Chia Seed Extract May Lower Inflammation in Brain, Study Finds

chia seeds and inflammation

Compounds extracted from chia seeds could lower the inflammatory activity of brain immune cells, a study suggests.

Although additional research is needed, these findings could have implications for patients with neurodegenerative diseases such as Parkinson’s.

The study, “Neuroprotective effect from Salvia hispanica peptide fractions on pro‐inflammatory modulation of HMC3 microglial cells,” was published in the Journal of Food Biochemistry.

Microglia are a type of brain cell that play important roles in nervous system immunity. While these cells are crucial for protecting the brain from infectious invaders, once over-activated, they can also help drive inflammation in the brain. This neuroinflammation is believed to contribute to numerous neurological conditions, including Parkinson’s disease.

Chia (Salvia hispanica) is a plant species native to Central America. The consumption of chia seeds has increased over the years because they are high in mega-3 fatty acids and dietary fiber.

“A byproduct during the production of chia oils is the protein portion, which is a promising source of bioactive peptides [small proteins], with application in the prevention and treatment of chronic metabolic diseases,” the researchers wrote in the study.

In fact, some studies have suggested that compounds in chia seeds could lower inflammation.

To examine this, the researchers investigated the effect of proteins extracted from chia seeds on microglia. Specifically, they used the HMC3 cell line. This is a line of microglia that have been immortalized (engineered to divide indefinitely), which makes the cells easier to study in dishes in a lab.

The cells were treated with various fractions of chia seed extract. Essentially, the researchers isolated proteins from chia seeds, then divided the proteins based on size (in kilodaltons, or kDa). One fraction held all peptides under 1 kDa, one included those between 1 and 3 kDa, and one had peptides between 3 and 5 kDa.

None of the chia peptide fractions significantly decreased cell viability — that is, they weren’t toxic to the HMC3 cells. The researchers then tested how pre-treatment with the fractions affected how the cells responded to various stresses.

First, they treated the cells with tert-Butyl hydroperoxide (TBHP), an oxidative chemical that damages many cell structures. In cells with no pre-treatment, cell viability (the percent of living cells) was lowered to about 40%. Pre-treatment with all of the chia fractions significantly reduced the number of cells that died.

According to the researchers, “no peptide fraction … reported a cytotoxicity of less than 80%,” establishing them as safe for biological studies, since a given treatment with a viability of 80% or above is generally considered non-toxic.

TBHP treatment prompted the HMC3 cells to produce reactive oxygen species (ROS). These are unstable, highly reactive molecules that microglia make to help fight off bacteria, though they can also be highly damaging to surrounding neurons in the context of the brain.

Pre-treatment for 48 hours with any of the chia peptide fractions significantly lowered TBHP-induced ROS production. The most effective in this regard was the 1-3 kDa fraction, which returned ROS levels to nearly what they were without TBHP treatment.

Because microglia become activated in response to infection, the researchers also treated the HMC3 cells with a bacterial molecule called lipopolysaccharide (LPS) that activates them.

In response to LPS treatment, the HMC3 cells produced increased levels of ROS, as well as other pro-inflammatory molecules, including nitric oxide, tumor necrosis factor alpha, and various interleukins.

Pre-treatment with the chia protein fractions significantly decreased all LPS-induced inflammatory processes. The greatest reductions across all of these inflammatory markers were seen after pre-treatment with the 1-3 kDa fraction.

This study supports the anti-inflammatory action of proteins in chia seeds, particularly peptides in the 1-3 kDa fraction. This fraction, “is an important study target for future research on the neuroprotective effect,” the researchers wrote.

Future investigations will be needed to understand exactly which protein(s) in this fraction are responsible for the observed effect and how they work.

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APOE Variant Directly Tied to Lewy Body Dementias in 2 Studies

APOE4 study

A variant of the apolipoprotein (APOE) protein, called APOE4, has been shown to directly affect Lewy body dementias, such as Parkinson’s disease.

