Progress and Prospects in Parkinson's Research/Therapy/Symptomatic Relief

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Claims of the reversal of all PD symptoms are largely confined to animal models or in vitro studies. Complete reversal in humans appears occasionally in isolated case notes. Examples of both types are recorded here as potential pointers to productive lines of research.

Bushen huoxue granule (BHG)
This is a herbal remedy used in Chinese medicine.

Yang et al (2010) record the results of a test at the Outpatient Department of the General Hospital of People's Liberation Army, Guangdong Provincial Hospital of Traditional Chinese Medicine, and Xijing Hospital and Tangdu Hospital in Xi'an on a cohort of 106 PD patients.

This was a randomized double blind test and 55 patients were given BHG and 51 a placebo. Their UPDRS rating was measured at the end of one, two and three months. They were asked to rise, walk 10 metres, turn and walk back. The result:-

"BHG showed a better efficacy than the placebo (P<0.01) in improving motor function, shortening rise time of 10-meter back and forth test and relieving muscle tension. No adverse effects were found in this trial."

And the conclusion:-

"BHG plus Western medicine is effective and safe in improving motor dysfunction of PD patients"

Li et al (2011) described an experiment at the Institute of Traditional Chinese Medicine at the PLA General Hospital, Beijing. Two cohorts of 47 PD patients were prescribed Madopar and in addition one group was given regular doses of BHG and the other a placebo.

After 3 months the levels of dopamine being expressed by their brains were measured by encephalofluctuography and positron emission tomography. The BHG group was found to have signicantly higher dopamine levels. The conclusion stated:- "BHG could improve the DA level of PD patients, and increasing DAT contents in the striatum, thus playing a role in effectively treating PD."

Li et al (2012) conducted a double-blind placebo controlled test of BHG on a cohort of 120 PD patients over period of 9 months and commented on the results:-

"Bushen Huoxue Granule showed a higher efficacy than the control in improving life quality of patients with PD by improving scores of UPDRS II, PDQ-39 and PDSS (P<0.05). No adverse effects were found in this trial."

Comment

Traditional Chinese Medicine - TCMis not usually reported in Western peer-reviewed medical journals. Western medicine is dedicated to the identification and treatment of evidence based diseases. TCM seeks to return harmony to the whole body of the patient as an individual. This approach may have some resonance when dealing with an idiosyncratic condition such as PD. There is plainly a case for further evaluation of BHG to determine its chemistry.

CLR01
Amyloidal fibrils] are abnormal aggregates of insoluble proteins that can occur in different parts of the body for different reasons. They are associated with 20 diseases currently considered incurable, the most common of which are Alzheimer’s Disease, Type 2 Diabetes and Parkinson’s Disease.

In the case of PD the protein involved is alpha synuclein and the fibrils aggregate into clumps called called Lewy Bodies after their discoverer.

UCLA Professor of neurology Jeff Bronstein and UCLA associate professor of neurology Gal Bitan. along with their colleagues, report the development of a novel lead molecule compound (CLR01) known as a "molecular tweezer," which in a living animal model blocked α-synuclein aggregates from forming, stopped the aggregates' toxicity and, further, reversed aggregates in the brain that had already formed. And the tweezers accomplished this without interfering with normal brain function. The CLR01 molecule is shaped like a letter C and when it comes across a fibril it binds itself to it and the two arms come together and pick at it structure..

After first testing the compound in vitro the researchers injected it subcutaneously into transgenic zebra-fish with induced PD symptoms. The Lewy bodies dissolved and the PD symptoms were reversed with no apparent adverse effects. Similar results were obtained with transgenic mice.

The compound was then tested on laboratory mice with an induced form of Alzheimer's Disease, where more than one type of amyloidal fibril is involved. The compound successfully crossed the blood brain barrier and dispersed the fibrils. The process has been described in some detail by Zheng, X.et al (2015)

Some thought is being given to organising a Class 1 clinical trial with PD patients. References

Comment

It would be difficult to overstate the significance of this research, which has far reaching implications for PD patients. The majority of PD cases involve Lewy Body formation and they are also a key feature of a devastating Parkinson's Plus syndrome called Lewy Body Disease.

Cogane
Cogane is a protein developed by a company called Phytopharm.  It was recently the subject of a Phase II Clinical Trial. This was a 400 patient multi-national, randomised, double blind, placebo controlled, dose ranging study. The study compared the safety, tolerability and efficacy of three doses of Cogane™ and placebo when administered for 28 weeks to untreated patients with early stage Parkinson’s.

