2 Compounds Show Ability to Protect Neurons, Raise Dopamine Levels

dopamine and Parkinson's

Two compounds with hormone-like effects — prostaglandin E1 (PGE1) and prostaglandin A1 (PGA1) — may help to increase dopamine levels in the brain and slow Parkinson’s progression by activating a protein, called Nurr1, that supports dopaminergic neurons, a study reports.

The study, PGE1 and PGA1 bind to Nurr1 and activate its transcriptional function,” was published in the journal Nature Chemical Biology.

Prostaglandins have various roles in controlling body functions, such as the contraction and relaxation of smooth muscle, the dilation and constriction of blood vessels, blood pressure control, and modulating inflammation.

Nurr1 is a protein that plays a key role in the development and maintenance of midbrain dopaminergic neurons — those that produce dopamine and are gradually lost throughout Parkinson’s disease. It does so by inducing the expression of genes that are essential for dopamine production and nerve cell survival.

A previous study found that Nurr1 was present at lower levels in the substantia nigra (a brain region rich in dopaminergic neurons) of Parkinson’s patients, suggesting Nurr1 could be a therapeutic target for treating the condition.

Scientists at Nanyang Technological University in Singapore (NTU Singapore) and Harvard University set out to identify molecules that may bind to Nurr1 and activate its protective properties.

“Considering the essential function of Nurr1, we have been searching for its activating molecules in the body,” Yoon Ho Sup, a professor at the NTU School of Biological Sciences and study author, said in a press release

The team identified PGE1 and PGA1 as two molecules able to bind to Nurr1. Using dopaminergic neurons derived from rodents, researchers further observed that PGE1 and PGA1 were able to induce the expression of Nurr1’s target genes, increase dopamine levels, and protect against cell death.

Of note, gene expression is the process by which information in a gene is synthesized to create a working product, like a protein.

Treatment with PGE1 and PGA1 was seen to significantly lessened motor symptoms in a mouse model of Parkinson’s disease. 

While PGE1-treated mice showed a more extensive recovery of motor function than PGA1-treated mice, both PGE1 and PGA1 protected dopaminergic neurons in the substantia nigra from cell death. Dopamine levels were also increased by both prostaglandins.

“We have successfully identified that PGE1/PGA1 is the molecular pair that acts specifically on Nurr1 and can lead to neuroprotective effects on the brain,” Yoon said.

Data also suggest “that native and/or synthetic ligands of Nurr1 may be developed as a novel class of mechanism-based neuroprotective drugs for PD [Parkinson’s disease] and other human disorders involving Nurr1 dysfunction,” the researchers wrote.

“Given that all candidate Parkinson’s drugs have failed to show neuroprotective abilities in clinical trials, our findings may offer an opportunity to design mechanism-based disease-modifying therapeutics to treat Parkinson’s disease with little side effect,” Yoon said.

“PGA1 is not a new kid on the block, but a molecule known to exhibit anti-inflammation and anti-tumour properties. Prostaglandins like PGE1 are available for clinical use, for example in obstetrics cases. This means that the compound can potentially be re-positioned to treat Parkinson’s patients, which can accelerate the time needed to take an experimental drug to the clinic,” added Lim Kah Leong, vice dean of research at the NTU Lee Kong Chian School of Medicine.

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My Pet Rabbit Helps Me Live with Parkinson’s 

“Until one has loved an animal, a part of one’s soul remains unawakened.” ― Anatole France

Dogs can help as emotional and physical support animals for humans with various disabilities and chronic illnesses, including Parkinson’s. These animals help make life easier for their humans and improve their quality of life.

Rabbits can’t be classified as support animals because they can’t be trained to help with physical tasks. However, they can provide emotional support by furnishing comfort and other therapeutic benefits to their owners through companionship.

Budgie Bunny

In 2010, my Budgie Bunny was found wandering in a park, fending for himself. Members of a local rabbit rescue organization asked me to foster him until his forever home could be found. That was 10 years ago. Needless to say, I failed at being a foster parent. As a friend once said to me, there are worse things in life to fail at.

Little did I know that five years after saving Budgie, I would be diagnosed with Parkinson’s. Now he is helping to save me.

How could a 4-pound fur ball possibly help someone with Parkinson’s? More than once when I was in the depths of despair, having a pity party for myself over my current health situation, I have crawled into a ball on the floor and started crying. Many times, Budgie would come over and give me bunny kisses. My tears would melt away, and I would be filled with gratitude to have such a great little buddy who seems to sense my emotions. I do not feel so alone having Budgie in my house.

