Mechanism of Parkinson’s Disease Drugs: History
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Subjects: Clinical Neurology
Contributor:
Palanisamy Sivanandy

Parkinson’s Disease (PD) is a progressive degenerative neurological disorder commonly presenting with symptoms of muscle rigidity, instability, tremor, bradykinesia (slow in movement), and lack of coordination. There are conventional drugs used in treating Parkinson’s disease such as levodopa, dopamine agonists, anticholinergics, catechol-O-methyltransferase (COMT) inhibitors, monoamine oxidase-B (MAO-B) inhibitors, and amantadine. Other drugs used in treating PD related psychosis include antipsychotics. 

  • Parkinson’s Disease (PD)
  • drug
  • machanism

1. Introduction

Parkinson’s Disease (PD) is a condition that is characterized by various motor symptoms and is due to the neurodegeneration of the nigrostriatal pathway [1]. There are several factors that will initiate neurodegeneration, which includes ageing, ethnicity, pesticides, family history, genetics, radiation, and trauma or infection. The dopamine level drops due to the degeneration of the substantia nigra neurons which results in the disruption in the thalamus and motor cortex connection [2]. The reduced level of dopamine initiates changes in the density and sensitivity of the dopamine receptors due to compensatory mechanism [3]. The dopamine D1 and dopamine D2 receptors are activated by the dopaminergic neurons in the dorsal striatum which originates from the substantia nigra and terminates in the caudate and putamen [4]. When dopamine level drops, it will result in the relative over-activity in the indirect pathway due to disinhibition of the substantia nigra. The striatum extends to the external globus pallidus in the indirect pathway, using GABA as a neurotransmitter. Then, the external globus pallidus extends to the substantia nigra which is responsible for providing excitatory input by utilizing glutamate as the neurotransmitter. Reduced inhibition that exerts on the direct pathway causes an additional disinhibition of the output nuclei which is the internal globus pallidus and substantia nigra. The internal globus pallidus output nuclei inhibit the thalamus at a higher intensity and lesser excitatory input to the motor cortex [5]. This causes the main pallidal-thalamic outflow pathway to exhibit too much inhibitory signal to the thalamus which in turn results in suppression of the thalamo-cortical-spinal pathway. Thus, it leads to parkinsonian signs such as bradykinesia. However, the involvement of basal ganglia in the pathophysiology of PD is not clear [6].
The reduced level of dopamine in the brain can be restored by a compensatory mechanism to mask the deleterious effect of the depletion of dopamine levels. The brain can increase dopamine levels by elevating the production of dopamine [7]. Another compensatory mechanism is the reduction of the dopamine transporter, which results in less dopamine neurotransmitter reuptake and restoring the dopamine level [8].
The mitochondria dysfunction and protein aggregation also play a vital role in the development of PD. When protofibrils are translocated to the membranes, Abeta peptide and alpha-synuclein may interact to cause mitochondrial and plasma membrane damage. The accumulation of Abeta and alpha-synuclein oligomers in the mitochondrial membrane may result in the release of cytochrome C, triggering the apoptosis cascade. Conversely, the oxidative stress and mitochondrial dysfunction associated with Alzheimer’s and Parkinson’s disease may increase membrane permeability and cytochrome C release, promoting Abeta and alpha-synuclein oligomerization and neurodegeneration [9].

2. Levodopa

The mode of action of levodopa involves absorption from the gastrointestinal tract, crossing through the blood-brain barrier (BBB), uptake by neurons, enzymatic action of the aromatic amino acid decarboxylase to be converted into dopamine and the synaptic release of dopamine [10]. The disruption of the nigrostriatal pathway reduces dopamine levels and produces the symptoms of Parkinson’s disease (PD)[11]. Hence, the dopamine from exogenous levodopa will activate the central dopamine receptors, thus improving the symptoms of PD. Since aromatic-L-amino-acid decarboxylase (AADC) and catechol-O-methyltransferase (COMT) are responsible for the metabolism of levodopa peripherally, it is usually in combination with AADC inhibitors such as carbidopa and benserazide or COMT inhibitors such as entacapone and tolcapone. Levodopa has to be administered multiple times daily since it has a short half-life of about 36–96 min which will cause the fluctuation in plasma levels [10]. Treatment with Levodopa alleviates bradykinesia and other typical motor manifestations of PD. Long-term Levodopa treatment, on the other hand, is associated with complications such as motor fluctuations and dyskinesia, which severely impair quality of life. The combination of levodopa and carbidopa is most widely used to treat PD and Parkinson-like symptoms that may develop after encephalitis (brain swelling), or nervous system injury caused by carbon monoxide or manganese poisoning [12].

