Dietary Silicon-based Antioxidant Agent Prevents Parkinson’s in Mouse Study

antioxidant agent

A new dietary silicon-based antioxidant agent prevented neurodegeneration, and motor balance and coordination problems, in a mouse model of Parkinson’s disease.

By promoting production of the antioxidant molecule hydrogen, the agent  also was shown to prevent kidney failure in a rat model of chronic kidney disease, another condition associated with oxidative stress.

Oxidative stress is an imbalance between the production of potentially damaging molecules called reactive oxygen species (ROS), and the ability of cells to clear them with antioxidants.

“These are striking results that show that our Si [silicon]-based agent is effective in preventing the progression of chronic kidney disease and Parkinson’s disease in well-established animal models,” Shoichi Shimada, the study’s co-senior author at Osaka University, in Japan, said in a press release.

“Our findings could provide new insights into the clinical management of patients with these diseases, for which currently no curative approach exists,” he added.

The study, “Renoprotective and neuroprotective effects of enteric hydrogen generation from Si-based agent,” was published in the journal Scientific Reports.

Oxidative stress contributes to a number of conditions, including neurodegenerative diseases such as Parkinson’s and Alzheimer’s, as well as cancer, kidney failure, and diabetes.

In Parkinson’s, high levels of oxidative stress are thought to be closely associated with a dysfunction in mitochondria (the cell’s powerhouses), ultimately leading to the death of dopamine-producing, or dopaminergic, neurons.

Notably, not all ROS are alike, and while hydroxyl molecules are the strongest oxidant ROS and highly damaging to tissues, other ROS are part of the normal immune response.

Therefore, “eliminating only hydroxyl radicals is important to avoid disrupting normal physiological processes,” said Yuki Kobayashi, lead author of the study.

Several therapeutic approaches to reduce hydroxyl-based oxidative stress have been focused on hydrogen, a molecule that reacts only with hydroxyl molecules among ROS and can rapidly diffuse into tissues and cells.

However, approaches so far — such as inhaling hydrogen gas, drinking hydrogen-dissolved water, or injecting hydrogen-dissolved saline solution — have shown limited results, including in Parkinson’s disease.

“We wanted to develop a new dietary agent that efficiently enables the elimination of damaging hydroxyl radicals,” Kobayashi said.

To do so, the team of researchers at Osaka University developed a new antioxidant agent based on tiny particles (nanoparticles) of silicon, previously shown to produce hydrogen in contact with water.

The new oral agent was found to produce high levels of hydrogen for more than 24 hours in an environment similar to the intestine (the target organ, as from there hydrogen can enter circulation and spread throughout the body). These levels were the equivalent of drinking 22 liters of hydrogen-rich water.

To assess whether this was enough to have therapeutic benefits, the researchers looked at the effects of administering the agent to a mouse model of Parkinson’s disease and a rat model of chronic kidney disease.

The Parkinson’s mouse model was based on the injection of oxidopamine, a compound known to promote the loss of dopaminergic neurons in substantia nigra (a brain region rich in such neurons and affected in Parkinson’s), into one side of the mice’s brain.

Results showed that feeding oxidopamine-injected mice with a silicon-based agent-containing diet reduced the loss of dopaminergic neurons and prevented impairments in motor balance and coordination, compared with those fed a normal diet.

The researchers noted there was no remarkable difference in motor activity between the two groups, which may be explained by the partial neurodegeneration in the injected side of the brain and the presence of dopaminergic neurons in the non-injected side.

The agent also prevented oxidative stress and kidney damage in the chronic kidney disease rat model.

“Only hydrogen generated from Si-based agent is absorbed in the body, while Si-based agent is hardly absorbed, and therefore, Si-based agent is thought to be physiologically highly safe,” the researchers wrote, adding that no safety concerns were found in these mice.

These findings highlighted that the new dietary silicon-based antioxidant agent has neuroprotective and kidney-protective effects and may be “an innovative approach to treating a wide variety of diseases mediated by oxidative stress,” the researchers wrote.

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CoQ10 Injected Into the Brain Eases Parkinson’s Symptoms in Rats

CoQ10 and Parkinson's

Coenzyme Q10, an antioxidant supplement that, when taken orally, has shown limited effectiveness, can alleviate Parkinson’s disease symptoms when injected directly into the brain, a study in rats suggests.