What else has my bunny done to help me fight Parkinson’s?

Living with a rabbit has taught me some valuable lessons. Budgie has helped me to live in the moment. He taught me to be more patient. And he helped me keep laughter in my life.

Live in the moment

Budgie gets me out of bed in the morning. If I don’t feed him on his schedule, he will make a racket by pushing around his food bowl. If he wants attention, especially when I try to meditate in another room, he will create a lot of noise by working on a bunny construction project or thumping his hind leg. At times like these, I forget in that moment that I have Parkinson’s, and I become aware that Budgie needs something from me.

His life is so precious and he gives me so much comfort.

Patience is a virtue

Since rabbits are prey animals, they tend to be afraid of their own shadow and do not automatically trust humans. It takes a deliberate investment for one to build a relationship with a rabbit. Initially a bunny may be shy, afraid, independent, or hesitant to trust a human. I developed a lot of patience waiting for Budgie to be comfortable with me. It took him a long time to realize I wouldn’t eat him for lunch.

Now that I experience bradykinesia, a Parkinson’s symptom, I can become impatient with myself when I get dressed in the morning. However, the patience I developed while caring for Budgie has helped me to better cope with my slowness of movement.

Laughter is the best medicine

Budgie’s antics never fail to make me smile or laugh. Just this week, I forgot to put his litter box in his pen and he decided to use his food dish as his litter box. Much to my surprise, he didn’t even miss!

Instead of getting annoyed, I chuckled and gave my sweet bunny a few scratches behind his ears.

Laughter can alter dopamine and serotonin levels that are reduced in depression. Depression can affect up to half of all people with Parkinson’s at some point during the course of their disease. Budgie keeps me laughing, and laughter makes me feel good.

Although Budgie cannot provide physical assistance or balance and support like a guide dog, he does provide companionship and makes a great emotional support animal for me. Studies have linked pet ownership with reducing signs of depression in people with chronic illnesses and with reducing loneliness.

Having Parkinson’s can bring about many emotional and mental health problems. The calming nature of a therapy or emotional support animal (yes, even a rabbit) can help ease anxiety, release endorphins, and reduce stress.

“Rabbits will always have a special place in my heart. They are often discredited as being good pets because they don’t ‘do anything’—ask any rabbit owner and watch how they laugh!” – Shenita Etwaroo


Note: Parkinson’s News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or another qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website. The opinions expressed in this column are not those of Parkinson’s News Today or its parent company, BioNews Services, and are intended to spark discussion about issues pertaining to Parkinson’s disease.

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Gene Therapy Trial Patients, in Death, Helping Show What Did and Didn’t Work

gene therapy

Delivering a gene therapy directly to the substantia nigra, an area of the brain affected by Parkinson’s disease, led to sustained protein production for up to eight years, a post-mortem of analysis of two patients revealed.

The therapy’s use failed to show significant benefits in its clinical trials, but these evaluations — covering the longest number of years for such an analysis in gene therapy trial participants — are likely to help researchers working to improve the effectiveness of this approach. 

The study, “Long-term post-mortem studies following neurturin gene therapy in patients with advanced Parkinson’s disease,” was published in the journal Brain.

Parkinson’s is caused by the dysfunction or death of nerve cells that produce dopamine (dopaminergic neurons). A neurotransmitter, dopamine is produced in the substantia nigra, a part of the brain the controls balance and movement.

CERE-120, an investigative gene therapy first developed Ceregene, now part of Sangamo Therapeutics, is designed to protect these neurons. It works to deliver a gene called NRTN directly to the substantia nigra and surrounding area known as the putamen. This gene carries the instructions for a protein known as neurturin (NRTN) — a neurotrophic factor — which supports the growth and survival of neurons. 

In animal models, the human NRTN gene carried on a harmless virus known as adeno-associated virus serotype 2 (the CERE-120 therapy), and surgically implanted, was seen to protect dopaminergic neurons and led to an increase in dopamine production. 

An early open-label Phase 1 clinical trial (NCT00252850) in Parkinson’s patients showed CERE-120 was safe and well-tolerated, with some patients reporting benefits. However, a double-blind Phase 2 trial (NCT00400634), in which CERE-120 was surgically delivered to the putamen, failed to show significant improvement compared to those given a sham surgery.

Post-mortem studies of those treated showed persistent but limited NRTN protein production in the putamen. These levels were not sufficient to provide significant benefits. 

A second trial (NCT00985517) was designed to enhance NRTN production by delivering a higher dose to a larger area of the putamen as well as directly to the substantia nigra. Again, CERE-120 failed to show improvement beyond sham surgery in this new group of Parkinson’s patients.

