Compiled by: Dr. Mary Thomas, Danville, California

Parkinson’s disease is a neurodegenerative condition associated with deposition of a protein called Alpha-synuclein in the brain cells, particularly in Substantia nigra. Spread of this protein clumps in the brain parallels the progress of the disease. Failure of the brain to process and clear this protein is believed to be the cause of damage to the brain in PD.

Curative medications are not yet found out for Parkinson’s disease. Various research studies are going on all over the world to find out a possible cure and to get control over symptoms without many side effects on long term therapy. Most of the research studies are confined to the fields of Biotechnology and Regenerative Medicine.

Studies in Antidyskinetic drugs have shown promising results in PD patients to improve muscle control, to reduce stiffness and to get more normal body movements. Various target receptors when activated or blocked they may prevent dyskinesias.

Antidyskinetic Drugs – Promising Studies:


Catechol-O-Methyltransferase Inhibitor – e.g. Entacapone, Tolacapone:

These allow larger amount of Levodopa to reach the brain, thereby raising dopamine levels for its better effects to last longer to manage ‘off time’.

MPTP Studies –

In these studies, lesioned primates are used in trials to demonstrate Levodopa induced dyskinesias (LID). 5-hydroxy tryptamine, cannabinoid and opioid transmitter systems are assessed for antidyskinetic potential in human studies.

Eleven non dopaminergic drugs having antidyskinetic efficacy in the MPTP primate study have been advanced for proof of concept in ‘11 a’ studies in PD patients. (Drugs – Nabilone, Fipamezole, Sarizotan, Clozapine, Istradefylline, Amantidine and few others.)

In primate study at least one drug proved efficacy and in phase 2 studies, out of eleven specific molecules tested, 8 showed antidyskinetic effects to certain extend. Failure to meet all the terms of protocol might have caused false negative conclusion.

In certain large Cohort studies in animals, sustained tobacco use showed decrease in development of Parkinson’s disease. Nicotinic acetylcholine receptors playing a role as potential target in dopamine release. These receptors are decreased with nigro-striatal damage. Lesioned monkeys in MPTP studies, nicotine found to attenuate LIDs without increasing PD symptoms. Selective nicotine agonists that target nigro-striatal alpha4B2 and alpha6B2 may provide benefit in risky cases. (Human study results not available.)

Modulating neurotransmitter activity is a promising approach having varying degree of success in animal and preclinical studies.

Cannabinoid (CBI) receptors agonists – e.g. Nabilone.

In human studies it exhibited limited antidyskinetic benefit and some of the drugs in this group not found effective. Fipamezole – (Alpha2 adrenergic receptor antagonist):

Activation of these receptors on presynaptic non-adrenergic terminals and postsynaptic GABA-ergic spiny neurons may facilitate activation of direct striatal pathways in the basal ganglia with development of LID. Fipamezole in higher doses, i.e., 60 mg and 90 mg trials, the severity of LID reduced to 23% and 31% respectively without affecting the anti parkinsonian response to Levodopa.

FJORD Study:

Four weeks placebo controlled study conducted with Fipamezole 30 mg to 90 mg dose simultaneously in India and in the US. The study in India not exhibited notable positive results, while the study in the US shown improvement in the drug receiving group in high dose (90 mg), where LIDs found reduced without any effect in placebo group. Further studies warranted in this trial to confirm the beneficial result. - An anti-seizure drug:

It has been tried to evaluate its impact on LIDs. Two placebo controlled studies, first with 32 patients conducted for a period of 11 weeks and results evaluated by UPDRS and modified by AIMS to assess dyskinesias. The medicine receiving group in this study showed significant improvement and placebo group not. Second phase study was for a cross over period and both having a mild but significant antidyskinetic effect. More studies needed for exact results.

A potential agonist at D2D3 receptors with lower affinity to D4 and alpha-1 adrenergic, 5HT7 receptors. It is having lower tendency to cause dyskinesias and neuropsychiatric side effects comparing to other dopaminergic therapies. In an over seven weeks trial with a dose between 0.3 mg and 42 mg for 51 patients, promising results obtained with only one patient developing troublesome dyskinesias.

Dopamine agonists – e.g. Pramipexole, Bromocriptine:

These drugs mimic the effects of dopamine by supplementing the last function of died out dopamine cells. With prolonged therapy Levodopa can induce dyskinesias and oral dopaminergic therapies, e.g. dopamine agonists, delay the need for initiating Levodopa therapy, there by delaying onset of dyskinesias. Alternate delivery methods by parenteral administration enable continuous dopamine availability, mainly in early stages.

Serotonergic (5HT1A) agonists – e.g. Sarizotan and (5HT2B) antagonist – e.g. Clozepam:

These groups affect striatal dopaminergic transmission, Y- amino-butyric acid (GABA) and glutamate output regions of basal ganglia. In animal models, when these drugs administered, there was a synergistic effect on development and severity of dyskinesias. Human study results currently not available.

Carbidopa-Levodopa Formulations— recently approved by FDA. 1PX066-RYTARY-

Oral extended release formulation of Carbidopa - Levodopa, composed of beads that dissolve at varying rates, producing smooth and prolonged intestinal absorption time. Exposure of Levodopa increases to 30% and a maximum of 87%, giving sustained levels with fewer fluctuations.


A gel formulation of Carbidopa / Levodopa, which is delivered directly to small intestine of patients as an infusion through surgically placed tube. It is mainly given to patients in advanced stage PD to control fluctuations in motor function.

Regenerative Medicine

Stem cell genex offers patients access to cutting-edge adipose tissue stem-cell therapy. In the US, these clinical studies are conducted through National Institute of Health and only by US Board certified doctors.