The study, “Intrastriatal administration of coenzyme Q10 enhances neuroprotection in a Parkinson’s disease rat model,” was published in Scientific Reports.

Parkinson’s disease is characterized by the death of dopamine-producing (dopaminergic) neurons in the brain, specifically affecting a brain region called the striatum. It is believed that this neuronal death is driven by oxidative stress, which is an imbalance between the production and clearance of toxic reactive species that are harmful to cells.

Antioxidants — substances that clear out these toxic molecules — may have therapeutic value in Parkinson’s. Coenzyme Q10 (CoQ10), an antioxidant that is found naturally in the body, has garnered some interest for this purpose. However, when taken by mouth, very little of the antioxidant reaches the striatum, limiting its effects.

In the new study, researchers in Korea tested whether injecting CoQ10 directly into the striatum would achieve better therapeutic effects than oral administration in a rat model of Parkinson’s.

Parkinson’s rats were established by treating them with 6-hydroxydopamine, a chemical that kills dopamine-producing neurons similarly to what happens in Parkinson’s. They were divided into five groups. One group received no treatment, one was given oral CoQ10 (at a dose of greater than 45 mg per day), one was outfitted with striatum-injecting pumps without CoQ10, and two groups were outfitted with striatum-injecting pumps that injected CoQ10 at one of two doses (about 1.8 and 2.6 micrograms per day).

The rats’ behavior was assessed with a rotation test; in this test, rats with more dopaminergic neuron damage will rotate more times. In untreated rats, the number of rotations gradually increased from four to seven weeks. In rats given oral CoQ10, the number of rotations plateaued such that, by weeks six and seven, they rats had significantly fewer rotations than untreated rats.

“This delayed efficacy could be attributed to the delayed increase in CoQ10 concentration in the brain that is often observed with oral administration of CoQ10,” the researchers wrote.

Rats injected with the lower dose of intrastriatal CoQ10 generally had fewer rotations than the untreated group, but the difference was statistically significant only on weeks five and six. Rats injected with the higher dose of CoQ10 had significantly fewer rotations than untreated rats at all time points measured.

Notably, the overall dose administered for the highest injection dose is about 17,000 times lower than the overall oral dose, “implying very high bioavailability of intrastriatally delivered CoQ10,” the researchers wrote.

The researchers assessed dopaminergic neurons in biopsied brains from the rats. In untreated rats, almost all dopaminergic neurons were dead by week seven. Rats given oral CoQ10 had some protection of these neurons, but rats given the higher dosage intrastriatal injection of CoQ10 had markedly greater neuronal protection.

“These results indicated that intrastriatally delivered CoQ10 had a significant neuroprotective effect, which was more prominent than that of orally administered CoQ10 at a very high dose,” the researchers wrote.

Furthermore, rats that received CoQ10 into the brain had significantly higher levels of molecules associated with neural and blood vessel growth, whereas they had lower levels of the inflammatory molecule tumor necrosis factor alpha, than untreated rats. Oral CoQ10 generally did not significantly affect levels of the molecules assessed; when there was a significant effect, it was of a markedly lesser magnitude than injected CoQ10.

“Although invasive, the strategy of intrastriatal CoQ10 delivery may still enable high bioavailability in the target site, which could eventually achieve therapeutic efficacy in the prevention of Parkinson’s disease progression,” the researchers concluded.

“CoQ10 is known to elicit effects in models of other neurodegenerative diseases, such as Huntington’s disease, progressive supranuclear palsy, and Alzheimer’s disease. Therefore, the intrastriatal delivery of CoQ10 described herein is a promising strategy to prevent the progression of various neurodegenerative diseases, including Parkinson’s disease,” they added.

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Study of Manganese Exposure in Welders Could Help in Treating Parkinson’s

cognitive problems

A $3.7 million federal grant is funding a project aiming to clarify how exposure to manganese, a trace metal, affects the brain and causes cognitive problems.

Findings from this research may help in better understanding Parkinson’s disease.

Manganese is an essential nutrient, a mineral that is necessary in very small quantities (usually obtained from food) for the body to function. However, exposure to high amounts of manganese can cause problems in the nervous system, including movement and cognitive difficulties.

These symptoms of high manganese exposure (sometimes called manganism) are similar to Parkinson’s symptoms, possibly because both manganism and Parkinson’s are caused by similar types of damage to the brain.

