Minds on Medicine - Parkinson’s Disease: Experimental Models & Emerging Therapies

What is Parkinson’s disease?

Parkinson’s disease is a neurodegenerative disease which results from loss of neurons in the substantia nigra, which is a structure found in the basal ganglia in the brain. The disease affects 1% of people over the age of 60. The literal Latin translation of substance nigra is “black substance”- neurons in this region of the brain have neuromelanin, a black pigment. Indeed, the association between loss of substantia nigra neurons and Parkinson’s disease was first identified through postmortem analysis of brains of patients with Parkinson’s disease - it was found that these brains had a decreased pigmented area of substantia nigra compared to normal brains.

Neurons lost from the substantia nigra in Parkinson’s disease communicate to other neurons in different brain regions through the neurotransmitter dopamine. These neurons are involved in control of movement. Hence, it is understandable how the primary symptoms of Parkinson’s disease are associated with movement - these include increased limb rigidity, a shuffling gait, a “pill rolling” tremor at rest, a stooped posture, reduced limb movement, difficulty initiating movements, loss of associated movements and loss of facial expression. Other symptoms of Parkinson’s disease which are not associated with movement are loss of cognitive function, depression, anxiety and sleep disturbances. Often, deaths due to Parkinson’s disease are due to complications of the disease, rather than directly due to the disease itself.

Experimental models of Parkinson’s disease

Animal experimental models are an important way for scientists to investigate the causes and consequences of a disease, and hence develop potential therapies which could be translated to human clinical trials. All animal experimentation follow government ethical guidelines and are carried out in specific ways to minimise any pain inflicted on the animals.

Mice and rats are often used to model human disease as they have a fast reproductive and growth rate, are readily available, are efficient to rear and have a biology which is relatively similar to human biology. 6- OHDA treated rats are an example of a rat model which is used to model Parkinson’s disease - neurons which project to the basal ganglia substantia nigra are injected with the toxin 6-OHDA which causes destruction of the dopamine neurons, mimicking neurodegeneration seen in Parkinson’s disease. The quantities of toxin injected and the location of injection can be varied to investigated the effects of specific neuronal destruction in the pathology of the disease.

Mice treated with the toxin MPTP are also an effective model of Parkinson’s disease. This toxin is taken up specifically by the neurons of the substantia nigra, so does not need to be injected into specific neuronal areas. MPTP inhibits the mitochondria in these neurons, causing neuronal cell death. Between the 1970s and 1980s, there was a Parkinson’s disease epidemic in the US amongst a younger age-group of patients than would have been expected - and this was found to be due to contamination of an illegal recreational drug with the toxin MPTP.

Although both of these animal models are accurate reflections of the disease state in humans, their artificial neuronal induction does not reflect the progressive death of the neurons which is characteristic of the human disease state. Hence, the full capabilities of these experimental models are limited.

A minority of Parkinson’s disease cases (around 15%) are caused by genetic mutations, and these cases tend to have an earlier age of onset. Some of the mutations which cause Parkinson’s disease are associated with the accumulation of Lewy bodies in the dopamine neurons of the substantia nigra - which are thought to cause oxidative damage and neuronal cell death. Mice with common mutations which lead to Parkinson’s disease may be a better model of the progressive neurodegenerative nature of the disease - however, such mouse models are more difficult and expensive to acquire.

Therapeutic management of Parkinson’s disease - current and emerging

It has not been possible to identify a treatment which is able to prevent the neurodegeneration of substantia nigra neurons, thus Parkinson’s disease therapies aim to manage and hinder the progression of the symptoms of the disease rather than treat the disease itself. Given that there is a loss of dopamine neurons in the disease, drugs which increase the availability of dopamine in the brain are most commonly prescribed for patients.

L-DOPA is a precursor to dopamine, which is converted to dopamine by an enzyme in the brain and is the the first line treatment for Parkinson’s disease. Dopamine itself is not given to patients for two reasons - dopamine is unable to cross the blood brain barrier (a tight seal which prevents the movement of substances from the systemic circulation into the brain) and, secondly, as dopamine can have side-effects in peripheral tissue. To address the latter issue, the L-DOPA is also commonly administered with a peripheral decarboxylase inhibitor, which prevents the conversion of L-DOPA to dopamine in the peripheries and ensures all the L-DOPA is available to cross the blood brain barrier.

Other, newer approaches are also being explored for the management of Parkinson’s disease. Deep brain stimulation is one example. Electrodes are implanted into specific areas of the basal ganglia and high frequency stimulation are applied. The exact mechanism of action is not clear, but these electrical stimulations significantly improve the motor symptoms of patients. It is possible that electrically stimulating different areas of the basal ganglia activates other neuronal pathways which can control movement. Deep brain stimulation is an approved treatment option for Parkinson’s disease, as well as other neurological diseases including epilepsy and severe obsessive-compulsive disorder.

Another, less developed avenue which has been researched is the treatment of brains of patients with Parkinson’s disease with transplanted foetal induced pluripotent stem cells. This option has several concerns - there is the obvious ethical consideration of the use of foetal stem cells for treatment of human disease. Furthermore, it has been found that the effects of such a transplant are not long term - after 10 years, neurons in treated brains have been found to accumulate Lewy bodies again and the symptoms of Parkinson’s disease return. Also, given the number of cases of Parkinson’s disease, this would not be viable as a potential treatment option on a population scale due to the lack of availability of foetal induced pluripotent stem cells.

Conclusion

In this blog, I have explored the discovery, features and symptoms of Parkinson’s disease. I have discussed various experimental models which are used to investigate the disease and then delved into current and potential treatment avenues for the disease.

In my opinion, these branches of Parkinson’s disease research offer an exciting example of the emerging, ever-advancing nature of medical sciences. It reflects how the molecular and anatomical principles of a disease can be practically investigated in various animals models. Results can then be translated to a clinical scenario, resulting in improved clinical outcomes, as seen with emerging treatments for Parkinson’s disease.

By Rhea S (Medicine, University of Oxford)