Parkinson’s disease: Focusing on the On-Off phenomenon

In the early 19th century, Parkinson’s disease was first clinically reported by an English physician, James Parkinson. He termed the neurological condition as the shaking palsy, based on its characteristic clinical feature of the Parkinsonian tremor.

Being a neurodegenerative disorder, Parkinson’s disease causes deterioration of the dopamine-producing neurons of the nigrostriatal tract. A poorly controlled motor circuit results in a multitude of movement defects including bradykinesia, broad-based gait, and fine ‘pill-rolling’ tremors of the hands.

Levodopa, a dopamine analog, has been the mainstay of pharmacological treatment ever since the early 1960s when dopamine deficiency was first tied to Parkinsonism and levodopa was found to curb various movement deficits secondary to the neurodegenerative disorder.


Herbs containing L- Dopa: An update

“Mucuna pruriens (M.P) commonly known as velvet beans or cowitch are used in case of spasms associated with Parkinsonism. The clinical efficacy of seeds of this plant was confirmed and the efficacy was contributed to its L-Dopa content. M.P extract showed twice the anti-parkinsonism activity compared with synthetic L-Dopa.”

More here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3330839/pdf/ASL-27-50.pdf


Levodopa therapy is undertaken in gradually increasing doses so as to minimize the adverse drug effects. However, an important side effect associated with the long-term levodopa therapy is the ‘on-off phenomenon’. The term ‘off’ marks the endpoint of the therapeutic efficacy of levodopa where the primary clinical manifestations include bradykinesia, resting tremors and muscle rigidity.

Parkinson's ShuffleThis stage is also termed as ‘wearing off phenomenon’ or ‘end-of-dose deterioration’. On the contrary, a subsequent dosage of levodopa leads to rapid resolution of the ‘off’ phase symptoms. This ‘on’ phase is characterized by a satisfactory return of motor functions accompanied by dyskinesia. This usually takes place within an hour of taking the drug. However, there are several reports of a ‘delayed on response’ where the ‘on’ phase is deferred by more than an hour.

The on-off mechanism is a clinically recognized challenge in a majority of patients with Parkinsonism where the commonest occurrence involves the ‘early morning’ wearing-off phenomenon. This is mainly attributed to significantly lower plasma levels of levodopa during early hours of the day, thereby intensifying the phase of akinesia.

Interestingly, the on-off mechanism has been linked to early depletion of the levodopa stores which can be a common occurrence within the presynaptic dopaminergic neurons. This can also be accompanied by reduced responsiveness at the postsynaptic dopamine receptors. Multiple effective approaches have been proposed to counter the wearing-off phenomenon.


Dopamine

Dopamine processing in a synapse. After release dopamine can either be taken up again by the presynaptic terminal, or broken down by enzymes.

TH: tyrosine hydroxylase
DOPA: L-DOPA
DAT: dopamine transporter
DDC: DOPA decarboxylase
VMAT: vesicular monoamine transporter 2
MAO: Monoamine oxidase
COMT: Catechol-O-methyl transferase
HVA: Homovanillic acid


One major intervention is to delay the commencement of levodopa therapy or perhaps, modify drug dosage to suit the patient’s physiological requirements. Some adjuvant therapies are also available which include the following: dopamine agonists (bromocriptine; strengthens the dopaminergic activity); catechol-O-methyl transferase (COMT) inhibitors (e.g., entecapone) and monoamine oxidase (MAO) inhibitors (e.g., selegiline). COMT/MAO inhibitors are known to boost the half-life of levodopa which helps reduce the frequency of on-off symptoms.

It is noteworthy that despite being the first-line treatment, levodopa can derange the recovery process in Parkinson’s disease through on-off phenomenon. It is essential for the neurologists to grasp the necessary tidbits about this clinical entity so they may optimize the therapeutic regimen of their patients.

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