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.

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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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Early Parkinson’s Detection Technique Validated in Prion Animal Models, Study Shows

Parkinson's and IL-17A

The early detection of diseases characterized by protein misfolding and aggregation, such as Parkinson’s disease, moved one step closer by the validation in animal models of a sensitive technique to capture and analyze misfolded and aggregated proteins in the blood quickly and efficiently.

The technique was validated by showing that prions — a misfolded protein that causes prion disease — can be captured, isolated, analyzed, and transferred between species, a study has shown. 

The study, “Enhanced detection of prion infectivity from blood by preanalytical enrichment with peptoid-conjugated beads,” was published in the journal PLOS ONE

Parkinson’s disease is caused by the damage or death of dopamine-producing nerve cells (neurons) in a region of the brain that controls balance and movement. 

A hallmark of the disease is the accumulation of a misfolded form of a protein called alpha-synuclein, a protein typically located near the tips of nerve cells and associated with the regulation of dopamine release.

To function properly, a protein must fold into a specific shape. However, when alpha-synuclein does not fold properly or misfolds, it clumps together to form plaques in the brain, causing cell damage and death. 

A misfolded protein is also the causative agent in transmissible spongiform encephalopathies or prion diseases. The most famous prion disease is bovine spongiform encephalopathy (BSE) — otherwise known as “mad cow disease” — where misfolded proteins, called prions, from cows in the food chain or infected people trigger other proteins in the brain to misfold and aggregate. 

The outbreak of BSE in European cattle and several hundred associated cases in humans in the late 1980s has spawned efforts to find methods to detect the very low levels of prions in the blood of infected people.

One method that has been successful, called the misfolded protein assay (MPA), involved selectively capturing prions using molecules that mimic the parts of the prion that bind together to form aggregates.

These mimicking molecules — known as peptoids — are composed of modified versions of the naturally occurring amino acids (building blocks) of prion proteins.

The peptoids are fixed to magnetic beads (PSR1) which can be mixed, then easily isolated from blood and tested for prions. One of the advantages of MPA over other tests is that it can analyze large numbers of samples quickly and for less cost.

The MPA technique was used to successfully identify prions in a patient with prion disease when other tests failed. In addition, the utility to capture and analyze prions extends beyond prion diseases to other conditions characterized by protein misfolding, such as Parkinson’s, and may provide a means to diagnose the disease years before symptoms arise.

Before MPA can be used in humans, efficacy must be determined in animal models, so researchers designed a study to test the reliability and sensitively of MPA to detect prions using mouse and hamster models of prion disease.

Brain tissue from hamsters bred to develop prion disease was injected into 40 healthy hamsters, and five control hamsters were inoculated with brain tissue from non-infectious hamsters. 

Blood was withdrawn from the hamsters before and after the appearance of prion disease symptoms, namely ataxia (lack of muscle control), loss of appetite, and poor grooming. 

The PSR1 magnetic beads were mixed with these blood samples and were washed to remove extra proteins. The washed beads were then injected into a special breed of mice — Tg(SHaPrP) — that expressed the normal form of hamster prion protein. If infectious misfolded prions were captured by the beads, they would trigger the normal form of hamster prion protein to misfold in the mice and lead to prion disease. 

The results demonstrated that in mice that were inoculated with beads mixed with blood from hamsters with prion disease symptoms, nearly all of the mice (25 of 28 injected) developed prion disease. Prion disease was confirmed by examining mice brain tissue under a microscope. 

In contrast, mice injected with beads mixed with non-symptomatic hamster blood (or controls) did not develop signs of prion disease. 

“We therefore conclude that PSR1 beads highly efficiently capture prion infectivity from plasma from presymptomatic and symptomatic cases and are able to transmit infectivity to Tg(SHaPrP) mice,” the researchers wrote. “We found that the readout of the peptoid-based misfolded protein assay (MPA) correlates closely with prion infectivity in vivo, thereby validating the MPA as a simple, quantitative, and sensitive surrogate indicator of the presence of prions.” 