To better understand the reasons for this failure, researchers at the Rush University Medical Center in Chicago conducted post-mortem assessments on two Parkinson’s patients who participated in the CERE-120 gene therapy clinical trials. 

One was from the first Phase 2 trial (putamen only) and survived for 10 years after surgery, while the other was enrolled in the second Phase 2 trial (putamen plus substantia nigra) and lived for another eight years. 

As a comparison, the team also evaluated the brains of two age-matched Parkinson’s patients who were not given gene therapy, and those of two age-matched people who neither had Parkinson’s nor other psychiatric or neurological illnesses at the time of their death.

In both treated patients, there was a persistent but limited production of NRTN in the putamen, and an associated increase in levels of an enzyme known as tyrosine hydroxylase (TH) — a key enzyme in the production of dopamine. TH levels were substantially higher in the case with combined putamen plus substantia nigra delivery compared to putamen delivery alone. 

The NRTN protein was found in up to 19% of remaining dopaminergic neurons in the substantia nigra of the patient who received CERE-120 delivered to the putamen only. In the patient with CERE-120 delivered to both the putamen and substantia nigra, NRTN was detected in up to 39% of the remaining neurons.

This protein was not detected in samples from patients not treated with gene therapy, or people without Parkinson’s. 

NRTN signaling works through a multi-component system, including a receptor known as RET. Consistently, RET expression levels were higher in the patient with combined CERE-120 delivery than in the patient with putaminal CERE120 delivery only.

In Parkinson’s patients, dopaminergic neurons are damaged by the buildup of the alpha-synuclein protein, which forms clumps called Lewy bodies. Studies have suggested that alpha-synuclein can reduce the expression of the RET receptor,  limiting NRTN production. 

Alpha-synuclein clumps were found in neurons that also showed NRTN, RET, and TH. No differences were seen in the numbers of Lewy bodies between the two treated and untreated Parkinson’s patients. 

Finally, low levels of the viral AAV vector were detected in both the putamen and the substantia nigra of patients compared to animal models, but its presence did not cause inflammation. 

“In summary we demonstrate that gene delivery of NRTN can induce long-standing transgene [artificially introduced gene] expression in Parkinson’s disease subjects lasting for at least 8–10 years with prominent upregulation of TH in focal areas of the putamen and substantia nigra that express NRTN,” the researchers wrote.

“If gene therapy is ever to be considered as a treatment for Parkinson’s disease, we will have to find a way to meaningfully increase TH-positive terminals in the striatum [brain area that includes the putamen], as motor benefits are primarily dependent on TH expression in the putamen,” they added.

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New Parkinson’s Treatment Target – Drp1 Protein Linked to Sense of Smell – Found in Rat Model, Study Reports

Drp1 Protein Sense of Smell

A new potential target for treating Parkinson’s, a protein named Drp1, has been identified using a rat model of the disease, a study reported.

The target was found to play a central role in the underlying cause of the degeneration and inflammation of nerve cells in the olfactory bulb, the area responsible for the sense of smell. Losing the sense of smell is an early symptom of the progressive neurodegenerative disease. 

The study, “Drp1, a potential therapeutic target for Parkinson’s disease, is involved in olfactory bulb pathological alteration in the Rotenone-induced rat model,” was published in the journal Toxicology Letters.

One early non-motor symptom of Parkinson’s is a loss of the sense of smell. Before it appears in the brain, the toxic buildup of the protein alpha-synuclein — a hallmark of the condition — occurs in the olfactory bulb, which is the the neural structure located above the sinuses that’s responsible for the ability to smell. 

However, the underlying mechanism that leads to early-stage olfactory bulb impairment is unclear.

A common phenomenon in Parkinson’s is the improper functioning of the mitochondria, or the small structures within the cell that produce energy — the cells’ powerhouses. A protein called dynamin-related protein 1 (Drp1) regulates mitochondria dynamics, notably in the cell division process. Chemicals that target this protein have been shown to cause mitochondrial fragmentation leading to the loss of neurons. 

Mitochondrial fragmentation also is known to drive a pro-inflammatory response, a common characteristic of neurodegenerative diseases. 

This prompted researchers to investigate whether Drp1-mediated mitochondrial damage played a role in the impairment of the olfactory bulb. The team used a rat model in which Parkinson-like symptoms were induced by the infusion of rotenone, a mitochondria inhibitor.

