Current treatments for Parkinson’s disease are mainly dopaminergic drugs. However, these are limited by several side effects and can only treat the symptoms. Here, we summarise a recent article, published in Brain Research Bulletin, that has reviewed developments in preclinical and clinical studies of novel drugs for the treatment of Parkinson’s disease.
Parkinson’s disease (PD) is a common neurodegenerative disease. It is characterised by the loss of dopaminergic neurons in the substantia nigra. Symptoms range from tremors and rigidity to cognitive impairments. The main therapeutic options for PD are dopaminergic drugs, which compensate for the loss of dopamine (DA) in the brain. However, these drugs are only for symptomatic treatment and cannot delay or stop disease progression. Therefore, there is an ongoing need for new therapeutic targets and drugs.
The death of dopaminergic neurons is the pathological hallmark of PD. However, the pathogenesis of PD remains unclear. Studies have suggested that predominant risk factors include ageing, genetic variants and environmental factors. Moreover, pathogenic factors include α-synuclein aggregation, mitochondrial dysfunction, neuroinflammation and brain-gut axis.
Current drugs for Parkinson’s
Dopaminergic drugs are well-established for PD treatment. Nonetheless, their effects are compromised by their side effects and reduced efficacy after long-term use. Examples include:
- Levodopa – A metabolic precursor of DA and the most effective treatment for motor symptoms. Novel formulations have been designed to reduce side effects.
- DA receptor agonists – There are five subtypes of DA receptors. DA agonists are mainly D2 agonists with partial agonistic action of D3 or D1 receptors. Clinical trials for new dosage forms of DA agonists are still in progress. Additionally, a novel D1 receptor partial agonist has entered a Phase 1 clinical trials.
- MAO-B inhibitor – MAO-B is a flavin protein in the mitochondrial membrane and catalyses the oxidative deamination of monoamines. Inhibition of MAO-B reduces DA oxidative deamination, increases DA levels in the brain and slows down the degeneration of neurons.
Novel drugs being developed
Drugs that are based on other targets beyond dopaminergic pathways, such as mitochondrial dysfunction and neuroinflammation, are under development. Both preclinincal and clinical research in these areas have shown promising results. Examples include:
Studies have shown that selective α-synuclein antibodies can reduce α-synuclein accumulation and mitochondrial dysfunction in astrocytes. They can also reduce misfolded α-synuclein uptake and cell-to-cell transmission, attenuating the loss of dopaminergic neurons.
NADPH is the primary source of ROS. Targeting NADPH oxidase could reduce microglia activation and oxidative stress levels. Simvastatin in particular is suggested to exert a neuroprotective effect on PD. A Phase II clinical trial assessing the disease-modifying effect of simvastatin is currently being undertaken.
Nurr1 is an orphan nuclear receptor. It plays an essential role in the development, maintenance, differentiation and survival of dopaminergic neurons. Studies have indicated that Nurr1 is decreased in the peripheral blood of PD patients, suggesting it may be a potential target. Candidate compounds targeting Nurr1, such as IRX4204, bexarotene and amodiaquine, are currently under development and study.
Adenosine receptor A2
GABA neurons express both adenosine receptor A2 and D2 receptor. Activated adenosine receptor A2 decreases the affinity of D2 receptors. Research has shown that pre-treatment with adenosine receptor A2 antagonists can restore microglial recruitment and reverse damage caused by neuroinflammation. Several adenosine receptor A2 antagonists, including SCH 420814 and BIIB014, have so far failed to prove more effective than placebo in clinical trials.
Epidemiology suggests that smoking can reduce the risk of PD by 30-60%. Nicotine has been shown to form a transient complex with α-synuclein and inhibit the formation of α-synuclein oligomers. A recent study, demonstrated that nicotine protected dopaminergic neurons, but did not improve symptoms after injury. This suggests that nicotine may be a potential prevention strategy rather than a treatment.
Glutamate metabolism-related targets
Glutamate is an excitatory neurotransmitter in the central nervous system. Its overproduction causes neurotoxicity. Research has shown that targeting mGluR5, mGluR3 and mGluR4 could improve motor or cognitive impairment in animal models. However, current clinical trials have failed to prove efficacy or have been limited by the number of patients recruited.
Mutations on the glucocerebrosidase (GBA) gene, which encodes GCase, is a known genetic risk factor for PD. It is expected that targeting GCase will reduce α-synuclein accumulation and protect dopaminergic neurons. Ambroxol in recent research has shown to enhance GCase activity and reduce oxidative stress in GBA mutant cells. However, further investigations are needed to test its therapeutic effects.
Elsewhere, recent studies have indicated that PD has a shared pathology with diabetes and Alzheimer’s disease (AD). As a result, well-established drugs for these diseases could provide potential alternative therapeutic options for PD. One that is showing particular promise is exenatide. Exenatide is a glucagon-like peptide-1 (GLP-1) receptor agonist commonly used as a hypoglycaemic drug in diabetes. Studies have demonstrated that this drug may have neuroprotective effects. A Phase II clinical trial of this drug significantly alleviated the motor symptoms of PD patients.
In recent years, the development of PD drugs has focussed on improving existing drugs and developing new drugs based on novel targets. Nonetheless, only a few drugs that have been entered into clinicals trials have proven effective. Among these, no drug has been found to fundamentally improve disease. Additionally, many drugs have shown therapeutic effects in animal models but then failed in human clinical trials. This emphasises the gap in transforming animal experiment results into clinical practice. Therefore, PD research requires more accurate models and a higher standard to evaluate the therapeutic effects of target compounds.
With the accumulation of knowledge regarding PD pathogenesis, more research has focussed on the development of new drugs and repurposing of existing drugs that share common pathological changes with PD. Given the complexity of the disease, it may be that a combination of drugs with multiple mechanisms would be an appropriate option.
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