Ronald Zuckermann, PhD, study co-author and senior scientist at the Lawrence Berkeley National Laboratory Molecular Foundry, in Berkeley, California, noted in a news release, “Our peptoid beads have the ability to detect the misfolded proteins that act as infectious agents, so it could have a significant impact in the realm of prion diseases, but we have also shown that it can seek out the large aggregated proteins that are the disease agents in Alzheimer’s and Parkinson’s diseases, among others.” 

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Parkinson’s Foundation Launches International Cycling Event to Promote Exercise, Raise Funds

cycling event, fundraising

The Parkinson’s Foundation is launching a new initiative called Parkinson’s Revolution, a global cycling event designed to highlight the benefits of exercise in Parkinson’s disease while also raising funds for research.

A new signature event for the foundation, Parkinson’s Revolution is an indoor cycling program taking place Feb. 8 at studios in seven U.S. cities — Boston, Chicago, Dallas, Miami, New York City, San Francisco, and Washington, D.C. The program will also involve select locations in Canada and the United Kingdom. The fundraising goal for each site is $10,000.

“Parkinson’s Revolution is a great example of how the international [Parkinson’s] community is rallying together to combine the benefits of exercise and critical fundraising for research in one event,” John Lehr, the foundation’s president and CEO, said in a press release. “We are honored to work alongside Parkinson Canada and Parkinson’s UK to further our mission to make life better for people with Parkinson’s.”

In a high-energy environment including motivational music and instruction, participants of all abilities will select either a 90- or 45-minute ride as individuals or as part of a team. Supporters who can’t make it in person may saddle up at home or a local studio and raise funds as “virtual riders.” The foundation is asking each person to commit to fundraising a minimum of $250.

Money raised will go directly toward research, resources, and patient care. In addition to offering an opportunity to meet fellow supporters, each Parkinson’s Revolution event will include information about the Parkinson’s Foundation.

Click on a city or “virtual ride” at this site to register. After signing up, participants will be sent tools needed to reach — or exceed — fitness and fundraising goals.

Exercise is particularly important for Parkinson’s patients, helping them maintain balance, mobility, and the ability to do daily tasks. Scientists have found that those who exercise at least 2.5 hours weekly also experience a slower decline in their quality of life.

In addition, researchers have studied the brains of mice that exercised under conditions similar to a human being on a treadmill. While exercise did not increase the number of neurons or amount of dopamine in mice’s brains, it did prompt their brains to use dopamine more efficiently.

Dopamine is a neurotransmitter that helps regulate movement and emotional response. A lack of it is associated with neurodegenerative disorders including Parkinson’s, which affects nearly 1 million U.S. residents and 10 million individuals globally.

Watch this Parkinson’s Revolution video from the Parkinson’s Foundation:

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Deep Brain Stimulation Eases Parkinson’s Symptoms by Directly Raising Dopamine Levels, Study Suggests

deep brain stimulation study

Deep brain stimulation (DBS) eases tremors and muscle rigidity, and improves cognition and mood in Parkinson’s patients by raising dopamine levels in the brain, a small study from Johns Hopkins Medicine suggests.

The research, “Effect of STN DBS on vesicular monoamine transporter 2 and glucose metabolism in Parkinson’s disease,” was published in the journal Parkinsonism and Related Disorders.

DBS is given to Parkinson’s patients whose motor symptoms do not respond well to medication. In this procedure, fine wires are inserted into the brain and connected to an electrical current source to stimulate areas responsible for movement control, such as the subthalamic nucleus (STN).

But the processes through which DBS changes brain activity are not completely understood.

Studies using positron emission tomography (PET) imaging indicate that brain metabolism is altered but dopamine levels unchanged after DBS. Still, the vast network linking dopamine-producing neurons to various brain regions suggested to the Hopkins team that this chemical messenger could still be a key part in the efficacy of DBS.

“Even if dopamine-producing cells are not activated directly, electrically stimulating other parts of the brain, particularly those that receive information from dopamine-producing cells, can indirectly increase dopamine production,” Kelly Mills, MD, a study co-author, said in a news release written by Vandana Suresh.