Previous research has shown that high amounts of manganese can kill dopamine-producing neurons in the brain. These are the same neurons that die off in Parkinson’s disease, which is the primary cause of its motor symptoms. Therapies that replace lost dopamine (e.g., levodopa) are mainstays of treatment for both manganism and Parkinson’s.

However, while this mechanism explains motor problems in both conditions, it’s less clear how cognitive problems — such as memory issues, irritability, aggression, and confusion — arise in manganism, or in Parkinson’s.

“People think of Parkinson’s disease as a movement disorder, and it is, but cognitive problems are also very common,” Susan Criswell, MD, a professor at Washington University School of Medicine who is leading the project, said in a press release.

“The cognitive issues you see in people exposed to manganese are very similar to mild cognitive impairment and dementia in Parkinson’s disease. Understanding the causes of these cognitive issues is going to be very helpful in ultimately finding better treatments for people exposed to manganese and people with dementia linked to Parkinson’s,” Criswell added.

Funded by the National Institute of Environmental Health Sciences of the National Institutes of Health, the project focuses on welders, who are often exposed to high amounts of manganese through fumes they inhale as part of their job. Previous research by Criswell and colleagues has shown that welders with higher manganese exposure tend to have more Parkinson’s-like symptoms.

“When we do screenings with welders, we always find some with very mild symptoms that only a trained neurologist would detect,” Criswell said. “But their symptoms can worsen over time, and that progression does seem to be related to the amount of manganese exposure. The welders … could yield real insight into how the disease develops and how we can stop it.”

Some 60 welders working in the Midwest are undergoing a series of cognitive tests, as well as a positron emission tomography (PET) brain scan. This scan can assess the health of two types of neurons: those that produce dopamine (dopaminergic neurons), and those that produce acetylcholine (cholinergic neurons).

While the involvement of dopaminergic neurons in manganism is well established, little is known about the role of cholinergic neurons.

Because these two neuron types are located close together in the brain, Criswell and other researchers believe that they could be involved, too. Namely, the researchers think that damage to cholinergic neurons may account for some of the cognitive issues not explained by damage to dopaminergic neurons.

By studying the brains of these welders, the project could shed light on the underlying neurology of manganism. Since the conditions are so similar, these insights may also help in better understanding — and, eventually, finding ways to better treat — Parkinson’s disease.

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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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Number of Dopaminergic Neurons at Birth Could Affect Lifetime Parkinson’s Risk, Report Suggests

Dopaminergic neurons at birth

The number of dopamine-producing (dopaminergic) neurons at birth could influence a person’s lifetime risk of developing Parkinson’s disease, according to a group of experts.

Because these nerve cells die over the course of the disease, having fewer of them to begin with could translate to a higher risk, the scientists said.

Their report, “Does Developmental Variability in the Number of Midbrain Dopamine Neurons Affect Individual Risk for Sporadic Parkinson’s Disease?” is a review of scientific literature on the topic. It was published in the Journal of Parkinson’s Disease.

Parkinson’s is a progressive neurodegenerative disease, meaning that it steadily worsens as neurons die over time. The hallmark of Parkinson’s 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.

The substantia nigra communicates with a neighboring brain structure called the striatum and it is believed that the loss of dopamine and dopaminergic neurons in these structures must cross a certain threshold before the symptoms of Parkinson’s become noticeable. The number of dopaminergic neurons an individual is born with, therefore, might influence how soon this threshold is reached.

Precisely how many of these neurons must die before symptoms appear remains an open question. No datasets of nigral (belonging to the substantia nigra) dopaminergic neuron counts are available for individuals with recent onset of Parkinson’s symptoms.

Nor is there a strong scientific consensus regarding the number of dopaminergic neurons in normal substantia nigra. Different methods for marking both dopaminergic neurons and age-related changes that can limit the number of functional neurons within the brain hinder precise counts.

To estimate the variation in dopaminergic neuron numbers across people, a team of scientists now examined the data in four previous studies. Each study followed strict exclusion criteria, such as not admitting patients with histories of neuropsychiatric disease and/or other neurological damage.

The studies are: Ageing of substantia nigra in humans: cell loss may be compensated by hypertrophy, published in 2002; The absolute number of nerve cells in substantia nigra in normal subjects and in patients with Parkinson’s disease estimated with an unbiased stereological method, published in 1991; Unbiased morphometrical measurements show loss of pigmented nigral neurones with ageing, published in 2002; and Morphometry of the human substantia nigra in ageing and Parkinson’s disease, published in 2008.