To examine the effects of rotenone on the olfactory bulb, a group of rats were treated and compared with a group of untreated rats. In a second experiment, these two groups of animals were compared with a third group treated with a specific Drp1 inhibitor.

Compared with the untreated group, rats treated with rotenone lost more weight and displayed parkinsonian features such as poor motor coordination. The treated rats also had a characteristic depletion of dopamine — the chemical messenger or neurotransmitter produced by dopaminergic neurons that are progressively lost in Parkinson’s disease.

An examination of olfactory tissue under the microscope showed that the density of dopamine-producing neurons was significantly reduced in rotenone-treated rats compared with the untreated group. 

Rotenone triggered the activation of olfactory-specific astrocytes — star-shaped neuroglia or neural support cells — and microglia, a type of brain-specific immune cell. The accumulation of these cells was accompanied by a significant increase in the production of pro-inflammatory markers. 

An examination of the mitochondria in the control animals found typical rod-like shapes characteristic of healthy olfactory cells. In contrast, large numbers of mitochondria in the rotenone-treated group were small and damaged. 

Rotenone injection also caused a dramatic reduction of Drp1 outside of the mitochondria and a significant increase on the inside. 

Finally, the researchers found that adding a Drp1 inhibitor led to a significant reduction in the loss of dopaminergic neurons, increased the presence of healthy mitochondria, and blocked the production of pro-inflammatory markers. 

“In summary, the present findings demonstrate that Drp1-mediated mitochondrial fragmentation induced by rotenone injection participated in neuropathologic changes in the olfactory bulb,” the researchers concluded. 

They said further study needs to be done “to elucidate the network as well as focus on the aberrant mitochondrial dynamics to explore the mechanism.”

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Scientists Uncover New Therapeutic Molecule BT13 That May Possibly Protect Against Neurodegeneration

therapeutic molecule BT13

Scientists have uncovered a new therapeutic molecule, called BT13, that can get to the brain to boost dopamine levels — the brain chemical that’s in short supply in Parkinson’s disease — and could potentially protect against neurodegeneration.

While the research is in the early stages, and the molecule has only been tested in mice and cellular models of the disease, the researchers say BT13 shows promise as a way to slow or stop Parkinson’s instead of just treating its symptoms.

The findings were described in the study, “Glial cell line–derived neurotrophic factor receptor Rearranged during transfection agonist supports dopamine neurons in Vitro and enhances dopamine release In Vivo,” published in Movement Disorders.

Evidence shows that a small protein known as glial cell line-derived neurotrophic factor, or GDNF, supports the growth, survival, and differentiation of dopaminergic neurons — those that produce dopamine and progressively degenerate in Parkinson’s disease.

In animal models of Parkinson’s, as well as in human clinical trials, GDNF has shown neuroprotective effects.

However, due to its large size, GDNF is not able to cross the human blood-brain barrier (BBB), and complex surgery is required to deliver the treatment to the brain. The BBB is a semipermeable membrane that protects the brain against the external environment, but is a major barrier for the efficient delivery of therapies that need to reach the brain and central nervous system to work.

BT13, another molecule that binds the same signaling receptor — or RET receptor — for the GDNF molecule family, is much smaller in size than GDNF. Researchers say BT13 has the potential to produce the same neuroprotective effects as GDNF and should be able to more easily cross the blood-brain barrier.

Now, a team of scientists from the University of Helsinki in Finland set out to study this small molecule’s effects in immortalized nerve cells — neurons that are engineered to proliferate indefinitely — and in live mice.

The results revealed that after binding to RET, BT13 triggered molecular signaling cascades related to cellular survival and growth in normal dopamine-producing immortalized neurons. However, when cells were engineered to lack the RET receptor, BT13 had no effect.

BT13 was found to protect against Parkinson’s-related neurodegeneration, which was simulated in the lab by exposing dopaminergic neurons in dishes to 6-OHDA and MPP+ — both neurotoxins that induce cell death and mimic disease symptoms. Importantly, BT13 only protected these neurons when they expressed the RET receptor.

In addition, when BT13 was administered to mice — through an injection directly into the brain — it was able to cross the blood-brain barrier. When in the brain, the molecule activated cell survival and growth pathways and promoted the release of dopamine from the animals’ striatum, a motor control brain area primarily affected by Parkinson’s.

“People with Parkinson’s desperately need a new treatment that can stop the condition in its tracks, instead of just masking the symptoms. One of the biggest challenges for Parkinson’s research is how to get drugs past the blood-brain barrier, so the exciting discovery of BT13 has opened up a new avenue for research to explore, and the molecule holds great promise as a way to slow or stop Parkinson’s,” David Dexter, PhD, deputy director of research at Parkinson’s UK and professor of neuropharmacology at Imperial College London, said in a press release.