Specifically, the investigators focused on a protein called vesicular monoamine transporter (VMAT2), which regulates dopamine packaging into tiny vesicles and its subsequent release into the synapse, the site where two nerve cells communicate. Using PET scans, prior research confirmed that increases in brain dopamine levels with levodopa — a mainstay of Parkinson’s treatment — are associated with decreases in the amount of VMAT2, and vice versa.

The team used a tracer for VMAT2 and another for glucose, intended to track changes in brain activity. Among the seven patients (mean age of 67, range 60–74; all white), four were men and three were women.

Besides PET scans taken before and four-to-six months after DBS targeting of the subthalamic nucleus, these patients also underwent motor function evaluations with the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale, psychological assessments — such as the Hamilton Depression Rating Scale and the Neuropsychiatric Inventory — and cognitive tests.

Results revealed that DBS led to significantly fewer tremors and, to a lesser extent, lesser muscle rigidity. Other benefits included improvements in cognitive function and mood, with depression scores lowering as much as 40%.

Suggesting higher amounts of dopamine, all seven patients showed lower levels of VMAT2 after DBS in the caudate and the putamen — two brain areas important to motor control — and in the brain’s cortical and limbic regions, which are implicated in movement, mood, and cognition.

Glucose metabolism was also lower in the striatum — which includes the caudate and the putamen — and higher in cortical areas and the cerebellum, which has a major role in motor coordination, balance, and speech. Of note, the striatum is a key component of the motor and reward systems of the brain.

The data further demonstrated that lower VMAT2 levels were associated with eased tremors and lesser depressive symptoms. They also correlated with decreased striatal, and increased cortical and limbic, metabolism.

Overall, the correlation between VMAT2 and glucose PET scans suggest that having more dopamine may be central to the restored brain activity achieved with DBS, Mills said.

Shifting the approach taken to track dopamine was key for these findings, the scientist added. “Rather than looking at the amount of dopamine bound on receptors of dopamine-receiving cells, we looked at VMAT2 concentrations within dopamine-producing cells, which may be more sensitive to detecting changes in dopamine with deep brain stimulation,” she said.

Gwenn Smith, PhD, the study’s lead author, added: “Our study is the first to show in human subjects with Parkinson’s disease that deep brain stimulation may increase dopamine levels in the brain, which could be part of the reason why these people experience an improvement in their symptoms.”

Although cautioning that larger studies are needed to more effectively gain from DBS use, likely by determining better targets for stimulation, the scientists added that a deeper understanding of how this procedure works in Parkinson’s “will inform [the] development of more effective treatments, treatment response predictors and ultimately, will have implications for improving the clinical care” of people with Parkinson’s, depression and Alzheimer’s.

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Specific Dopamine-producing Neurons Crucial to Adaptive Movement, Early Study Finds

motor skills and Parkinson's

Dopaminergic neurons — nerve cells gradually lost to Parkinson’s progression — that contain an enzyme called aldehyde dehydrogenase 1A1 are essential for acquiring the motor skills needed for proper movement in given situations, a mouse study reports.

The research, “Distinct connectivity and functionality of aldehyde dehydrogenase 1A1-positive nigrostriatal dopaminergic neurons in motor learning,” was published in Cell Reports. The work was developed by the Intramural Research Program of the National Institute on Aging (IRP-NIA).

Parkinson’s disease severely affects dopaminergic neurons, those that produce dopamine, a neurotransmitter (cell-signaling molecule) that relays information between nerve cells and between the brain and the rest of the body.  These neurons are found in two specific brain regions involved in motor control: the striatum and the substantia nigra.

Nerve cells may or not contain aldehyde dehydrogenase 1A1 (ALDH1A1), an enzyme that is involved in cellular detoxification. Parkinson’s seems to mostly damage ALDH1A1-positive dopaminergic neurons, suggesting the enzyme may be a key player in this neurodegenerative disorder.

Both ALDH1A1-positive and ALDH1A1-negative dopaminergic nerve cells contribute to voluntary motor behavior. But the degree to which ALDH1A1-positive neurons are crucial to acquiring motor skills remains to be understood.