Two separate studies, published simultaneously, found that APOE4 directly regulates levels of alpha-synuclein, which clumps  to form the nerve-damaging Lewy bodies that are the main culprits of the nerve cell death that defines Parkinson’s.

Their combined results help in understanding how APOE4 works, and how it affects disease progression. Greater insights into these mechanisms are vital for advancing research into treatments for Lewy body dementias.

Published in the peer-reviewed journal Science Translational Medicine, the two studies are “APOE4 exacerbates α-synuclein pathology and related toxicity independent of amyloid,” and “APOE genotype regulates pathology and disease progression in synucleinopathy.”

“It’s nice when you do science separately … but reach similar conclusions,” Guojun Bu, PhD, senior author of one study and chair of neuroscience at the Mayo Clinic, said in a news release published in Neurology Today.

APOE4 has been the focus of research into both Alzheimer’s and Parkinson’s for some time. Studies have shown that it strongly associates with these diseases, and that it plays a strong functional role in the accumulation of amyloid-beta and tau within neurons.

Whether APOE4 directly promotes alpha-synuclein aggregation or affects disease progression as a result of these aggregates, however, is not known.

In each of these studies, scientists engineered mice to express one of three APO variants — E2, E3, or E4 — or to have no APOE at all (knockout mice). They then used different methods to examine associations between the APOE variants and disease features, or pathology.

Albert Davis, an assistant professor of neurology at Washington University School of Medicine in St. Louis and colleagues monitored one group of each type of mice, looking for the development of alpha-synuclein aggregates. His group injected groups of each of these engineered mice with alpha-synuclein fibrils to induce protein clumping, and see how its spread varied in each genetic background.

Among the first group, those expressing APOE4 (E4) showed higher amounts of insoluble and phosphorylated (pathologic) alpha-synuclein, and evidence of reactive gliosis — a type of neuroinflammation — than did mice in other groups.

Reactive gliosis refers to inflammation of glial cells, a class of protective neurons that include microglia, a cell often seen to be damaged in Parkinson’s. This inflammation typically occurs in response to damage to the central nervous system (CNS), such as the formation of Lewy bodies.

Mice carrying the E2 variant survived longer and did not show the motor difficulties seen in the other mouse groups.

Among mice injected with alpha-synuclein fibrils to monitor its spread throughout the brain, the E4 mice showed the greatest signs of pathology within the substantia nigra, the brain region most affected by alpha-synuclein aggregates in Parkinson’s.

This finding closely matched that of another recent paper, which concluded that microglia play “an integral role in the propagation and spread of alpha-synuclein pathology.”

The two papers reached different conclusions, however, regarding the order of events in inflammation and alpha-synuclein/Lewy body formation. While Davis’s group concluded that alpha-synuclein pathology leads to an inflammatory response, the other research group, lead by Jeffrey Kordower of Rush University, concluded that inflammation came first and played a driving role in alpha-synuclein aggregation.

“We and others in the field are going to look closely at that and follow up,” Davis said in the release.

Davis’ group also examined the genetic background of two groups of Parkinson’s patients, as a comparison to the mouse models. His group found people that in both cohorts, those with two copies of the E4 variant, showed the fastest cognitive declines.

“Our results demonstrate that APOE genotype directly regulates alpha-synuclein pathology independent of its established effects on [beta amyloid] and tau, corroborate the finding that APOE e4 exacerbates pathology, and suggest that APOE e2 may protect against alpha-synuclein aggregation and neurodegeneration in synucleinopathies,” these researchers concluded in their paper.

In the second study, led by Bu at the Mayo Clinic, mice were injected with viruses carrying different APOE variants.

Similar to Davis’ study, Bu’s group found that mice expressing E4, but not E2 or E3, showed more alpha-synuclein pathology and Parkinson’s-related symptoms, such as impaired behavior and the loss of neurons and synapses (the junctions between neurons where information is passed from one nerve cell to another). The E4 mice also showed deficits in their fat and energy metabolism.

