Parkinson’s disease is one of the most prevalent neurodegenerative disorders, affecting over 10 million people worldwide. It is characterised by progressive, dysfunctional tremor, slowness and rigidity. Finding a cure for Parkinson’s disease is a complex challenge that the medical community has been tackling for decades, resulting in various neurological discoveries.
Parkinson’s disease through the centuries
The first notions suggestive of Parkinson’s disease date back thousands of years to ancient Indian and Chinese medical manuscripts that reported symptoms similar to those seen today. However, a more recent understanding of Parkinson’s disease dates to 1817, when Dr James Parkinson, an English surgeon and apothecary, published his seminal work titled An Essay on the Shaking Palsy.
In his essay, Dr Parkinson summarised his own clinical observations, combining and contrasting them with those reported by his predecessors and contemporaries, characterising the disease, ultimately named in his honour, as presenting progressive agitation, tremor and motor deficits. Such findings sparked interest in the medical community, initially defining a neurological malady that would grow into a distinct field of research.
Subsequent decades of rigorous scientific investigation elucidated the molecular mechanisms of Parkinson’s disease, characterised by progressive degeneration and loss of dopaminergic neurons in brain regions including the striatum, substantia nigra and globus pallidus, which ultimately lead to substantial motor deficits.
Additionally, while its precise aetiology still remains unknown, risk factors for Parkinson’s disease have been confirmed, including age (it is more common in people aged over 60 years), gender (it is more prevalent among males) and certain environmental factors (eg, exposure to pesticides and herbicides).
While Parkinson’s disease remains incurable, the significant body of work produced by generations of scientists has armed today’s patients with treatment options that can help them maintain their quality of life to an extent unavailable to yesterday’s patients, with tomorrow’s patients facing a promising future with potential cures.
First curative attempts: the nineteenth century
While Dr Parkinson’s essay laid foundations for today’s research, his treatment proposals, including bloodletting and purposeful, localised blistering to divert inflammatory pressure and blood away from the brain, appear deeply archaic by today’s standards; however, in their obscurity, they initiated a focus on symptom management – an effort that would also help to gradually explore the causes of Parkinson’s disease.
In turn, Dr Jean-Martin Charcot, another important nineteenth century neurologist, together with his intern Leopold Ordenstein, successfully investigated belladonna alkaloids as pharmacological treatments for Parkinson’s disease, while also examining potential non-pharmacological treatments (eg, physical therapy using the ‘shaking chair’). While physical therapy was dismissed at the time, being considered inapplicable to patients with Parkinson’s disease, the belladonna alkaloids diminished the disease symptoms through what would later be understood as improving the cholinergic/dopaminergic balance in the striatum. Of note, Dr Charcot’s preferred treatment for Parkinson’s disease centred on anticholinergic alkaloids – specifically, hyoscyamine (a plant-based agent manufactured as pills or a syrup) sometimes combined with rye-based ergot derivatives. Subsequent research would establish dopamine agonists as a basis of treatment for Parkinson’s disease, as hyoscyamine was found to substantially stimulate striatal dopamine receptors, resulting in increased dopamine activity.
Dr William Richard Gowers, Dr Charcot’s British contemporary, promoted similar treatment strategies, stressing the avoidance of mental and physical strain and recommending a life that would be “quiet and regular, freed, as far as may be, from care and work”. Similar to Dr Charcot, Dr Gowers recommended hyoscyamine for tremor, as well as cannabis, having observed symptom amelioration following treatment with it (cannabis is now known to have some dopaminergic activation properties).
Bridging to modernity: from the twentieth century to modernity
The two crucial discoveries of the twentieth century that propelled further progress in the development of a treatment for Parkinson’s disease were the localisation of dopamine in the brain (ie, in the striatum) and the development of the original reserpine model; these provided a growing body of evidence supporting the role of dopamine in Parkinson’s disease treatment and the conceptualisation of new medicines. In turn, Dr Herbert Ehringer and Dr Oleh Hornykiewicz investigated human brain specimens, finding striatal dopamine depletion and post-encephalitic symptoms in the brains of individuals affected by Parkinson’s disease. Their discoveries emboldened the scientific community to conduct human trials in patients with Parkinson’s disease.
Levodopa – the precursor to dopamine – was a natural drug candidate. Dr Walther Birkmayer, having been supplied with levodopa by Dr Hornykiewicz, began intravenously injecting it into patients with Parkinson’s disease. The observed anti-akinetic effects represented a landmark step towards improving the formulation, thus leading to the development of oral preparations. Notably, the aforementioned reserpine model, the first model of Parkinson’s disease, was shown to be reversed by administering levodopa.
Successfully disseminating and formulating levodopa for the treatment of Parkinson’s disease was a landmark event in the ongoing quest to treat the disease. Levodopa remains an important medication in the treatment of Parkinson’s disease, with other therapeutic options including dopamine agonists (that induce similar but milder effects to levodopa), monoamine oxidase B inhibitors (that block/reduce the breakdown of dopamine in the system) and catechol-O-methyltransferase (COMT) inhibitors (administered to patients with later stages of Parkinson’s disease to prevent levodopa breakdown by COMT).
Modernity: the exploratory frontiers
Following decades of intense research, modern patients with Parkinson’s disease and the healthcare professionals (HCPs) working with them are presented with a repertoire of treatments, such as levodopa and COMT inhibitors, that can help manage the symptoms of the disease. Given the complexity of the condition, an ultimate cure still remains in the realm of opaque speculation; however, with the rapid pace at which drug development progresses today, providing more efficacious, convenient and tolerable agents to manage the symptoms of Parkinson’s disease is an unmet need that can hopefully be answered.
While dopaminergic therapy has been the mainstay to manage symptoms such as – but not limited to – tremor, difficulties with communication and abnormal standing posture, other agents have now been identified that could yield better results, including botulinum toxin (an isolated neurotoxin) and istradefylline (an adenosine A2A receptor agonist). Furthermore, inhibitors of the c-ABl pathway, which are currently used to treat leukaemia, have been considered as potentially having neuroprotective effects in Parkinson’s disease.
Parkinson’s disease: a case of slow but consistent medical progress
From the time of Parkinson’s disease in ancient civilisations, the unwavering curiosity, clinical perspicacity and Herculean bravery of patients, researchers and HCPs from around the world have led to some medical success.
Modern scientific knowledge and tools are allowing us to fathom the furthest depths of the Earth’s oceans and examine the intricate details of the rings of Saturn. Nevertheless, the human brain, an evolutionary miracle that is believed to host our consciousness, remains perhaps the most complex mystery known to man. Expanding the frontiers of today’s medical knowledge of neurological diseases should help us better understand Parkinson’s disease and develop treatments for it.
References used in this article are available upon request.