“We are constantly working on improving the effectiveness of BT13,” said Yulia Sidorova, PhD, the study’s lead researcher. “We are now testing a series of similar BT13 compounds, which were predicted by a computer program to have even better characteristics.

“Our ultimate goal is to progress these compounds to clinical trials in a few coming years,” Sidorova said.

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Imaging Technique Finds Key Neurons in Brain Interact, May Support More Targeted Treatments

nerve cell communication

Two key types of brain nerves cells affected by Parkinson’s disease — cholinergic neurons and dopaminergic neurons — communicate and interact via signaling systems, researchers were able to “see” using a new imaging approach.

This beneficial neuron-to-neuron interaction, confirmed through the novel approach in a rat model of the disease, also supported further work on targeted treatments for Parkinson’s, including a potential gene therapy.

Their study, DREADD Activation of Pedunculopontine Cholinergic Neurons Reverses Motor Deficits and Restores Striatal Dopamine Signaling in Parkinsonian Rats,” was published in Neurotherapeutics.

Parkinson’s is a progressive neurodegenerative disease, meaning that it steadily worsens as neurons die over time. One of its hallmarks is the loss of dopamine — a neurotransmitter crucial for coordinating movement and regulating mood — that occurs when dopaminergic neurons in a brain structure called the substantia nigra malfunction and die.

Cholinergic neurons — those that produce the neurotransmitter acetylcholine — are nerve cells found in the pedunculopontine nucleus (PPN) of the brain. They are also implicated in Parkinson’s, since in post mortem studies of patients’ brain tissue a significant amount of these cells are found dead.

Researchers had previously used used a harmless virus to deliver a genetic modification to cholinergic neurons in a rat model of Parkinson’s disease. This technique is called designer receptors exclusively activated by designer drugs (DREADDs), and consists of a class of engineered proteins that allow researchers to hijack cell signaling pathways in order to look at cell-to-cell interactions more easily.

The animals were then given a compound designed to activate the genetic ‘switch’ and stimulate the target neurons. After treatment, almost all animals had recovered and were able to move.

Now, this same research team used positron emission tomography (PET), a brain imaging technology, together with DREADDs to selectively activate cholinergic neurons in the brains of diseased rats and look at how other brain cells responded.

They found that stimulating cholinergic neurons led to the activation of dopaminergic neurons in the rat brain, and dopamine was released.

This means that cholinergic activation restored the damaged dopaminergic neurons. The parkinsonian rats appeared to completely recover — they were able to move without problems and their postures returned to normal.

“This is really important as it reveals more about how nerve systems in the brain interact, but also that we can successfully target two major systems which are affected by Parkinson’s disease, in a more precise manner,” Ilse Pienaar, PhD, a researcher at the University of Sussex and Imperial College London and study author, said in a press release.

“While this sort of gene therapy still needs to be tested on humans, our work can provide a solid platform for future bioengineering projects,” Pienaar added.

This new technique has several advantages over deep brain stimulation (DBS), a surgical procedure that sends electrical impulses to the brain to activate the neurons.

Deep brain stimulation can help to relieve some Parkinson’s symptoms, but is invasive and has had mixed results. Some patients show improvements while others experience no changes in symptoms or even a deterioration. This may be due to therapy imprecision, as DBS stimulates all types of brain nerve cells without a specific target.

This study sought to address the selectivity issue by looking at the activation of one type of cell in a specific part of the brain to get a better understanding of how other parts might be influenced.

“[T]he current data could allow for designing medical approaches capable of improving the ratio between desirable and undesirable outcomes and leaving nonimpaired functions intact. For example, specific genetically defined neurons … could be targeted to treat motor symptoms of [Parkinson’s], without inducing a cognitive detriment, and vice versa,” the researchers wrote.

“For the highest chance of recovery, treatments need to be focused and targeted but that requires a lot more research and understanding of exactly how Parkinson’s operates and how our nerve systems work,” Pienaar said. “Discovering that both cholinergic and dopaminergic neurons can be successfully targeted together is a big step forward.”

The researchers concluded, “[t]his study supports the hypothesis that it is the cholinergic neuronal population, projecting from the PPN, which delivers some of the clinical benefits associated with PPN-DBS.”

