We have recently completed two large scale, long term, open label, photopharmacological studies whereby patients have been treated for a period of time ranging from one to nine years. The results demonstrate that not only do Parkinson’s disease patients show a favourable, acute, therapeutic response to light in regard to their depression, insomnia and anxiety but also a progressive, incremental improvement in motor function is also seen over the longer course of the disease. These studies are ongoing at the Bronowski Clinic in Australia and have been undertaken in the presence of a range of doses of dopamine replacement ranging from very high to subclinical. As an institution dedicated to the practice of translational neurobiology we endeavour to bring new, non-invasive therapies to the clinic as soon as is practicable to alleviate the suffering and return quality of life to Parkinson’s disease patients.
A controlled trial examining the efficacy of light therapy has been completed with 30 patients at the Bronowski Institute of Behavioural Neuroscience. From this trial, we are refining our current treatment approach using the photopharmacological method and increasing its therapeutic benefits to reduce the side effects of dopamine replacement. It is essential that our hypothesis has been put to the test implementing this blinded, placebo controlled strategy, as it remains the golden standard to test various therapeutic avenues in biomedical research. The results of the first trial for this work will be available shortly via formal scientific publication.
Due to the limited response of Parkinson’s Plus syndromes to traditional dopamine replacement therapy we have done preliminary work on the effect of phototherapy or photopharmacological treatment on Multiple Systems Atrophy (MSA), Progressive Supranuclear Palsy (PSP) and Diffuse Lewy Body Disease (LBD). In the preliminary case studies to date we have observed that not only does the application of dopamine replacement in these patients produce unusually adverse effects, but the strategic application of light effectively improves various motor, cognitive and vegetative symptoms of these disorders. The effect of prolonged phototherapy on PD symptoms and the disease’s mortality is also at the focus of work undertaken.
In consideration of the effect that phototherapy has had on tremor in Parkinson’s disease, we have tested the possible use of phototherapy on various forms of tremor. To date intentional tremor, familial, essential and benign tremor have had varying responses to phototherapy, most of which have been favourable. Future observational studies will be undertaken to examine the potential benefit in patients with tremor but particularly in those dealing with issues of polypharmacy.
Now that the preclinical proof of concept work on the anti-Parkinsonian effect of intraocular administration of therapeutic drugs has been completed we are now moving toward Phase I Clinical trials to be conducted here in Australia. This will involve 6 Parkinson’s disease patients with the disease expressed bilaterally. This study will be undertaken with the intention of establishing the safety and efficacy of this method of drug administration. Ocular toxicology and confirmation of the safety of intravitreal administration of therapeutic candidates is currently underway.
With numerous anti-Parkinsonian drugs now found to be effective when delivered by the intraocular route in models of the disease, further work on retinal involvement as a therapeutic option is underway. Completed preclinical studies on intraocular delivery of a catalogue of anti-Parkinsonian drugs and their relative therapeutic effects are being prepared for publication in international biomedical journals. Single injection or long term delivery systems are also being explored.
There are many other benefits that are emerging from our work. Not only do our findings relate to the aetiology and treatment of Parkinson’s disease but as an extension of this, we have discovered that the retina and other parts of the circadian system might function, or malfunction, in disorders such as Schizophrenia and drug addiction. Furthermore, therapeutic intervention at the level of the retina might also provide a more effective way of finding minimal therapeutic doses as well as eliminating adverse side effects and optimising treatment compliance. Implementing less invasive means of treatment using phototherapy or phototherapy plus pharmacological intervention are also being explored as alternative approaches to established methods of treating these disorders.
During the course of our preclinical work, we found that the drug, which reversed experimental forms of Parkinson’s disease, also had a positive effect on models of other disorders. When symptoms of psychosis, anxiety and anorexia were measured at the same time, we found that our test drug, ML-23 (a drug that blocks melatonin) and others like it produced significant improvement in experimental forms of these diseases. As with Parkinson’s disease, this work has provided a new direction and new hope for those suffering from these debilitating disorders.
Parkinson’s Disease Publications From the Bronowski Institute of Behavioural Neuroscience Appearing in Refereed Scientific Journals
The effect of intravitreal cholinergic drugs on motor control.
Willis GL, Freelance CB.
Behav Brain Res. 2018 Feb 26;339:232-238. doi: 10.1016/j.bbr.2017.11.027. Epub 2017 Nov 24.
The effect of light exposure on insomnia and nocturnal movement in Parkinson’s disease: an open label, retrospective, longitudinal study.