Gu and his colleagues examined the brains of patients with Lewy body dementia, and discovered that those who had the APOE4 variant also showed greater alpha-synuclein pathology.

Eric Reimann, the executive director of Banner Alzheimer Institute, praised the studies, while adding that their results need to be confirmed in larger groups of both Parkinson’s patients, “including those without comorbid (simultaneously occurring) Alzheimer’s disease,” and healthy controls.

When two or more medical co-existing conditions can be common, telling the effects of one apart from the other is challenging. This is especially the case in disorders such as Parkinson’s and Alzheimer’s, which share many of the same disease features.

Reiman had also found the E4 variant to associate with higher odds for Lewy body dementia. In contrast to Davis’ study, however, Reiman found no link between the E2 variant and a lower disease risk.

Alice Chen-Plotkin, an associate professor of neurology at the University of Pennsylvania Perelman School of Medicine, commented in the release that “the data for E4 being bad is much stronger than for E2 being good.”

Although she expressed surprise at the strength of the effect Davis’s group found APOE4 to have on glial cells, she noted that researchers are coming to think much more about these nervous system support cells.

An ongoing Phase 2 clinical trial (NCT04154072), for instance, seeks to improve Parkinson’s outcomes by blocking glial activation and inflammatory signaling. At the same time, the National Institutes of Health (NIH) recently awarded a $4.8 million grant to study how APOE4 induces neurodegeneration.

The E2 variant is also the focus of an ongoing Phase 1 gene therapy trial (NCT03634007), seeking to deliver this protein to patients’ CNS as a way of treating Alzheimer’s disease.

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Immune Biomarkers May Better Classify Patients, Direct Therapy, Study Says

biomarkers, brain inflammation

Biomarkers of brain inflammation could provide a useful means for classifying Parkinson’s and Alzheimer’s patients and defining the mechanisms underpinning each person’s disease.

Testing for these biomarkers could support clinicians in providing precision medicine, by helping people with the progressive neurodegenerative disorders to choose treatments with a greater chance of benefiting them, based on their individual characteristics.

The study, “Multicenter Alzheimer’s and Parkinson’s disease immune biomarker verification study,” was published in the journal Alzheimer’s & Dementia.

Typically, diseases such as Parkinson’s are defined largely on the basis of patients’ symptoms. But while individuals share the same diagnosis, the underlying molecular and cellular causes of their illness may differ.

This also could explain why treatments do not work equally for all patients. Using these individual differences to identify patient groups may help clinicians choose more tailored treatment choices.

Many researchers propose that neurodegenerative illnesses could be defined on the basis of their molecular features, before evident symptoms occur in later stages of the disease.

To address this hypothesis, the AETIONOMY project, an European public-private partnership funded by the Innovative Medicines Initiative, is exploring potential molecular classifiers for Alzheimer’s and Parkinson’s.

Candidate markers include tracers of neuroinflammation, meaning trackers of the inflammatory reactions occurring in the brain and spinal cord, which comprise the central nervous system, or CNS.

Neuroinflammation probably begins early in neurodegenerative diseases, when the immune system senses the presence of misshaped or aggregated proteins — including beta-amyloid in Alzheimer’s, or alpha‐synuclein in Parkinson’s.

The formation of abnormal clumps of each of these proteins in the brain is believed to be at the root cause of each disease. In Parkinson’s, alpha-synuclein proteins clump together in aberrant aggregates termed protofibrils, which are toxic and thought to play an important role in the death of nerve cells (neurodegeneration).

In the first stages of the disease, these aggregates are known to activate immune cells called microglia and other supportive cells in the brain, known as astroglia. Later, immune reactivity — in which the body mistakenly attacks its own healthy cells — propagates in response to nerve cell death, with immune signals released as a consequence of the damage.