In the review, the researchers focused on individuals who died before their 51st birthday, to minimize the risk that any observed variation was due to age-related effects, or to undiagnosed progressive disorders.

The studies showed a wide variation between individuals — ranging from 147% to 433% — in terms of the difference between those with the most and the fewest dopaminergic neurons. Such variation must be better understood to properly understand its significance, the researchers said.

Many of the genes implicated in rare developmental abnormalities in humans also are involved in determining the location, formation, and size of the dopaminergic neuron population. Based on past studies, the researchers suggest that subtle changes in how active these genes are throughout development likely determine the variation witnessed between individuals.

Although clearly defining these changes poses a significant challenge, some clues are emerging.

One recent study, for example, linked Parkinson’s risk to single nucleotide polymorphisms (SNPs) — changes of one single letter of the genetic code — that affected gene regulatory elements involved in early nervous system development. This, in turn, affects the number of neurons an organism has.

Other studies have shown that Parkinson’s-related mutations also can reduce the number of dopaminergic neurons capable of being grown in the lab.

The alpha-synuclein protein plays a well-documented role in Parkinson’s progression. Its role in early development is less understood. One mouse study showed that the expression of the alpha-synuclein gene could affect the number of dopaminergic neurons in the substantia nigra. This suggests that, beyond the pathogenic role it plays in Parkinson’s, alpha-synuclein may help determine the early development and survival of dopaminergic neurons.

Non-genetic factors also appear to impact dopaminergic neurons by affecting critical periods of brain development. These factors include viral infection, exposure to environmental toxins, and hypoxia (low oxygen) at birth.

Based on the information collected throughout their review, the researchers propose that the number of nigral dopaminergic neurons individuals are born with and that survive immediately following birth affects their lifetime risk of developing Parkinson’s disease.

However, the researchers note that current knowledge of the factors influencing the development and survival of dopaminergic neurons is incomplete.

Therefore, “we need to explore the changes that occur both during development and during adulthood and aging when we seek to understand the full landscape of [Parkinson’s] risk,” they said.

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Awakening Dormant Neurons Could Provide Disease-modifying Parkinson’s Treatment, Early Study Suggests

dormant neurons

Together with dying nerve cells, dormant neurons also may be at the root cause of Parkinson’s disease, according to a recent study in animal models.

Reawakening these neurons by targeting a type of brain cells called astrocytes can restore dopamine production in the brain and reverse Parkinson’s motor symptoms, the study found. These findings could lead to a potential new disease-modifying treatment, especially at the early stages of Parkinson’s.

The study, “Aberrant Tonic Inhibition of Dopaminergic Neuronal Activity Causes Motor Symptoms in Animal Models of Parkinson’s Disease,” was published in the journal Current Biology.

Despite its prevalence and debilitating consequences, current medical therapy for Parkinson’s relies on alleviating symptoms. Research investigating ways of modifying the disease or reversing its symptoms is scarce, based on the firm belief that Parkinson’s is caused by the irreversible death of nerve cells — also called neurons — in a region of the brain called the substantia nigra.

In this brain region, nerve cells known as dopaminergic neurons are responsible for producing the neurotransmitter dopamine, a chemical messenger that allows nerve cells to communicate. Dopamine plays a key role in motor function control and also is involved in behavior and cognition, memory and learning, sleep, and mood.

Levodopa, a mainstay of Parkinson’s treatment, works by supplying extra dopamine to the brain. However, it only alleviates motor symptoms and does not alter the disease course. Moreover, its long-term use can cause serious side effects, including involuntary, erratic, and writhing movements.

Now, a team of Korean researchers have discovered additional clues about the underlying mechanisms of Parkinson’s that may offer hope for the development of disease-modifying treatments that could reverse the condition.

Using mouse and rat models of Parkinson’s, they found that the motor abnormalities that mark the disease begin earlier than was previously thought. They are triggered when dopaminergic neurons in the substantia nigra are still alive but in a dormant state, unable to produce dopamine.

However, what holds the key to that dormant state is another type of cells called astrocytes, star-shaped cells present in the brain and spinal cord that play important roles in the protection and regulation of the nervous system.

When neurons die, nearby astrocytes react by proliferating, and start to release an inhibitory neurotransmitter called gamma-aminobutyric acid (GABA) at excessive levels. This puts neighboring neurons “on hold,” suspending their production of dopamine.