3. Dopamine Agonists

Dopamine agonists can be categorized into two classes, which are ergot and non-ergot dopamine agonists. They have antiparkinsonian activity due to the direct-acting effect on dopamine receptors which mimic the neurotransmitter. Bromocriptine, cabergoline, pergolide, and lisuride are examples of ergot dopamine agonists whereas non-ergot dopamine agonists include ropinirole and pramipexole. Ergot dopamine agonists act primarily on the D2-like dopamine receptors including D2, D3, and D4 [13]. On the other hand, non-ergot dopamine agonist ropinirole is a potent and selective agonist of the D2 dopamine receptors while pramipexole has a higher affinity towards D3 receptors [13][14].

4. Anticholinergics

In PD patients, it has been theorized that a lesion is formed in the nigra striatum. This results in the reduction of intranigral dopamine concentrations. Imbalances of the dopaminergic and cholinergic neurological pathway lead to more cholinergic firing. The stimulation causes dyskinesia and tremors. Thus, the mechanism of anticholinergics is to block the cholinergic receptors from the activation of acetylcholine. They act to counteract the imbalance of neurotransmitters in the nigra striatal pathway [15]. Specifically, M4 receptor is targeted for the block by anticholinergics [16]. This eventually will reduce the tremor and dyskinesia conditions of the patient.

5. COMT Inhibitors

A COMT inhibitor acts by breaking down catecholamines such as dopamine and norepinephrine by inhibiting the enzyme COMT. The enzyme COMT can be found in peripheral and central circulation and the aim is to prevent the breakdown of levodopa while travelling to the brain region and crossing through the BBB. It works in combination with levodopa to prevent methylation of levodopa to 3-O-methyldopa in peripheral circulation, thus improving the bioavailability of levodopa [17]. Besides, low doses of levodopa in combination with COMT inhibitors may prevent dyskinesia.

6. MAO-B Inhibitors

MAO-B inhibitors (MAO-BIs) are the antiparkinsonian drugs that have the mechanism of action of preventing monoamine oxidase-B (MAO-B) from catalyzing dopamine metabolism, hence prolonging dopamine action in basal ganglia. It is considered as an adjuvant for PD, and it is usually used with L-Dopa for PD therapy. Besides PD, MAO-BIs are also the adjuvant for treating Alzheimer’s disease. MAO-BIs exhibit neuroprotection which is the protective effect of neuronal structure and function. Other than that, they also exhibit antioxidant effects and can prolong neuronal death caused by apoptosis as well as protect functions of mitochondria [18]. Current MAO-BI consists of selegiline and rasagiline. Both are selective and irreversible MAO-BIs [19].

7. Amantadine

The mechanism of amantadine in the brain is not well understood. Generally, amantadine works by inhibiting the N-methyl-D-aspartate (NMDA)-glutamate receptor and cholinergic muscarinic receptors, thereby increasing dopamine release, and blocking dopamine reuptake [20]. It reduces dyskinesia in PD patients receiving levodopa, as well as extrapyramidal side effects of medications. Multiple studies showed that NMDA-blocking is the most important mechanism to explain its antidyskinetic effect [21].

8. Antipsychotics Used for Treating PDP

Clozapine

Clozapine is an FDA-approved tricyclic dibenzodiazepine antipsychotic drug commonly used in schizophrenia patients [22][23][24]. It is classified as an ‘atypical’ antipsychotic due to the selectivity of binding towards the dopamine receptors that differ from typical antipsychotic drugs. Clozapine is focused as an off-label used in psychosis in PD patients. Psychosis happens when there is excessive dopamine level while clozapine able to antagonist the dopamine receptor to control the dopamine level. It has a high affinity towards dopamine D4 receptors while also targets D1, D2, D3, and D5 [14][23][24]. In other words, clozapine is more likely to act on limbic rather than striatal dopamine receptors thus reducing the psychosis symptoms in the parkinsonian patients [23][24]. In addition, clozapine is found to have an antagonistic effect on adrenergic (alpha-1), cholinergic (muscarinic M1, M2, M3, and M5), histaminergic, and serotonergic receptors [14][23][24]. Evidence has also shown that serotonin 2A receptors neurotransmission abnormalities are associated with psychosis in PD patients [25]. Clozapine has great efficacy in managing psychosis in PD but is underused due to its potential adverse events.

Olanzapine

Olanzapine is a second-generation antipsychotic that produces its effect on the dopamine as well as serotonin receptors. It works primarily on the mesolimbic pathway dopamine 2 receptor as a blocker [26]. It blocks the dopamine neurotransmitter from exerting the effects on the postsynaptic receptor. Olanzapine binds to the receptor loosely and so enables the normal amount of dopamine to carry out neurotransmission [27]. The effects of olanzapine on the dopamine 2 receptor led to the reduction in positive symptoms in the patient, which includes hallucination, delusion, and disorganized speech. As for the serotonin 5-HT2A receptors, the olanzapine works as an antagonist as well. Since serotonin 5-HT2A receptors are located in the frontal cortex, this results in reduced negative symptoms which include anhedonia, flat affect, alogia, and poor attention [28].