Pienaar and colleagues collaborated with Invicro, a precision medicine company, for this study. Lisa Wells, PhD, a study co-author on the study and Invicro employee added, “It has been an exciting journey … to combine the two technologies [DREADD and PET] to offer us a powerful molecular approach to modify neuronal signaling and measure neurotransmitter release. We can support the clinical translation of this ‘molecular switch’ … through live imaging technology.”

This work may make possible more selective and more effective treatment alternatives to deep brain stimulation.

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Baicalin Protected Rats Against Parkinson’s Neurodegeneration

baicalin study

A bioactive agent called baicalin prevented neurodegeneration of Parkinson’s disease in rats by protecting against oxidative stress and neuronal death, according to a recent study.

The results, “Neuroprotective effect and mechanism of baicalin on Parkinson’s disease model induced by 6-OHDA,” were published recently in the journal Neuropsychiatric Disease and Treatment.

Although Parkinson’s trigger is unknown, research indicates its causative mechanism involves genetics, malfunction of mitochondria (the cells’ “powerhouses”), and oxidative stress — an imbalance between the production of harmful free radicals and the ability of cells to detoxify them, resulting in cellular damage.

Taken together, these molecular and cellular changes eventually result in the death of dopamine-producing neurons, the nerve cell type that is gradually lost in Parkinson’s disease.

Available treatments only ease disease symptoms, and there are currently no disease-modifying therapies that can delay or prevent Parkinson’s neurodegeneration.

Baicalin, a compound isolated from the Chinese skullcap‘s (Labiatae Scutellaria Linn Scutellaria baicalensis Georgi) dry roots, has been shown to have antibacterial, antiviral, anti-inflammatory, anti-tumor, cardiovascular, and neuroprotective activities.

Importantly, evidence shows that baicalin protects against dopaminergic neuronal damage induced by either rotenone or MPTP, two neurotoxins that are commonly used to replicate Parkinson’s in animal models.

A Chinese team of researchers now investigated the effects of baicalin on a 6-hydroxydopamine (6-OHDA)-induced rat model of Parkinson’s disease. Like rotenone and MPTP, 6-OHDA induces the death of dopamine-producing neurons and mimics Parkinson’s symptoms.

Baicalin was given in one of three doses: low (50 mg/kg), medium (100 mg/kg), or high (150 mg/kg). Following baicalin continuous administration for eight weeks, scientists assessed animals’ fatigue, motor coordination, voluntary movement, anxiety and exploratory behavior on a weekly basis. Neuronal changes following baicalin treatment also were evaluated.

Baicalin was found to improve rats’ coordination and voluntary movement. The compound also prevented oxidative stress-related neuronal damage and death, and promoted the release of neurotransmitters to regulate dopamine-dependent communication within the rats’ brain by regulating six small metabolic molecules: N-acetyl-aspartate (NAA), aspartate, glutamate, gamma-aminobutyric acid, glycine, and taurine.

“NAA is a hallmark of neuronal changes in the brain, and a decreased level suggests a loss or dysfunction of neurons,” researchers noted. On the other hand, glutamate is mainly involved in signal transmission, and learning and memory formation.

Further analysis revealed rats with Parkinson’s had low levels of N-acetyl-aspartate (NAA) and high levels of glutamate in the striatum (a brain region involved in motor control). After continuous administration of baicalin for two months, NAA and glutamate concentrations in the striatum changed in a dose-dependent manner to almost similar levels of those seen in healthy animals: higher baicalin doses resulted in increased metabolite concentrations.

Importantly, the team believes that both NAA and glutamate levels could be potential diagnostic biomarkers to assess neurodegeneration in the context of Parkinson’s disease.

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Cannabinoids Ease Motor Symptoms in Mouse Model of Parkinson’s, Early Results Show


Cannabinoid-based formulations in development at GB Sciences were able to ease behavioral symptoms linked to the loss of dopamine producing-nerve cells — a hallmark of Parkinson’s — in a mouse model of the disease, the company said.

GB Sciences will use these early results to support an Investigational New Drug Application it plans to file with the U.S. Food and Drug Administration, requesting to open a clinical trial later this year.

“These positive preclinical results suggest that our cannabinoid-containing complex mixtures may be useful for the treatment of Parkinson’s disease symptomology,” Michael Farley, president and director of GBS Global Biopharma, said in a press release.

Results to date are part of the study’s midterm report, the company said, and the study is continuing.

Parkinson’s is characterized by the degeneration and death of a specific group of nerve cells — called dopaminergic neurons — in the substantia nigra, a brain region that regulates muscle movement and coordination. These cells are responsible for the production of dopamine, a critical brain chemical, or neurotransmitter, that regulates brain cell activity and function.