GABA prevents the neurons from firing electrical impulses and causes them to stop making an enzyme, called tyrosine hydroxylase, that’s essential for the production of dopamine. In effect, GABA puts the neurons into a dormant, or sleeping state.

One of the most important discoveries of the study was that surviving dormant neurons could actually be “awakened” from their “sleeping” state and rescued to alleviate motor symptoms.

“Everyone has been so trapped in the conventional idea of the neuronal death as the single cause of PD. That hampers efforts to investigate roles of other neuronal activities, such as surrounding astrocytes,” C. Justin Lee, PhD, the study’s corresponding author, said in a press release.

“The neuronal death ruled out any possibility to reverse PD. Since dormant neurons can be awakened to resume their production capability, this finding will allow us to give PD patients hopes to live a new life without PD,” Lee added.

Treatment with two different compounds that block GABA production in astrocytes, called monoamine oxidase-B, or MAO-B, inhibitors, was sufficient for neurons to recover the enzymatic machinery necessary to produce dopamine, the study found. This significantly alleviated Parkinson’s motor symptoms in the study animals.

In fact, the MAO-B inhibitors used for the study — selegiline (brand names EldeprylCarbex, Zelapar, among others), and safinamide (brand name Xadago) — are already prescribed to Parkinson’s patients as an add-on therapy to levodopa. They are believed to prevent the break down of dopamine in the brain.

Importantly, the existence of dormant neurons was observed in the brains of human patients. Analysis of postmortem brains of individuals with mild and severe Parkinson’s had a significant population of dormant neurons surrounded by numerous GABA-producing astrocytes.

The researchers hope that “awakening” neurons using MAO-B inhibition could be an effective disease-modifying therapeutic strategy for Parkinson’s, especially for patients in the early stages of the disease. At that time, inactive, yet live dopaminergic neurons are still present.

Although the results from several clinical trials have cast doubt on the therapeutic efficacy of traditional MAO-B inhibitors, researchers say they have recently developed a new inhibitor, KDS2010. KDS2010 effectively inhibits astrocytic GABA production with minimal side effects in Alzheimer’s animal models and also could be effective for alleviating Parkinson’s motor symptoms, the investigators said.

“This research refutes the common belief that there is no disease-modifying treatment for PD due to its basis on neuronal cell death,” said Hoon Ryu, PhD, a researcher at KIST Brain Science Institute, in South Korea, and one of the senior authors of the study.

“The significance of this study lies in its potential as the new form of treatment for patients in early stages of PD,” Ryu said.

The fact that inhibition of dopaminergic neurons by surrounding astrocytes is one of the core causes of Parkinson’s should be a “drastic turning point” in understanding and treating not only Parkinson’s but also other neurodegenerative diseases, added Sang Ryong Jeon, MD, PhD, also a researcher at KIST and a study co-author.

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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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New Gene Therapy Delivery Method May Open BRAVE New World in Parkinson’s Research

BRAVE gene therapy method

A new method allows researchers to develop adeno-associated virus (AVV) — commonly used as the vehicle for gene therapies — that accurately target and deliver genes to specific cells in the body.

This new technology may be suitable to target dopaminergic neurons that are damaged in Parkinson’s disease.

“We believe that the new synthetic [lab-made] virus we succeeded in creating would be very well suited for gene therapy for Parkinson’s disease, for example, and we have high hopes that these virus vectors will be able to be put into clinical use,” Tomas Björklund, PhD, Lund University, Sweden, said in a press release.

Björklund is lead author of the study “A systematic capsid evolution approach performed in vivo for the design of AAV vectors with tailored properties and tropism,” which was published in the journal Proceedings of the National Academy of Sciences. 

The adeno-associated virus (AAV) is a common, naturally-occurring virus, which has been shown to work as an effective gene therapy delivery vehicle for genetic diseases, such as spinal muscular atrophy. In gene therapy, scientists deliver a working version of a faulty gene using a harmless AAV that was modified and inactivated in the lab. This way the virus functions only as a delivery vehicle and does not have the capacity to damage tissues and cause disease.

While AAVs have a natural ability to penetrate any cell of the body and infect as many cells as possible, their usefulness as a potential therapy requires the capacity to specifically deliver a working gene to a particular cell type, such as dopamine producing-nerve cells. Those are the ones hose responsible for releasing the neurotransmitter dopamine and that are gradually lost during Parkinson’s disease.

