The first drug treatments for Parkinson's disease appeared in the 1960s. Many strategies were then developed to treat this pathology. Nowadays the treatments are mainly symptomatic. Their aim is to reduce the symptom severity but they can't slow down or stop the progression of the disease.
The symptoms of Parkinson's disease are mainly caused by a degeneration of dopaminergic neurons in the nigrostriatal pathway of the basal ganglia. The neurons of this pathway use dopamine, which is a neurotransmitter, to regulate the activity of the basal ganglia, which are themselves in charge of initiation and motor regulation. The degeneration of dopaminergic neurons will lead to a decrease in dopamine concentration, poor regulation of the pathways involved and the appearance of the characteristic symptoms of Parkinson's disease.
In order to restore dopamine control in the basal ganglia, several strategies have been established:
Increase dopamine intake: L-DOPA
The levodopa or L-DOPA is the most prescribed molecule for the treatment of Parkinson's disease. L-DOPA can pass the BBB* and is converted into dopamine at the central level by the DOPA decarboxylase.
Why not provide dopamine directly to the patient?
Dopamine, unlike L-DOPA, can't pass the BBB* effectively. Consequently, it would remain in the circulatory system and would not be available at the cerebral level.
Carbidopa or benserazide are used in association with levodopa. They limit the degradation of levodopa at the peripheral circulatory before it passes to the brain. The aim is to increase the concentration of levodopa entering the central system by decreasing its degradation at the peripheral level.
The drugs based on this interaction are:
MODOPAR (levodopa/benserazide), available in oral form and prolonged release to limit the number of times the drug is taken.
SINEMET (levodopa/carbidopa): available in oral and prolonged release form.
DUODOPA (levodopa/carbidopa): available as an intestinal gel. An intestinal probe is implanted and allows the gel to be administered.
Limit dopamine degradation
At the physiological level, dopamine is metabolized by specific enzymes. In order to increase the available concentration of dopamine, treatments are based on blocking these enzymes to limit its degradation.
COMT inhibitor (catechol-O-methyl-transferase). This enzyme metabolizes dopamine to 3-methoxy-tyramine. The two molecules found in this family are entacapone and tolcapone. Entacapone is the most commonly used and is found in the COMTAN specialty in oral form.
MAO-B inhibitor (monoamine oxidase B). This enzyme metabolizes dopamine to DOPAC (di-hydroxyphenylacetic acid). This family includes rasagiline, selegiline and safinamide. These molecules are found in the specialties AZILECT (rasagiline), DEPRENYL (rasagiline) and XADAGO (safinamide) in oral form.
Mimicking the effect of dopamine: dopaminergic agonists
The purpose of these molecules is to reproduce the effect of dopamine on its receptors. Their structure will partly resemble the dopamine, allowing them to be recognized by the D1 and D2 receptors and to trigger a cascade of mechanisms at the cellular level.
Pramipexole (specialty: SIFROL, OPRYMEA), ropinirole (specialty: REQUIP) are found in oral form and prolonged release.
Bromocriptine (specialty: PARLODEL) may also be prescribed in oral form. In the case of severe motor fluctuations, the apomorphine pump (APOKINON) can be prescribed as an injectable solution as an adjunct treatment.
Finally, a form of transdermal patch is available and commercialized under the name NEUPRO. The dopamine agonist used is rotigotine.
In conclusion
Current treatments aim to modify dopaminergic metabolism or increase its concentration to ensure that the functions managed by this neurotransmitter are maintained.
The treatment of Parkinson's disease is broad and not limited to drug treatment alone. Other interventions will complete this care. Surgical intervention, deep brain stimulation, may be proposed in some cases.
Rehabilitation can compensate for some of the observed motor symptoms that are not very responsive to drug treatment, such as axial disorders.
Current technology now makes it possible to support care and rehabilitation. New solutions are being developed, such as the WALK, a medical device based on the use of a recognized rehabilitation technique.
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