Cannabinoids are the active chemicals that give the cannabis plant its medical and recreational properties. Numerous studies have looked at the chemicals’ potential to ease motor symptoms in several neurodegenerative conditions, including Parkinson’s.

GB Sciences is creating a pipeline of novel medicines based on the company’s patent-pending formulations of chemicals extracted from the cannabis plant.

Results of the preclinical study, led by Lee Ellis of Canada’s National Research Council (NRC), showed that several of GB’s cannabinoid formulations eased behavioral symptoms in a mouse model of Parkinson’s. One formulation completely relieved the symptoms, without signs of significant side effects.

“Several of GB Sciences’ mixtures were effective,” said Andrea Small-Howard, chief science officer and director of both GB Sciences and GBS Global Biopharma. “In fact, our most effective mixture was able to ‘rescue’ the PD-like behavioral changes to the point where the treated animal’s behavior was back to baseline. In addition, our PD formulas produced negligible side effects, which is equally important.”

The next and final phase of this ongoing study will look into the mechanisms underlying these formulations and the benefits seen. Researchers suggest that the cannabinoids either protect dopamine-producing neurons from dying, or enhance the production of dopamine by surviving neurons.

All results will be used to support the company’s request to the FDA.

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Cancer Medication Tasigna Safely Boosts Dopamine Levels in Brain of Parkinson’s Patients, Phase 2 Trial Shows

Tasigna, Parkinson's

Tasigna (nilotinib), an approved leukemia medication being tested as a repurposed treatment for Parkinson’s disease, was found to be safe and increased the levels of dopamine in the brain of patients with Parkinson’s disease, a Phase 2 trial shows.

The findings were reported in a study, “Nilotinib Effects on Safety, Tolerability, and Potential Biomarkers in Parkinson Disease: A Phase 2 Randomized Clinical Trial,” and published in JAMA Neurology.

Tasigna, developed by Novartis, is approved by the U.S. Food and Drug Administration and the European Medicines Agency to treat adults with chronic myeloid leukemia, a type of blood cancer that typically affects older adults.

The medicine blocks the activity of a protein called BCR-ABL, which is known to support cancer development. But this protein is also intimately linked to several mechanisms in the brain, such as oxidative stress (cellular damage as a consequence of high levels of oxidant molecules) and alpha-synuclein-induced neurodegeneration, which play critical roles in Parkinson’s and other brain disorders.

For that reason, researchers wondered if Tasigna could be repurposed to treat Parkinson’s disease. Drug repurposing refers to the process of testing a medication with established safety in conditions other than those for which it was originally intended.

pilot study in 12 individuals with Parkinson’s disease dementia and dementia with Lewy bodies suggested that this therapy could effectively treat Parkinson’s motor and non-motor symptoms, while also increasing dopamine metabolism (its use in the brain) and lowering alpha‐synuclein levels.

Subsequently, researchers in the new study sought to investigate the safety, tolerability, and pharmacokinetic properties of Tasigna in a placebo-controlled, Phase 2 trial (NCT02954978) carried out at Georgetown University Medical Center (GUMC). Pharmacokinetics refers to how a drug is absorbed, distributed, metabolized, and eliminated from the body.

The study enrolled 75 patients with moderate-to-severe Parkinson’s disease who were randomly assigned to receive one of two oral doses of Tasigna (150 or 300 mg daily), or a placebo, for a period of one year, followed by a washout period of three months, in which they stopped taking the medication or the placebo.

The mean dose of levodopa at enrollment was similar between groups.

Earlier findings from the study showed that treatment with a single low dose of Tasigna improved the brain’s ability to use dopamine stored in small vesicles in specific brain regions of Parkinson’s patients by reducing inflammation and the levels of toxic alpha-synuclein.

Most of the patients enrolled (88%) completed the study. A total of nine patients withdrew from the study, including two who had been assigned to the placebo, three who had been assigned to receive the lowest dose of Tasigna, and four who had been assigned to receive the highest dose of the medication. From these, two withdrew from the study due to serious adverse events.

Tasigna was considered reasonably safe and well-tolerated, with most adverse events being mild or moderate in severity. The most common non-serious adverse events included falls, and musculoskeletal, respiratory, and skin conditions. Gastrointestinal and heart problems were less common.

In a secondary exploratory analysis of biomarkers, the investigators found that patients treated with Tasigna experienced a reduction in the levels of two toxic proteins that are considered hallmarks of Parkinson’s disease: a 20% decrease in alpha-synuclein and 30% reduction in tau.