A team of researchers involved in the AETIONOMY project now sought to identify neuroinflammation-specific biomarkers. They screened 227 samples of cerebrospinal fluid or CSF, the fluid that surrounds the brain and spinal cord, collected from Alzheimer’s and Parkinson’s patients.

The goal was to look for relationships between the levels of these markers and patients’ characteristics — for example, age and sex — as well as their link with markers of neurodegeneration, such as tau, and measures of disease progression, like the Hoehn and Yahr scale for Parkinson’s.

People without dementia and patients diagnosed with mild cognitive impairment also were included for comparison.

The researchers specifically focused on 21 selected immunity markers. These included chemical messengers known as cytokines or chemokines, namely YKL‐40, TGF‐beta1, IP‐10, MCP‐1, MIF, and MIP‐1beta. The immune receptors sIl‐1RAcP, sAXL, sTyro3, sTREM2, sTNF‐RI/II, and sICAM‐1 also were targeted, as well as other complement and innate immune factors, including C-reactive protein and C1q, C3, C3b, C4, B, H, and properdin.

The findings were highly reproducible and consistent with previous findings. However, they revealed that immune markers were more tightly related to neurodegeneration — reflected by the levels of the protein tau — than having a diagnosis of Alzheimer’s, Parkinson’s, or mild cognitive impairment.

This suggests that such biomarkers may work better to discriminate the mechanisms underlying each patient’s illness.

Age was the “most striking covariate” with a “strong influence” on immunity markers. Older patients had increased levels of most immune proteins, and also tended to have more advanced disease.

The individual’s sex also influenced marker levels, as did APOE genetic variants — one of the strongest genetic risk factors for Alzheimer’s and a proposed risk factor for Parkinson’s — and center‐specific factors, or variations from the different centers from which patient data was obtained.

“These results are supportive of the use of mechanism‐based disease taxonomies [classifications] in addition to clinical features,” the researchers said.

Ageing seems to have a strong link with increased neuroinflammation; thus it should be taken into account when translating marker results to clinical practice or studies, the team said.

“Immunity biomarker levels in CSF reflect molecular and cellular pathology [disease characteristics] rather than diagnosis in neurodegenerative disorders. Assay standardization and stratification for age and other covariates could improve the power of such markers in clinical applications or intervention studies targeting immune responses in neurodegeneration,” the researchers concluded.

Looking ahead, the researchers reaffirm the need to characterize patients not only by symptoms but also by molecular markers that reflect their complex neurodegenerative disorders.

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Potential Oral Treatment Shows Promise in Early Study in Volunteers, Neuropore Says

trial results

A potential oral therapy for Parkinson’s disease and amyotrophic lateral sclerosis (ALS) was seen to be safe and well-tolerated at various doses in a Phase 1 trial in healthy volunteers, its developer, Neuropore Therapies, announced.

Steps are now underway to allow NPT520-34 to be evaluated in patients, the company said in a press release.

NPT520-34 is a small molecule that, in different animal models of Parkinson’s, was found to reduce levels of markers of brain inflammation and to improve motor function. Likewise, it was shown to ease inflammation and the buildup of toxic proteins in the central nervous system (brain and spinal cord) in animal models of Alzheimer’s disease and ALS.

The medication is administered orally and small enough to cross the blood-brain barrier, the highly selective and semipermeable membrane that encases and protects the brain.

The recently completed and placebo-controlled study (NCT03954600) investigated the safety, tolerability, and pharmacokinetic properties of oral NPT520-34 at multiple doses in 49 healthy volunteers. (Pharmacokinetics is the study of how a medicine is absorbed, distributed, metabolized, and eliminated from the body.)

The trial included an initial single-dose ascending phase, in which a one dose of NPT520-34 (125 mg, 250 mg, 500 mg and 1000 mg) or a matched placebo were given all study participants, with the possibility of incremental adjustments. This was followed by a second phase, in which participants received multiple-ascending doses (250 mg and 500 mg) of the compound, also with the possibility of incremental adjustments, or a placebo.

