Parkinson’s Disease and L-dopa

Imogen Quilty

This work was produced by Imogen Quilty for her subject 'Human Physiology' while enrolled in pharmaceutical science. It focuses on the Parkinson's medication 'L-dopa' and aims to investigate and communicate the rationale for use of a therapeutic approach in treating a defined disease state.

Parkinson’s disease (PD) is a progressive neurodegenerative disease. Approximately four people per one thousand Australians are diagnosed with Parkinson’s disease, with that prevalence rising to one in one hundred people over once over the age of sixty (Better Health Channel, 2021). While it is still largely unknown what causes the onset of Parkinson’s disease or the extent of interactions within neural pathways, it can be characterized by the major loss or dopaminergic neurons (Cure Parkinson’s, 2021). Patients with Parkinson’s experience a loss of motor functions, producing the symptomatic bradykinesia, resting tremors, and rigidity. L-dopa has been the primary source of treatment for Parkinson’s disease since the 1960s and remains today as the most effective medication for treatment of symptoms of Parkinson’s (Sujith, 2017). While it is not a cure for the disease, it does help to restore patients’ quality of life and daily function.

Normal Physiology and the Impact of Parkinson’s Disease The central nervous system is responsible for the regulation and production of fine motor control. This is determined by many sophisticated interactions that occur between related structures within the brain. An extremely important area within this process is the substantia nigra located in the basal ganglia of the ventral midbrain. It consists of an extensive network of neurons that connect itself through nigrostriatal pathways to the striatum, located within the forebrain (Triarhou, 2013). The substantia nigra mainly consists of dopaminergic neurons that produce and transport dopamine through nigrostriatal pathways to innervate neurons in the striatum. These neurotransmitters are vital to the planning and co-ordination of movement and allow for fluidity of movement. Dopamine acts as a regulator reducing the influence of the indirect pathway within the basal ganglia and increasing the efficiency of the direct pathway (Crocker, 1997). Therefore, decreased dopaminergic transmission caused by dopaminergic cell death associated in PD leads to an increase in cortical excitation of striatal neurons, producing an imbalance in the sects of striatal neurons that control the functional output of the basal ganglia (Triarhou, 2013). This can be seen in the increased innervation of GABAnergic neurons, leading to a heightened inhibitory effect from GABA (Belousov & Pol, 1997) and a rise in cholinergic neural activity, causing further disruption of neural transmission (Aosaki et al., 2010).

Effects of L-dopa on Target Cellular Components L-dopa is the primary treatment used to target PD symptoms. It is the chemical precursor to dopamine which once converted works to reestablish dopamine levels in depleted areas of the brain. As a conformational change occurs to produce its active form, it is classed as a pro-drug (DrugBank Online, 2021). This occurs through the action of the enzyme aromatic-L-aminoacid decarboxylase which cleaves 2 oxygen and 1 carbon off the L-dopa molecule to form dopamine.

The pro-drug delivery system is utilised as dopamine is unable to cross the blood brain barrier due to its polar nature. Therefore, levodopa is used to cross the blood brain barrier through an amino acid transporter called L type amino acid transporter 1 (LAT1). This occurs as L-dopa is a substrate by LAT1 which is prominently expressed in the blood brain barrier. The transmembrane protein properties of LAT1 allows for passage of L-dopa directly into the CNS where it can be metabolised into the active form (Puris et al., 2020).

Once inside the CNS L-dopa is up taken by dopaminergic neurons, dopa decarboxylase is present and a conformational conversion occurs. Briefly dopamine is stored within the cell until an action potential stimulus occurs. This opens voltage gated calcium channels and allows for the influx of calcium ions into the terminal. This produces a conformation change in docked synaptic vesicles containing dopamine to stimulate the fusion and release of the dopamine through exocytosis. Released dopamine can therfore diffuses across the synapse and can bind to G-coupled dopamine receptors D1-5 on the post-synaptic cell (Mishra et al., 2018). It should be noted that L-dopa is typically administered in combination with peripheral decarboxylase inhibitors. This is primarily to prevent the breakdown of levodopa in the periphery. Decarboxylase inhibitors improve the half life of the drug, as without it, most of the intended dopamine would be broken down and would never reach the target neurones (National Center for Biotechnology Information, 2021).

Use of L-dopa for Treatment of Parkinson’s L-dopa is used for the treatment of Parkinson’s symptoms, specifically bradykinesia. Typically, it is used once other anti-Parkinsonism drugs are unable to fully mitigate symptoms (Gandhi et al., 2020). The drug has no ability to stop dopaminergic cell death, only acting to improve dopamine levels directly by supplying L-dopa for conversion. Therefore, once a certain level of dopaminergic cell death occurs there is a lack of available neurons to perform the conformational change needed to produce dopamine from L-dopa. The medication has little to no success in prolonging lifespan but instead helps to improve quality of life as the disease progresses. The drug allows for the restoration of dopamine production in the substantia nigra as well as the nigrostriatal pathway for transport of the dopamine to the striatum. Permitting for the communication of motor pathways and related structures such as the thalamus and motor cortex once again. This increases the smoothness fluidity of movement within the patient.

There are a variety of commonly experienced side effects associated with both short term and long-term use of L-dopa. Gastrointestinal tract complications can produce persistent nausea and vomiting. (Parkinson, 2021). Long term use over 5-10 years can often result in levodopa- induced dyskinesia, producing symptomatic spasming in the neck, facial musical, jaw, and other structures. This is theorised to be produced by an increased sensitivity of dopaminergic neurons from L-dopa use (Sanjay, 2017).

Moreover, L-Dopa enhances patient well-being through the conversion of L-dopa to dopamine to counteracts the lack of dopaminergic transmission caused by dopaminergic cell death. Clearly the use of L-dopa within the treatment of PD is limited, as the treatment is unable to stop the diseases progression. However, it remains as the “golden standard treatment” (Sujith, 2017) due to its potency and efficiency in relieving symptoms.