In addition, they discovered that those taking Tasigna had an increase of more than 50% in the levels of dopamine (the brain chemical missing in those with Parkinson’s disease), suggesting that reducing the levels of toxic proteins could help the brain to use dopamine more effectively.

Those taking Tasigna performed better on motor tests and tended to have better scores in the PDQ-39 questionnaire (a measure of quality of life) compared to those treated with the placebo.

“We see that subjects on nilotinib performed better overall on motor testing and had a better quality-of-life measurement during the study than the placebo group. These are important observations suggesting that nilotinib stabilized the disease — a potential disease modifying effect that we haven’t observed with any other agents,” Fernando Pagan, MD, medical director of the GUMC Translational Neurotherapeutics Program and principal investigator of the study, said in a press release.

“These clinical findings need confirmation through larger studies with more diverse populations,” added Pagan, who also directs the Movement Disorders Clinic at MedStar Georgetown University Hospital.

The post Cancer Medication Tasigna Safely Boosts Dopamine Levels in Brain of Parkinson’s Patients, Phase 2 Trial Shows appeared first on Parkinson’s News Today.

Immunotherapy Reduced Alpha-synuclein Clumps, Improved Dopamine Levels in Parkinson’s Mouse Model

antibodies and alpha-synuclein

Antibodies that selectively target the misfolded form of the alpha-synuclein protein — that which underlies the development of Parkinson’s disease — reduced the formation of alpha-synuclein clumps and improved dopamine levels in a mouse model. 

The study with that finding also provided a framework for screening  antibodies (immunotherapies) that target alpha-synuclein to identify those with the best therapeutic properties.

The study, “Characterization of novel conformation-selective α-synuclein antibodies as potential immunotherapeutic agents for Parkinson’s disease,” was published in the journal Neurobiology of Disease.

Nerve cell damage in Parkinson’s disease is caused by the build-up of toxic forms of the protein alpha-synuclein that forms clumps of misfolded proteins known as Lewy bodies.

Studies have found that reducing misfolded alpha-synuclein may be an effective therapeutic strategy for treating the disease. 

One idea is to create antibodies that specifically target misfolded alpha-synuclein, avoiding the problems associated with reducing the levels of properly folded, fully functioning alpha-synuclein.

This was the approach taken by a group of researchers at the University of Pennsylvania in Philadelphia. Their first step was to create and isolate antibodies that were highly selective for misfolded alpha-synuclein, then test the best candidate in a Parkinson’s mouse model to find out if the antibody had therapeutic potential. 

To create these antibodies, mice were injected with misfolded alpha-synuclein and the antibodies generated during the immune response were isolated and screened to find the best candidate. 

Brain sections from Parkinson’s patients with high numbers of Lewy bodies first were used to identify antibodies that selected pathological (disease-associated) alpha-synuclein.

The team hoped these antibodies may be used in humans, so those that bound to both mouse and human alpha-synuclein were preferred. 

Further testing found antibodies that bound to only the misfolded form of alpha-synuclein, but not the normal form. 

The final screen was to identify a candidate that prevented the development of alpha-synuclein pathology in neurons. Mouse neurons were treated with the previously selected antibodies and were exposed to toxic forms of human alpha-synuclein protein. The highest performing antibody, named Syn9048, reduced pathology [disease manifestation] by 97%.

As antibody treatments for Parkinson’s are likely to be given after symptoms emerge (when brain disease is already established), a mouse model was chosen to test the effectiveness of Syn9048 to reduce disease and rescue nerve cell function. 

Mice were injected with misfolded alpha-synuclein, which triggered nerve cell loss in the same areas of the brain as seen in Parkinson’s patients. Then they were given Syn9048 or a control antibody every week for six months.  

All mice gained weight in a similar manner, showing that the therapy was well-tolerated.

Examination of the mouse brains showed that Syn9048 reduced the aggregation of alpha-synuclein in areas related to Parkinson’s disease. 

Although Syn9048 was not successful in rescuing cells responsible for producing dopamine (dopaminergic), it increased dopamine levels in the brain, which suggested that the reduction of alpha-synuclein pathology may improve the function of remaining dopamine-producing neurons.

“Our study suggests that immunotherapy will not likely reverse existing pathology, but may halt the spread of pathology through the brain, preventing further motor and cognitive decline,” the researchers wrote.

“Future studies assessing brain-wide spread patterns could help predict the maximal possible benefit of immunotherapy and could be used to determine when during disease progression immunotherapy would need to be administered to be most efficacious,” they added. 

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