Using a mouse model of Parkinson’s, scientists targeted  dopaminergic neurons positive for ALDH1A1, and produced a detailed connectivity map of these specific neuronal networks in the mouse brain.

ALDH1A1-positive neurons were found to be in constant communication with other brain structures there. Importantly, researchers found that those dopamine-producing neurons of the striatum and substantia nigra that received the greatest percentage of molecular information (input) were located in the caudate-putamen nuclei, a brain region involved in movement control.

Researchers then selectively removed ALDH1A1-positive neurons to mimic the degeneration pattern observed in late-stage Parkinson’s disease. The animals’ ability to show new motor skills — new ways of voluntary movement, like foot position for maintaining balance while walking on a moving surface — was assessed using the rotarod test. In this test, mice must learn to balance while walking on a constantly rotating rod much like a treadmill.

Mice without ALDH1A1-positive neurons displayed a distinctly poorer ability to learn new motor skills, and slower walking speeds compared to control animals.

“Compared with a modest reduction in high-speed walking, the ALDH1A1+ nDAN-ablated mice showed a more severe impairment in rotarod motor skill leaning,” the researchers wrote. “Unlike control animals … [these] mice essentially failed to improve their performance during the course of rotarod tests.” (nDANs are nigrostriatal dopaminergic neurons.)

These animals were then treated with dopamine replacement therapy, either levodopa or a dopamine receptor agonist, one hour before a new motor skills assessment. Dopamine replacement therapy is standard treatment for the motor symptoms associated with Parkinson’s.

Levodopa (L-DOPA) treatment allowed the animals without ALDH1A1-positive neurons to travel longer distances, and to walk more frequently at higher speeds during a session. But it failed to improve their ability to acquire new motor skills during repeated tests. Treatment with a dopamine receptor agonist was also ineffective.

“When the ALDH1A1+ nDANs were ablated after the mice had reached maximal performance, the ablation no longer affected the test results, supporting an essential function of ALDH1A1+ nDANs in the acquisition of skilled movements. These findings are in line with the theory that nigrostriatal dopamine serves as the key feedback cue for reinforcement learning,” the researchers wrote.

These results provide “a comprehensive whole-brain connectivity map,” they concluded, and reveal a key role of ALDH1A1-positive neurons in newly learned motor skills, suggesting that motor learning processes require these neurons to receive a multitude of information from other nerve cells and to supply dopamine with “dynamic precision.”

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Imbalance in Dopamine and Acetylcholine Levels May Drive Disease Progression, Study Finds


Therapies against motor loss and progression in Parkinson’s’ disease (PD) may need to tackle the imbalance between two neurotransmitters, dopamine and acetylcholine, instead of focusing on dopamine alone, an early study suggests.

The study, “Dopamine Deficiency Reduces Striatal Cholinergic Interneuron Function in Models of Parkinson’s Disease,” was published in the journal Neuron.

Motor and cognitive functions depends on the coordinated interaction in the brain of two neurotransmitters — substances produced in response to nerve signals that act as chemical messengers — called dopamine and acetylcholine.

In Parkinson’s, the degeneration of motor neurons that produce dopamine in a brain region called the striatum results in difficulties with voluntary movement control.

Therapies that increase dopamine or activate dopamine receptors, such as levodopa, are currently used to restore motor skills. However, these treatments are not fully effective and their benefits wear off over time.

Researchers have thought that a decline in dopamine levels would increase acetylcholine production. Higher levels of acetylcholine are suggested to cause the dyskinesia — uncontrolled, involuntary movements — observed in Parkinson’s patients under long-term dopamine therapy.

Researchers at Yale University questioned points in these assumptions. They investigated how dopamine affects acetylcholine by looking at a specific type of nerve cell, called striatal interneurons, that is the main source of acetylcholine in the striatum.

To test the effects of dopamine loss, the team used a mouse model genetically modified to mimic Parkinson’s that has a progressive decline in dopamine levels. When motor symptoms appear in these mice, it is estimated that about 30% of dopamine is already lost, increasing to 60–80% at their death.

This progressive dopamine loss, the researchers saw, was matched in the animals by an initial and smaller decrease in the production of acetylcholine by striatal interneurons, creating an imbalance.