 Stem-cell therapy trials are mostly limited to certain groups of PD patients:

a. Patients not responding to drug treatment.

b. To reduce patient’s reliance on medication.

c. Those patients willing to try stem-cell therapy before starting drug treatment.

Induced Pleuripotent Stem-cell Trials:

Beth Vernaleo PhD, Parkinson’s Research Grant FAQ-NY, conducted experiments with skin cells of PD patients who developed the disease by certain genetic mutations. By experimental technique namely IPSC, skin cells are transformed to dopamine producing stem-cell neurons of brain thereby researchers can study behaviour of dopamine producing neurons and how genetic mutations affect them.

Dr. Aiqun, a research fellow in New York Stem-cell Foundation is studying about mutation in a gene called GBA (Glucocerebrosidase) which produces an enzyme that can break down toxic substances and recycle worn out parts of cells.

In another study Dr. Li, MD, PhD, Dr. Cao’s Centre for Stem cell and Regenerative Medicine, has taken skin cells from two identical twins, both having mutation in GBA but only one developed PD. While studying dopamine-neurons developed from skin cells, he found that both twins had elevated levels of Alphasynurein and decrease in dopamine quantity. Another enzyme namely MAO-B is found in high levels in one of the twins having PD. This enzyme breaks down dopamine and so dopamine level found very low in the twin having PD. When dopamine producing cells of this twin treated with GBA and other chemicals that stop the function of MAO-B, the Alphasynuclein levels decreased to normal.

In another study, Dr. Ping Yue Pan PhD, Fellow of Mount Sinai School of Medicine found mutation in a gene called Synaptojanin-1, associated with Parkinson’s disease. Synaptojanin-1 produces a protein that helps to recycle the vesicles that hold chemical neurotransmitters such as dopamine. These vesicles help neurons to communicate to each other by delivering the neurotransmitters. Dr. Pan found that mutation in dopamine neurons cause faster breakdown of dopamine. Detection of mutation in Synaptojanin-1 is a relatively new finding and its cause yet to be found out. Dr. Pan and Dr. Li plan to collaborate in Pleuripotent Stem cell research.

PDOIA – (PDo1A – a new therapeutic drug designed to produce antibodies against alphasynuclein.)

In the US, a 2 year period project started from 2012 onwards, in which 32 patients were treated by injecting vaccine to stimulate immune system and thereby to develop antibodies against Alphasynuclein protein. More than half of the treated cases developed antibodies and the vaccine found to be safe and tolerated giving hope for further trials.

Monoclonal antibodies injected to patients as a direct therapy in another trial. These specific antibodies bind to a single substance which will target Alphasynuclein and further trials are going on in this field.

Neuro- Protective Therapy:

A small clinical study in Sweden about a Growth Factor called PDGF (Platelet Derived Growth Factor), a protein that acts as a fertilizer for cells, may be applied directly to brain cells of PD patients. At present, trials in animals found to be safe and well tolerated. Further trials with Growth Factors are going on to prove their efficacy to enhance brain’s own protective mechanisms by stimulating neuronal growth and thereby increased production of dopamine.

Research held by Anders Haegerstand, MD, PhD, at Newron, Sweden AB and scientists at Swedish universities and hospitals developing PDGF as a potential PD therapy by testing in human volunteers. In this trial, 4 treatment groups having 3 participants in each group are tested with PDGF-BB, given through small tubes to a specific part of the brain for 12 days. Most of the patients tested by administering PDGF-BB and few received placebo. PET scan of the patients done before and after treatment. Not much difference detected immediately after treatment for 12 days. But PET-scan after 90 days of treatment, the PDGF received patients developed marked improvement, while placebo group exhibited no difference.

Deep Brain Stimulation (DBS): 

In 1998, Dr. Philip A. Starr started putting electrodes in the Basal ganglia of PD patient’s brain. After surgery, Dr. Starr switched on the electrodes releasing steady electric impulses in their brains. In most cases effect was immediate and the reason thought to be due to shutting down of the malfunctioning neurons by DBS.

In a recent experiment, Dr. Starr and colleagues could understand the mechanism of DBS. It works by liberating the brain from an ‘electrical lock-step’ by altering brain’s electrical rhythm. Brain produces a set of electrical waves at different frequencies, of which ‘Beta rhythm’ is of low frequency and it keeps different parts of the brain synchronized and makes communication to other parts of brain on the same timetable. If the Beta-rhythm is too strong, the region of the brain may get stuck forming neural lock-step, unable to generate new signals. Too weak Beta- rhythms also do not work well.

In PD patients, Beta rhythm becomes stronger and as a result motor cortex gets more tightly synchronized than it is in normal people. In PD patients, it is hard for the brain to break this synchronization by itself, while DBS makes it less synchronized, enabling patient’s movements better. Even though DBS does not cure Parkinson’s disease, and in most cases it can turn the clock back for few years.

Gut Bacteriae and PD:

NPF’s National Medical Director Dr. Michael S. Okun’s article reveals H-Pylori infection causes reduction in the gut of bacteria called Prevotelleceae, which in turn causes reduction in absorption of PD medication. Experiments in 2006 to 2008 revealed better absorption of Levadopa from PD patient’s guts when treated for H-Pylori with antioxidants or antibiotics.

Most recent neurological study shows that certain intestinal micro biota can interact with the autonomic and central nervous system, through diverse pathways making brain susceptible of protein (Alphasynuclein) deposition. Further studies are going on in this field.


National Center for Biotechnology Information (NCBI),

Part of United States National Library of Medicine (NLM),

California Institute for Regenerative Medicine (CIRM),

Parkinson’s disease Foundation, New York – Blogs.

National Parkinson’s Foundation – Blogs.

Science News and Science Sunday.