A team of Swedish researchers have developed a new method — called barcoded rational AAV vector evolution, or BRAVE — that combines powerful computational analysis with the latest gene and sequencing technology to produce AAVs that can specifically target neurons.

To make AAVs neuron specific, the team selected 131 proteins known to specifically interact with synapses (the junctions between two nerve cells that allow them to communicate).

They then divided the proteins into small sequences, called peptides, and created a large library where each peptide could be identified by a specific pool of genetic barcodes (a short sequence of DNA that is unique and easily identified).

The peptide is then displayed on the surface of the AAV capsid, allowing researchers to test the simultaneous delivery of many cell-specific AAVs in a single experiment.

The team then injected these AAVs into the forebrain of adult rats and observed that around 13% of the peptides successfully homed to the brain. Moreover, 4% of the peptides were transported effectively through axons (long neuronal projections that conduct electrical impulses) toward the nerve cell’s body.

Researchers then selected 23 of these unique AAV capsids and injected them into rats’ striatum, a brain region involved in voluntary movement control and affected in Parkinson’s disease. Twenty-one of the new AAV capsids had an improved transport capacity within nerve cells than in standard AAVs.

One particular capsid, called MNM008, showed a high affinity for rat dopaminergic neurons. Researchers then tested whether this viral vector also could target human dopaminergic neurons.

The team transplanted neurons generated from human embryonic stem cells into rats’ striatum. Six months later, they injected either MNM008 or a control AAV capsid and found that MNM008 was able to target these specific cells and be transported into dopaminergic neuronal cell bodies through axons.

“Thanks to this technology, we can study millions of new virus variants in cell culture and animal models simultaneously. From this, we can subsequently create a computer simulation that constructs the most suitable virus shell for the chosen application — in this case, the dopamine-producing nerve cells for the treatment of Parkinson’s disease,” Björklund said.

Overall, researchers believe the BRAVE method “opens up the design and development of synthetic AAV vectors expressing capsid structures with unique properties and broad potential for clinical applications and brain connectivity studies.”

The team has established a collaboration with a biotech company, Dyno Therapeutics, to use the BRAVE method in the design of new AAVs.

“Together with researchers at Harvard University, we have established a new biotechnology company in Boston, Dyno Therapeutics, to further develop the virus engineering technology, using artificial intelligence, for future treatments,” Björklund said.

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Dosing Begins in Phase 2 Trial of CNM-Au8, Potential Therapy for Dopaminergic Neurons

Parkinson's pilot trial

A pilot Phase 2 study evaluating CNM-Au8, an investigational Parkinson’s treatment aiming to protect nerve cells, has started dosing patients, the therapy’s developer, Clene Nanomedicine, announced.

The open-label REPAIR-PD (NCT03815916) clinical trial is enrolling up to 24 people, ages 30 to 80 and diagnosed within the past three years, at its one site at the University of Texas Southwestern Medical Center.

“We are excited to be advancing CNM-Au8 clinically into Parkinson’s patients starting with the REPAIR-PD Phase 2 study” Rob Etherington, president and CEO of Clene, said in a press release.

Parkinson’s disease is characterized by the death of dopaminergic neurons in two brain regions, the striatum and the substantia nigra. These nerve cells rely on large amounts of energy to function, which is provided by mitochondria, the cell’s powerhouses. Failure to provide the energy that cells need contributes to their death.

Oxidative stress, an imbalance between the production of harmful free radicals and the ability of cells to detoxify them, is another hallmark of Parkinson’s disease. These free radicals, or reactive oxygen species, are produced during certain metabolic reactions that involve mitochondria, and can damage cells.

CNM-Au8 is a suspension of nanocrystalline gold designed to increase the production of energy. Specifically, it works by increasing the speed of conversion between two molecules — nicotinamide adenine dinucleotide (NADH) to its oxidized form (NAD+) — resulting in greater production of energy in the form of ATP (adenosine triphosphate, an energy-carrying molecule of cells).

In addition, CNM-Au8 has antioxidant properties that may help to protect cells against oxidative stress.

Preclinical (in the lab) data showed that CNM-Au8 aided the survival of dopaminergic neurons, and helped prevent the loss of mitochondria.