Martino JK, Freelance CB, Willis GL.
Sleep Med. 2018 Apr;44:24-31. doi: 10.1016/j.sleep.2018.01.001. Epub 2018 Jan 31.
Emerging preclinical interest concerning the role of circadian function in Parkinson’s disease.
Willis GL, Freelance CB.
Brain Res. 2018 Jan 1;1678:203-213. doi: 10.1016/j.brainres.2017.09.027. Epub 2017 Sep 25. Review.
Neurochemical Systems of the Retina Involved in the Control of Movement.
Willis GL, Freelance CB.
Front Neurol. 2017 Jul 5;8:324. doi: 10.3389/fneur.2017.00324. eCollection 2017.
The effect of directed photic stimulation of the pineal on experimental Parkinson’s disease.
Willis GL, Freelance CB.
Physiol Behav. 2017 Dec 1;182:1-9. doi: 10.1016/j.physbeh.2017.09.014. Epub 2017 Sep 15.
Circadian system – A novel diagnostic and therapeutic target in Parkinson’s disease?
Videnovic A, Willis GL.
Mov Disord. 2016 Mar;31(3):260-9. doi: 10.1002/mds.26509. Epub 2016 Jan 30. Review.
Parkinson’s disease, lights and melanocytes: looking beyond the retina.
Willis GL, Moore C, Armstrong SM.
Sci Rep. 2014 Jan 29;4:3921. doi: 10.1038/srep03921.
Breaking away from dopamine deficiency: an essential new direction for Parkinson’s disease.
Willis GL, Moore C, Armstrong SM.
Rev Neurosci. 2012;23(4):403-28. doi: 10.1515/revneuro-2012-0037. Review.
A historical justification for and retrospective analysis of the systematic application of light therapy in Parkinson’s disease.
Willis GL, Moore C, Armstrong SM.
Rev Neurosci. 2012 Mar 1;23(2):199-226. doi: 10.1515/revneuro-2011-0072.
New Vistas on Parkinson’s disease.
Willis GL, Armstrong SM.
Eur J Neurol. 2010 Apr;17(4):519-20. doi: 10.1111/j.1468-1331.2009.02852.x. Epub 2009 Nov 18. No abstract available.
Parkinson’s disease as a neuroendocrine disorder of circadian function: dopamine-melatonin imbalance and the visual system in the genesis and progression of the degenerative process.
Willis GL.
Rev Neurosci. 2008;19(4-5):245-316. Review.
Compromised circadian function in Parkinson’s disease: enucleation augments disease severity in the unilateral model.
Willis GL, Kelly AM, Kennedy GA.
Behav Brain Res. 2008 Nov 3;193(1):37-47. doi: 10.1016/j.bbr.2008.04.017. Epub 2008 Apr 26.
Intraocular microinjections repair experimental Parkinson’s disease.
Willis GL.
Brain Res. 2008 Jun 27;1217:119-31. doi: 10.1016/j.brainres.2008.03.083. Epub 2008 Apr 11.
Primary and secondary features of Parkinson’s disease improve with strategic exposure to bright light: a case series study.
Willis GL, Turner EJ.
Chronobiol Int. 2007;24(3):521-37.
The role of ML-23 and other melatonin analogues in the treatment and management of Parkinson’s disease.
Willis GL.
Drug News Perspect. 2005 Sep;18(7):437-44. Review.
The therapeutic effects of dopamine replacement therapy and its psychiatric side effects are mediated by pineal function.
Willis GL.
Behav Brain Res. 2005 May 7;160(1):148-60.
Recovery from experimental Parkinson’s disease in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride treated marmoset with the melatonin analogue ML-23.
Willis GL, Robertson AD.
Pharmacol Biochem Behav. 2005 Jan;80(1):9-26. Epub 2004 Dec 15.
The implementation of acute versus chronic animal models for treatment discovery in Parkinson’s disease.
Willis GL, Kennedy GA.
Rev Neurosci. 2004;15(1):75-87. Review.
A therapeutic role for melatonin antagonism in experimental models of Parkinson’s disease.
Willis GL, Armstrong SM.
Physiol Behav. 1999 Jul;66(5):785-95.
Orphan neurones and amine excess: the functional neuropathology of Parkinsonism and neuropsychiatric disease.
Willis GL, Armstrong SM.
Brain Res Brain Res Rev. 1998 Aug;27(3):177-242. Review.
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