Cogane was taken orally. Its aim was to stimulate the production of Glial cell-derived neurotrophic factor (“GDNF”) and Brain derived neurotrophic factor (“BDNF”). These are naturally occurring proteins in the brain that have been shown to be effective in re-growing damaged nerves.

The results of the trial were reported by Phytopharm plc in February 2013. There was no significant difference between the Cogane™ group and the placebo group, as measured by change in the UPDRS scores. Both groups showed a small deterioration in their scores. The study also looked for any change in cognition or quality of life; again the study group and the placebo groups showed the same rate of change. Moreover, the results were not affected by the baseline severity of symptoms nor by the duration of the disease since diagnosis. Given the strong evidence from pre-clinical data of the efficacy of Cogane™, the researchers were surprised and disappointed by the lack of efficacy as shown in this trial. Phytopharm plc plan to publish their results, which will add to the body of knowledge about Parkinson’s disease.

Light Therapy
2007

Willis and Turner tried out an experimental system of light therapy (LT) on PD patients. LT reduces melatonin expression and this had been observed previously to be an antidepressant. Twelve patients diagnosed with PD were exposed to white fluorescent light for 1-1.5 h at an intensity of 1000 to 1500 lux once daily commencing 1 h prior to the usual time of sleep onset, approximately 22:00 h in most patients.

"Within two weeks after commencing LT, marked improvement in bradykinaesia and rigidity was observed in most patients. Tremor was not affected by LT treatment; however, agitation, dyskinaesia, and psychiatric side effects were reduced, as verified by decreased requirement for DA replacement therapy. Elevated mood, improved sleep, decreased seborrhea, reduced impotence, and increased appetite were observed after LT. LT permitted the reduction of the dose of L-dopa, bromocriptine, or deprenyl in some patients by up to 50% without loss of symptom control."

2009

Trimmer and Bennett have produced evidence for a revised pathological model of sporadic PD, and suggested that the use of Low Level infrared Light Therapy could be effective.

"Light therapy (LT) with coherent laser light or light emitting diodes in the far red to near-infrared spectrum (600–860nm) modulates numerous biological processes and is currently being used worldwide to treat a wide range of human neurological conditions.... The distance near-infrared light penetrates and transmits through skin, fat, muscle, bone and organs depends on the wavelength being used, but the distance is sufficient to penetrate the brain when delivered through the scalp and skull...."

And

"After exposure of differentiated PD cybrid neuronal cells and rotenone-exposed SH-SY5Y cells to a low energy laser treatment (LLLT, 50mW/cm2 for 40 seconds, 810nm diode laser), the velocity of mitochondrial movement by axonal transport was increased and restored to control levels for several hours after completion of the LT (Trimmer et al, in press). LT has also been shown to reverse the cellular changes induced by MPP+ and rotenone in both cell and animal models (Liang, et al., 2008, Rojas, et al., 2008). In conclusion, reduced axonal transport of mitochondria is present in two models of sporadic PD pathogenesis and can be ameliorated by the application of a low energy laser treatment. Because laser LT is already in clinical trials for stroke, in light of these encouraging cybrid results it is feasible now for study in sPD."

2012

Willis et al revewed the prospects for light therapy in the treatment of PD.

Their basis for this work was the observation that:-- "Recent scientific work suggests that the retina plays a major role in NSD function and intimates light therapy in the management of PD. This was tested on a cohort of 129 PD patients." Their conclusions:-

"These results confirm the value of the strategic application of light therapy with controlled doses of DART (dopamine replacement theapy) in PD and warrants further controlled investigation. That the symptomatic improvement continued as long patients remained in the program suggests that exposure to light, under a strict daily regimen, combined with controlled DART, actively slows or arrests the progressive degenerative process underlying PD."

Rutten et al evaluated the use of bright light therapy in the treatment of sleep disorders in Parkinson’s disease.

"The few studies that focused on the efficacy of BLT in patients with PD demonstrated a positive effect of BLT not only on sleep and mood but also on motor function. "

Willis et al experimented with light therapy on a cohort of PD patients.

"That the symptomatic improvement continued as long patients remained in the program suggests that exposure to light, under a strict daily regimen, combined with controlled DART,[dopamine replacement therapy] actively slows or arrests the progressive degenerative process underlying PD. "