“We are excited to complete the Phase 1 clinical trial with NPT520-34″ and believe it “believe NPT520-34 represents a promising new small molecule therapeutic opportunity for patients living with Parkinson’s disease and amyotrophic lateral sclerosis,” Douglas Bonhaus, PhD, chief executive officer and chief scientific officer of Neuropore, said in the release.

“NPT520-34 proved to be safe and tolerable at all doses tested, including those believed to be therapeutically relevant,” Bonhaus added. “The results of this study support moving forward to a safety study in patients. Our team is currently evaluating the optimal study design and patient population for the next study.”

Trials of NPT520-34 in patients with neurodegenerative disorders are expected to begin this year.

We believe NPT520-34 represents a promising new small molecule therapeutic opportunity for patients living with Parkinson’s disease and amyotrophic lateral sclerosis.

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Activating Cannabis Receptors Could Help Treat L-DOPA-induced Dyskinesia, Mouse Study Finds


A compound that affects some of the same receptors in the brain as cannabis could help reduce dyskinesia — involuntary muscle movement — that develops following levodopa treatment in Parkinson’s disease, a new study done in mice suggests.

The mice were treated with HU-308, an agonist, or activator that binds to a cannabinoid receptor in the brain. It was found to reduce tremors without causing the “high” associated with cannabis.

Titled “Targeting the cannabinoid receptor CB2 in a mouse model of l-dopa induced dyskinesia,” the study was published in Neurobiology of Disease

Parkinson’s is characterized by the loss of neurons that make the neurotransmitter dopamine. Treatment with levodopa, or L-DOPA — a precursor to dopamine — has long been one of the gold standards for Parkinson treatment. However, this medicine can lead to uncontrollable movements, a condition called levodopa-induced dyskinesia, or LID.

The only treatment currently available for LID is Gocovri (amantadine). This is thought to reduce dyskinesia through a few different mechanisms, namely by reducing inflammation in the brain (neuroinflammation) and affecting glia, brain cells that serve a variety of specialized functions. Since glia function as the primary immune system in the brain, they play a role in neuroinflammation.

“If targeting neuroinflammation, and or glial signalling, offers a potential strategy, then cannabinoid based therapies could be an option for treating LIDs,” the researchers said. They explained that “cannabinoid-based therapies can exert effects on glia, are thought to suppress neuroinflammation, and have neuroprotective effects in preclinical animal models of several neurodegenerative disorders.”

However, cannabis itself is ill-suited to such therapeutic uses.

“Currently there is limited evidence about the effectiveness of medicinal cannabis,” Bryce Vissel, PhD, director of the Centre for Neuroscience and Regenerative Medicine at the University of Technology Sydney (UTS) and a study co-author, said in a press release. “One problem is that no cannabis preparation is the same and cannabis has numerous effects, some of which may not be beneficial in Parkinson’s disease.”

The compounds in cannabis act primarily via two chemical receptors in the brain, CB1 and CB2. Since CB1 is primarily responsible for the “high” cannabis can impart, which is not desirable in a medicine, the researchers investigated whether specifically activating CB2 could reduce LID without this adverse effect.

To test this, mice with modeled LID — essentially, modeled Parkinson’s disease followed by L-DOPA treatment to the development of LID — were treated with HU-308, a CB2 agonist (activator). Compared with mice that did not receive such treatment, LID was significantly decreased in the HU-308-treated mice, as evidenced both by behavioral observation and by decreased levels of FosB, a marker of LID in the brain.

To confirm that this effect was the result of CB2 activation, the researchers treated mice with both HU-308 and SR144528, which is an antagonist, or blocker, of CB2. This co-treatment eliminated the benefits imparted by HU-308 alone, suggesting that the effect is indeed due to CB2 activation.

In the same model, Gocovri also reduced LID, to a similar extent as HU-308. And, when both HU-308 and Gocovri were given simultaneously, the reduction in LID was greater than that seen with either treatment alone.