Quetiapine

Quetiapine, a dibenzothiazepine atypical antipsychotic, has a similar action to clozapine whereby it inhibits D2 receptors and serotonin 5-HT2A receptors. It also binds to serotonin 5-HT1A, D1, H1, alpha 1, and alpha 2 receptors [29]. Nowadays, quetiapine is the most widely used antipsychotic in the treatment of PDP as monitoring for blood dyscrasias is not required and it shows the minor effect on motor symptoms [30].

Risperidone

Risperidone is a benzisoxazole atypical antipsychotic which has high antagonistic activity on the 5-HT2A and D2 receptors [31]. Thus, it can cause a harmful effect on dopamine replacement therapy and can aggravate motor symptoms [30]. Unlike clozapine, risperidone does not cause seizures, and hematologic and antimuscarinic side effects [32]. In people with schizophrenia, risperidone does not cause more extrapyramidal symptoms at doses less than 6 mg/day compared to placebo as serotonin antagonism will be predominant at low doses. Furthermore, low doses of risperidone cause progressive occupancy of dopamine D2 receptor in comparison to typical neuroleptics, modulation of the dopamine system by serotonin 5-HT2 antagonism, and selective mesolimbic blockage instead of striatal dopamine receptors [32].

Ziprasidone

Ziprasidone is a second-generation atypical antipsychotic with the chemical structure of benzylisothiazolylpiperazine. It has inhibitory effects on D2, 5-HT2A, and 5-HT1D receptors as well as agonistic effects to 5-HT1A receptors. The inhibitory effect for the reuptake of norepinephrine and serotonin is moderate [29]. Among PDP medications, it is deemed to be efficacious and safe due to its profile of efficacy and safety [33].

9. Safinamide

Safinamide is an FDA newly approved drug used in treating PD. It is a derivative of benzylamino which has various modes of action [34][35]. The main mode of action of safinamide is that it inhibits MAO-B selectively and reversibly [34][36][26][35][37]. Moreover, safinamide has the non-dopaminergic mechanism of action which includes the state-dependent block of voltage-gated sodium channels in the inactivated state. Furthermore, safinamide also has antiglutamatergic activity. These actions may be responsible for its pain mitigating effects [34][36][26][35][37]. Safinamide also prevents the formation of free radicals through the inhibition of MAO-B [35].

10. Istradefylline

Istradefylline is known as the selective adenosine A2A receptor antagonist [38]. Adenosine A2A receptors are demonstrated to suppress the activity of GP projection by suppressing GABA which is transmitted and released in the striatum. This will lead to the enhancement of GABA in the GP [39]. Therefore, when istradefylline blocks A2A receptors, it can reduce outrageous excitability of the indirect output pathway, thereby minimizing the occurrence of the motor symptoms in PD patients [40]. In addition, istradefylline is considered as nondopaminergic due to the lack of effects on dopamine receptors and dopamine-metabolizing enzymes [41]. It does not have the inhibitory activity toward enzymes such as COMT, MAO-A, and MAO-B which metabolize dopamine or levodopa. It also has a low affinity for receptors such as dopamine (D1, D2), serotonin (5-HT1A, 5-HT2, 5-HT3), and noradrenaline receptors [31].

11. Pimavanserin

Pimavanserin is known as the selective antagonist or inverse agonist of 5-hydroxytryptamine (HT)2A receptor [42][30][43][44][45]. This is because of its ability to reduce 5-HT2 receptor activity without acting on other receptors. Thus, it does not induce a pharmacological reaction to agonists on other receptors [30]. Pimavanserin has a 40 folds higher affinity towards 5-HT2A receptors compared to 5-HT2C receptors [45]. However, it has a low affinity towards dopaminergic, muscarinic, histaminergic, or adrenergic receptors and has a low ability in blocking D2 receptors [42][30][44]. Therefore, the deleterious effect of pimavanserin on dopamine replacement therapy will not be the same as atypical psychotic drugs and it does not worsen motor symptoms [30]. Thus, pimavanserin is the first medication licensed in the United States for the treatment of Parkinson’s disease psychosis (PDP)-related hallucinations and delusions, eventually making pimavanserin the first agent approved by FDA in 2016 for treatment of PDP [42][46].

This entry is adapted from the peer-reviewed paper 10.3390/ijerph19010364

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