where some of its dopamine goes into the synaptic vesicles, while others go into the monoamine oxidase B (MAO-B), where Dopamine is degraded to epinephrine norepinephrine. ,. Catechol-O-methyltransferase (COMT) enzyme transfers methyl to dopamine converting it to 3-O-Methyldopa (3-OMD) which is a metabolite of L-DOPA

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When L-DOPA is taken into the body, it is absorbed across the GI tract, the DOPA Decarboxylase enzyme acts on it, converting it to dopamine, and Catechol-O-methyltransferase (COMT) enzyme converts L-DOPA into 3-O-Methyldopa (3-OMD). When this happens, it can cause side effects such as cardiovascular complications since dopamine cannot cross the blood-brain barrier. ,. The COMT also converts L-DOPA into 3-OMD which competes with dopamine crossing into the Blood-brain barrier but it it is important to know that the drug would not have enough effects since part of it can pass through as a result of the COMT action, while the rest remain stuck and can pass through the Blood-Brain Barrier after being acted upon by DDC..

In other to get the medication to work properly the L-Dopa cannot be taken alone, it has to be taken with another drug to block these enzymes. To block DOPA Decarboxylate (DDC), a drug known as CarbiDOPA is taken in combination with lavadopa (L-DOPA). CarbiDOPA inhibits the DDC not allowing it to convert the L-DOPA into dopamine, thereby allowing more L-DOPA to be used. , . Also, COMT can be inhibited, preventing the enzyme from converting L-DOPA to 3-OMD. To do this, EntaCapone or Tolcapone can be used. Tolcapone is not a good idea because it increases liver toxicity levels because it acts on both the peripheral and the central nervous system, so Entacapone is preferable as it doesn't act on the central COMT..

Using the combination of these drugs would help treat Parkinson's symptoms but would lead to side effects such as Dyskinesia. It is important to reduce the L-DOPA dosage given when accompanied by a combination of EntaCapone, and CarbiDOPA. The L-DOPA gets converted into DOPA in the neuron, and then converted into Dopamine. Remember that there is a DeCarboxylace in the neuron but this time around, the drug CarbiDOPA cannot work as it only works on peripheral DDC. It is done by Selageline inhibiting the Monoamine Oxidase-B not allowing Dopamine to be degraded to epinephrine norepinephrine. Drugs such as Bromocriptine can be used as Dopamine Agonists in the neurons. In other to keep the balance between Acytocholine and dopamine, the Cholinergic neuron is blocked preventing acetylcholine to bind to its receptor. Drugs such as Benztopine can be used to block acetylcholine from binding to its receptor.

Conclusion

Since Parkinson's disease is a neurodegenerative disease, it is currently not treatable, but its symptoms can be treated, and to do this, more dopamine needs to be allowed into the central nervous system. Since it is a degenerative disease, these drugs can only work for a limited amount of time, over time the dopaminergic neurons decreases, causing the drugs to have less effect, and with this, there could be more side effects being noticed. Deep brain Stimulation has also been introduced in recent times to treat the symptoms of Parkinson's disease.

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Image Reference
Image 1 || Wikimedia Commons || Stalevo

Image 2 || Wikimedia Commons || Levodopa pathway