In a rat model of Parkinson’s disease, treatment with CNM-Au8 improved the animal’s motor activity compared to control (untreated) mice. Of note, rats treated with CNM-Au8 in this test showed better results than did rats given carbidopa/levodopa, a standard Parkinson’s therapy.

“Our preclinical data with CNM-Au8 demonstrated improvements in neuronal bioenergetics, which may improve the survival of dopaminergic neurons in patients with PD [Parkinson’s disease], thereby helping slow the progression of this devastating disease,” Etherington said.

A Phase 1 clinical trial involving healthy volunteers (NCT02755870) found CNM-Au8 to be safe.

In the REPAIR-PD study, patients will first undergo a four-week screening period, after which they will drink two ounces of CNM-Au8 daily each morning for 12 weeks. Treatment will be followed by a four-week follow-up period.

The study’s primary outcome is to determine improvements in oxidative stress in the central nervous system (brain and spinal cord), assessed by the ratio of NAD+/NADH measured using magnetic resonance spectroscopy (MRS).

Additional (secondary) measures include assessing the effects of CNM-Au8 on energy production, and nerve cell metabolism.

“The objective of the REPAIR-PD Phase 2 study is to demonstrate improvements in brain bioenergetic metabolism in Parkinson’s disease patients treated with CNM-Au8. Participants will undergo 31phosphorous magnetic resonance spectroscopy (31P-MRS) imaging to show how treatment with CNM-Au8 results in improvements in brain metabolic and membrane biomarkers,” said Robert Glanzman, MD, chief medical officer of Clene.

Results from the REPAIR-PD trial are expected by mid-2020.

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Tiny Crystals May Help Scientists Trace Causes of Brain Inflammation in Parkinson’s, Study Reports

brain inflammation

Tiny and traceable man-made crystals, known as quantum dots, may be useful in carrying toxins to select cells in the brain, allowing researchers to better understand Parkinson’s neurodegenerative processes by being able to model and visualize them, researchers in Canada report.

Their study, “Quantum dot conjugated saporin activates microglia and induces selective substantia nigra degeneration,” was published in NeuroToxicology.

Microglia, primary immune cells of the brain and spinal cord, are known to contribute to the inflammation that underlies Parkinson’s neurodegeneration, which severely affects a brain area involved in motor control called the substantia nigra.

A key aspect of Parkinson’s research is to understand new and targeted ways of modulating microglia’s behavior, with a goal of influencing the survival or neurons or nerve cells. Such an ability would help to address the precise link between neurons and microglial cells.

Quantum dots, or nanoscale crystals, can be specifically taken up by microglia cells and may be useful as a direct way of targeting these cells. The nanoparticles also glow a particular color after being illuminated by ultraviolet light, allowing scientists to trace the molecules inside cells and study their cellular behavior.

Researchers at Carleton University investigated whether microglia within the substantia nigra of mice would take up quantum dots alone, and quantum dots carrying an immunotoxin called saporin. The latter works by inactivating ribosomes — cells’ protein builders — which compromises protein synthesis and leads to cell death. The scientists also studied how these nanoparticles affected microglia status (i.e., whether it is active or inactive).

Animals were given a four-minute infusion directly into their substantia nigra of either quantum dots alone, or of one of two doses of quantum dots conjugated with saporin. Within a week post-infusion, the mice’s balance and coordination were assessed.

Using imaging technology, researchers observed that quantum dots alone were selectively taken up by microglia and activated them. Microglia activation is a hallmark of inflammation in the context of neurodegenerative disorders. Despite their activated state, however, microglia had minimal effects on neurons and other neuronal support cells like astrocytes.

But in mice whose quantum dots were administered together with saporin, scientists observed a significant dose-dependent reduction in the number of nigral — meaning “of the substantia nigra” — neurons that produce dopamine, as well as impaired motor coordination six days after the infusion.

Quantum dots conjugated to saporin also increased the levels of a molecular mediator of inflammation, called WAVE2. This protein “is critical for the changes in activation state morphology of microglia,” the scientists wrote

The researchers believe that quantum dots carrying saporin could be a new and targeted way of modeling Parkinson’s-related inflammation, and evaluating new therapies aiming to treat it.

“[Quantum dots] might be a viable route for toxicant delivery and also has an added advantage of being fluorescently visible,” they wrote.

“Future work using this model should attempt to establish various degrees of neuronal loss. This model could then be used to test neuro-recovery or protective agents at differing stages of [the disease],” the researchers added.

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