“The fact that amantadine [Gocovri] has its own set of side effects, may not work in the long term, and is still the only drug available on the market that is approved for dyskinesias makes our study really exciting,” said Sandy Stayte, PhD, a researcher at UTS and a study co-author.

“First, our study shows HU-308 is equally affective so a drug like HU-308 will be useful for those people who can’t take amantadine. Second, for those who can tolerate amantadine, taking the combination may have even greater benefits than taking either drug alone,” Stayte said. “That means we may end up with a much more powerful treatment than currently available by ultimately prescribing both.”

Further analysis revealed that both treatments — separately and combined — reduced neuroinflammation, as evidenced by decreased levels of inflammatory signaling molecules in the brain. Additionally, both treatments reduced the numbers of inflammatory glia cells.

“By reducing inflammation in the brain — such as with HU-308 — these immune cells [glia] can support normal neural function again, rather than inhibiting it,” Vissel said.

Interestingly, though, treatment with both HU-308 and Gocovri together did not affect neuroinflammation to a greater extent than either therapy alone. This suggests that the additive effect seen at the behavioral level may be due to other mechanisms. However, the team said their “measures in this paper are too rudimentary to explore these various mechanisms, and much further research is needed.”

Nonetheless, the study does support using CB2 agonists as a treatment strategy for LID.

The researchers said approximately 52-78% of patients may develop LIDs within 10 years of starting levodopa treatment.

“Accordingly, clinical trials investigating [CB2 agonists’] efficacy for neurodegenerative diseases is currently in high demand,” the investigators said.

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Plant Chemical Chrysin May Protect Against Parkinson’s-related Changes, Mouse Study Suggests

chrysin, protective effects

Chrysin, a chemical commonly found in plants, may ease behavioral, cognitive, and neurochemical changes in Parkinson’s disease, according to a mouse study.

The study, “Chrysin protects against behavioral, cognitive and neurochemical alterations in a 6-hydroxydopamine model of Parkinson’s disease,” was published in Neuroscience Letters.

Studies have confirmed the involvement of neuroinflammation and oxidative stress in the development of Parkinson’s disease. Oxidative stress is an imbalance between the production of free radicals and the ability of cells to detoxify them, resulting in cellular damage as a consequence of high levels of oxidant molecules.

Both molecular phenomena have been implicated in the degeneration of dopamine-producing neurons — the type of nerve cell that is lost in Parkinson’s disease.

Chrysin is a naturally occurring flavone commonly found in fruits and vegetables. Evidence indicates the plant chemical has anti-allergic, anti-cancer, anti-inflammatory, and antioxidant properties.

A Brazilian team of researchers have now investigated the effects of a 28-day chrysin treatment (10 mg/kg/day, given orally) on a female aged mouse model of Parkinson’s disease.

Researchers first injected a neurotoxin called 6-hydroxydopamine (6-OHDA) into the mice’s right striatum — a brain region involved in voluntary movement control that is severely affected in Parkinson’s. This neurotoxin causes cellular dysfunction and death of dopaminergic neurons, enabling the molecular replication of Parkinson’s disease in a laboratory setting. Injected mice were all 20 months old, which is equivalent to a human age of more than 60 years.

Following the 28-day chrysin treatment protocol, the researchers performed memory, locomotor, and biochemistry tests these animals.

Compared with healthy control animals, chrysin was found to reduce the loss of dopamine and its metabolites (meaning “small products of metabolism”) in the striatum of the Parkinson’s mice, indicating the plant chemical may protect against disease-related dopamine metabolism degradation.

In line with the biological mechanism of Parkinson’s, 6-OHDA administration increased inflammatory responses by elevating levels of proinflammatory cytokines, or small proteins. Chrysin treatment prevented this response, supporting previous research on the compound’s anti-inflammatory properties.

Chrysin was also able to prevent the increase in oxidative stress levels that resulted from 6-OHDA injections. The animals’ antioxidant response also improved following treatment.