“While the concentrations of both dopamine and acetylcholine decline, the balance between these two neurotransmitters shifts to favor acetylcholine,” the researchers wrote.

Subsequent release of dopamine from remaining axon terminals push an increase of acetylcholine, worsening the imbalance between both neurotransmitters.

Under dopamine depleted conditions, proper motor function is dependent on adequate levels of both acetylcholine and dopamine, the study concluded.

Its findings suggest that progressive dopamine deficiency reduces the activity of striatal cholinergic interneurons, resulting in progressive motor difficulties.

Future treatments aiming to slow Parkinson’s progression should include those targeting the balance between acetylcholine and dopamine.

“Our findings suggest that targeted cholinergic therapy [those that mimic the action of acetylcholine] has a place in the management PD and highlight the need for additional experiments that will offer therapeutic options distinct from disease prevention,” the researchers wrote.

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Gene Therapy Used to Produce and Sustain Dopamine in Brains of Primate Model of Parkinson’s

gene therapy study

Direct delivery of two dopamine-synthesizing enzymes to the midbrain, using a safe and inactive form of an adenovirus, was able to reverse signs of motor difficulties in a primate model of Parkinson’s disease, a study reports.

Continuous dopamine production via a gene therapy approach may be a promising one-time treatment strategy for Parkinson’s patients, providing long-lasting improvement and lowering the chances of motor fluctuations and other side effects associated with oral dopaminergic medication, its researchers suggest.

The study, “Vector-mediated L-3,4-dihydroxyphenylalanine delivery reverses motor impairments in a primate model of Parkinson’s disease,” was published in the journal Brain.

Treatment with levodopa — a precursor molecule of dopamine — remains the leading standard treatment of Parkinson’s, easing effects caused by damaged or dead dopamine-producing brain cells, the main cause of this disease.

Such treatment effectively helps to manage Parkinson’s motor symptoms, but dopamine agonists often becomes less effective over time. This is believed to be due, at least in part, to lesser production of the enzymes involved in dopamine production.

Recently researchers have focused on developing types of gene therapy that might overcome the long-term ineffectiveness of available treatments.

An international team of researchers designed a gene therapy approach to re-establish the amount of available enzymes known as TH and GCH1 — both necessary for dopamine production — in the midbrain.

Using an engineered adeno-associated viral (AAV) vector to simultaneously deliver the DNA coding sequences of the two enzymes, researchers injected different doses of the gene therapy directly into the putamen — one of the brain areas mostly affected by the disease — of 29 rhesus monkeys. Four animals were left untreated as a control group.

The putamen is also the brain region where most dopamine-producing cells are located.

One group of animals, initially given the lowest dose, was given a second and higher dose six months after a first injection to simulate “a clinical scenario where patients entering early in the safety trial could be offered a therapeutic dose at the end of the trial.” All animals were analyzed 10 months after the initial dosing.

“The re-dosed animals showed a significant recovery over the following 2 months, reaching the same level of recovery as the initial high-dose treatment group,” the study notes.

Importantly, the primates had been treated with increasing L-DOPA doses before the injection of the gene therapy, “given twice daily for 2 weeks to induce L-DOPA-induced dyskinesia,” the scientists wrote.

Findings showed that the therapy induced a significant and dose-dependent improvement in motor control up to a level similar to that obtained with the optimal dose of injectable levodopa.

Reported improvements in motor function also came without any signs of dyskinesia — the uncontrolled, involuntary movements that are often associated with long-term levodopa use.

Analysis of brain tissue samples collected from the monkeys showed that this AAV-mediated gene therapy could induce an increase of 760- to 5600-fold of TH and 1.2- to 1.5-fold of GCH1 enzymes compared to untreated animals.

“These results provide proof-of-principle for continuous vector-mediated L-DOPA [dopamine] synthesis as a novel therapeutic strategy for Parkinson’s disease,” the researchers wrote.

“This gene therapy approach may thus offer the possibility to prolong and sustain the ‘good years’ many patients with Parkinson’s disease experience during the initial stages of L-DOPA therapy,” they added.

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