Pre-Clinical Models of Levodopa - Induced Dyskinesia
The classic motor symptoms of Parkinson’s disease (PD), i.e. bradykinesia, rigidity and tremor, are due to a reduction of the neurotransmitter dopamine in the striatum. The mainstay of PD therapy consists of administering the precursor of dopamine, levodopa, which alleviates disease manifestations. However, with disease progression and long-term administration of levodopa, people with PD (PwPs) almost invariably develop abnormal involuntary movements, referred to as dyskinesia. Once dyskinesia has developed, it tends to occur every time levels of levodopa in the blood reach a certain threshold. In the clinic, dyskinesia can be divided into chorea or dystonia, depending on their phenomenology. Whereas some PwPs do not realise that they experience dyskinesia, it can be very disturbing to other individuals, interfering considerably with their quality of life.
Treatment options for dyskinesia are limited, with only amantadine being approved by the Food and Drug Administration for the indication, while the atypical anti-psychotic clozapine is deemed to be efficacious by the International Parkinson and Movement Disorder Society. Unfortunately, not all PwPs respond to amantadine, and the use of clozapine entails life-long blood samplings to monitor for the development of a potentially life-threatening agranulocytosis. Novel therapies for the treatment of levodopa-induced dyskinesia are therefore needed, to improve the quality of life of PwPs who experience dyskinesia.
In our quest to discover such new therapies, animal models have played an invaluable role. PwPs who develop dyskinesia generally have severely diminished dopamine in the striatum. To achieve such decreased levels of dopamine, two neurotoxins are traditionally administered, 6-hydroxydopamine (6-OHDA) in mice and rats, and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in non-human primates. 6-OHDA does not enter the brain and is therefore injected intra-cerebrally, while MPTP readily penetrates the brain and can be administered systemically, traditionally subcutaneously. It is important to mention that these experimental models of PD do not recapitulate the synuclein pathology present in the human condition, but nevertheless enable the assessment of potential symptomatic therapies, several of which have moved on to clinical testing after they have successfully alleviated parkinsonian symptoms or dyskinesia in these animal models.
Dyskinesias are then elicited by exposing animals repeatedly to levodopa (various regimes have been used to induce the abnormal movements), i.e. the dyskinesia induction or “priming” phase. Dyskinesias eventually reach a stable level upon each administration of levodopa, which is maintained by daily or every other day administration of levodopa over the experimental period.
In rodents, dyskinesias are rated using the “ALO AIMs” scale, which evaluates dyskinesia affecting the “axial”, “limbs” and “oro-lingual” body parts. A fourth parameter, “locomotor” AIMs, has also been described, but is not evaluated as often as the other components. AIMs can be rated both for their duration and suppressibility during the evaluation period, as well as their overall amplitude. In non-human primates, both chorea and dystonia can be observed, which are reminiscent of the manifestations in humans. Various dyskinesia rating scales have been used by different groups to rate the severity of dyskinesia in primates, some of which also enable to differentiate between disabling and non-disabling dyskinesia, based upon the impact of the abnormal involuntary movements on the animals’ normal behaviour.
The 6-OHDA-lesioned rodent and MPTP-lesioned primate models of PD have been used for decades to assess the effects of experimental treatments on the severity of dyskinesia and have played invaluable roles in the discovery of new anti-dyskinetic therapies. Testing promising novel molecules in pre-clinical models of PD is a critical step in the development of drugs towards the clinic. Thus, not only are animal models required to demonstrate an anti-dyskinetic effect that would buttress further development or studies in humans, they are also key in detecting possible adverse effects before administration to humans. They are therefore essential in showing that compounds that eventually made it through to clinical testing have a compelling potential to display efficacy, while having low risk to elicit adverse effects, thereby reducing the risk of unnecessarily exposing humans to potentially inefficacious or harmful substances.
Models in both species have been validated with standard of care treatments, as each of amantadine and clozapine were shown to reduce dyskinesia severity in parkinsonian rodents and primates. Several drugs that made it to clinical trials in recent years with dyskinesia endpoints first showed efficacy in rodent and/or primate models of dyskinesia, for instance (not exhaustive list, presented in alphabetical order) befiradol, dipraglurant, eltoprazine, foliglurax and mesdopetam. One possible caveat of the dyskinetic 6-OHDA-lesioned rodent and MPTP-lesioned primate models is that, while they have good predictive value of the efficacy of an experimental molecule on dyskinesia up to the Phase II level, their predictive accuracy of efficacy at the Phase III or of an eventual approval for dyskinesia is not as high. The reason(s) for this remains unclear, but may pertain to the complexity of Phase III trials and of the regulatory process before approval for clinical use.
In addition, a considerable body of knowledge relating to the mechanisms underlying levodopa-induced dyskinesia has been garnered by experiments conducted on the 6-OHDA-lesioned rodent and MPTP-lesioned primate. Examples include in situ injection of selective pharmacological agents in selected brain areas, which enables to precisely determine the effect of a receptor in a given brain region on the dyskinetic phenotype. Moreover, post-mortem experiments conducted on brain tissue have led to the detection of molecular markers of the dyskinetic state, and have identified receptors that are altered in dyskinesia, which could eventually be targeted to alleviate the abnormal movements.
In conclusion, pre-clinical models of levodopa-induced dyskinesia remain to this day an invaluable tool to refine our comprehension of dyskinesia and to discover new therapies to reduce the burden that the abnormal movements cause on PwPs quality of life. They have been extensively validated over decades, during which they have been a source of knowledge and hope for the PD community, including PwPs and their families.
References
Philippe Huot, MD, PhD is a researcher at The Neuro (Montreal Neurological Institute-Hospital) which is a bilingual academic research and healthcare institution affiliated with McGill University where he researches experimental models of Parkinson’s disease to develop new drugs for treatments and provides care to patients suffering from Parkinson’s disease.
Ideas and opinions expressed in this post reflect that of the author solely. They do not reflect the opinions or positions of the World Parkinson Coalition®