In addition, chrysin alleviated disease-related behavioral changes — which in mice manifests as rotational (circling) behavior — and cognitive deterioration including memory and spatial learning abilities. Researchers also noted that “age-related memory decline was partially protected by chrysin at a dose of 1 mg/kg, and normalized at the dose of 10 mg/kg.

“In the present study, chrysin was beneficial against behavioral, cognitive and neurochemical changes in a [Parkinson’s disease] model induced by 6- OHDA in aged female mice. Mechanisms underlying chrysin effects include decrease of oxidative stress and neuroinflammation, which eventually attenuates behavioral and cognitive impairments,” the researchers concluded.

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Manganese Exposure May Be Linked to Parkinson’s Development, Study Suggests


Exposure to the metal manganese may lead to the development of Parkinson’s disease by promoting the release from nerve cells of alpha-synuclein, the subsequent aggregation of which causes inflammation and neurodegeneration, according to a study.

The study, “Manganese promotes the aggregation and prion-like cell-to-cell exosomal transmission of α-synuclein,” was published in the journal Science Signaling.

Increasing studies have reported that aggregated alpha-synuclein — the main component of Lewy bodies, a Parkinson’s characteristic — is able to migrate within the central nervous system (brain and spinal cord), a process associated with Parkinson’s progression.

Alpha-synuclein induces brain inflammation and neurodegeneration after being secreted from nerve cells in exosomes — tiny vesicles thought to play a role in cell-to-cell transmission of misfolded proteins.

Small amounts of manganese are essential for the proper functioning of certain enzymes in the body. However, exposure to this metal — which has a range of industrial uses as an alloy — in contaminated air and drinking water, as well as in agricultural products, may lead to a movement disorder called manganism with manifestations similar to those of Parkinson’s. Additionally, occupational exposure to manganese in welding fumes has been linked to a higher risk of parkinsonism, a general term for disorders causing movement problems that resemble Parkinson’s.

However, the precise mechanisms through which manganese exerts a neurotoxic effect, as well as its role in alpha-synuclein propagation, are not well-understood by scientists yet.

Researchers at Iowa State University conducted a range of in vitro (in the lab) and in vivo (in animal models) experiments to address this lack of knowledge as well as to evaluate whether exosomes are involved in the transmission of alpha-synuclein.

The in vitro assessments in dopamine-producing nerve cells of mice revealed that exposure to manganese induced the release of misfolded alpha-synuclein through exosomes. These exosomes were then taken up by immune cells called microglia, producing neuroinflammatory responses as reflected by the release of proinflammatory molecules TNF-alpha, interleukin (IL)-12, IL-1beta, and IL-6.

“These results support recent observations indicating that neuroinflammation plays a major role in [Parkinson’s],” the researchers wrote.

In a model of human dopaminergic neurons, exosomes caused toxicity or apoptosis — which refers to “programmed” cell death, as opposed to cell death caused by injury.

A subsequent imaging analysis found that orally delivered manganese accelerated cell-to-cell transmission of aggregated alpha-synuclein, leading to toxicity in dopamine-producing cells. This was assessed in mice injected with a viral vector to produce alpha-synuclein coupled with a fluorescent tag to enable visualization.

Mice that were given both the viral vectors and manganese exhibited more impaired motor function than those injected with the vectors alone, as well as severe loss of dopamine-producing nerve cells in the substantia nigra — an area of the brain known to be affected in Parkinson’s disease.

Researchers also found higher levels of alpha-synuclein in exosomes in blood samples from eight welders, at a mean age of 46 years, with no symptoms of Parkinson’s, compared with 10 healthy individuals used as controls.

“As a group, welders are at risk of prolonged exposures to environmental levels of metals, including [manganese],” the researchers wrote.

The team also observed that injecting alpha-synuclein-containing exosomes collected from cells exposed to manganese into the mouse striatum — a brain region connected to the substantia nigra that also shows lower levels of dopamine in Parkinson’s disease — induced more lethargic behavior as observed by reduced exploratory activity after six months. This was associated with an inflammatory response in the brain.

“Together, these results indicate that [manganese] exposure promotes [alpha-synuclein] secretion in exosomal vesicles, which subsequently evokes proinflammatory and neurodegenerative responses in both cell culture and animal models,” the researchers wrote.

“As the disease advances, it’s harder to slow it down with treatments,” Anumantha Kanthasamy, PhD, the study’s senior author, said in a press release. “Earlier detection, perhaps by testing for misfolded alpha-synuclein, can lead to better outcomes for patients. Such a test might also indicate whether someone is at risk before the onset of the disease.”

Kanthasamy is the Clarence Hartley Covault distinguished professor in veterinary medicine and the Eugene and Linda Lloyd endowed chair of neurotoxicology at Iowa.

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Emapunil Holds Promise as Parkinson’s Treatment, Mouse Study Results Show


A compound called emapunil prevented the characteristic loss of nerve cells associated with Parkinson’s disease, lowered levels of dopamine, brain inflammation, and motor deficits in a mouse model of the disease.

Researchers suggest that treatment with emapunil, already proven safe in humans as a therapy for anxiety disorders, may be effective for people with Parkinson’s.

The study, “Translocator protein ligand protects against neurodegeneration in the MPTP mouse model of Parkinsonism,” was published in the Journal of Neuroscience.

In Parkinson’s, the progressive loss of dopamine-producing neurons in the substantia nigra — a brain region implicated in motor control — is associated with brain inflammation.

Pro-inflammatory stimuli may activate microglia (key immune cells in the central nervous system that protect nerve cells against harmful agents and pathogens), which further contributes to oxidative stress, neurotoxicity, and disease progression. Several genes associated with familial forms of Parkinson’s have been linked with the immune response, while variations in genes encoding inflammatory molecules are linked with a higher risk for the sporadic form of the disease.

The levels of a specific protein, called translocator protein (TSPO), are elevated in microglia during inflammatory activation. TSPO ligands have been used to monitor neuroinflammation, including in patients with Parkinson’s, and have shown neuroprotective effects. However, the mechanisms through which TSPO ligands modulate inflammation are still unclear.

Researchers at the German Center for Neurodegenerative Diseases (DZNE) and University Medical Center Goettingen, Germany, investigated the therapeutic potential of emapunil, a synthetic TSPO ligand, in a mouse model of Parkinson’s disease. Emapunil previously had shown anti-inflammatory properties, as well as the ability to cross the blood-brain barrier — a semipermeable membrane that protects the brain against the external environment, and is a major obstacle for the efficient delivery of certain therapeutics that need to reach the brain and central nervous system.

“This compound is able to penetrate into the microglia and flip a molecular switch that attenuates the inflammatory reaction,” Anja Schneider, the study’s senior author, said in a press release. Emapunil, added Schneider, “has already been tested in clinical studies on humans as a possible remedy for anxiety disorders. Therefore, data on this substance exists that proves its safety and tolerability in humans.”

The findings revealed that treatment with emapunil (every two days for up to 15 days) completely prevented loss of nerve cells in the substantia nigra, preserved dopamine metabolism in the striatum (a brain area that shows reduced levels of this neurotransmitter in Parkinson’s) lessened inflammation, and restored the animals’ motor function and postural control.

The team also found that emapunil lessened the unfolded protein response — a cellular stress reaction upon defects in protein folding that may lead to cell death — by reducing the RNA levels of the active form of a molecule known as XBP1 (XBP1s). Also, emapunil induced a shift from pro- to anti-inflammatory gene expression in microglia, which may underlie the compound’s protective effects, the team noted.

Mice given emapunil also showed normalized expression of genes linked to the innate immune response, production of inflammatory molecules, and nerve cell generation and differentiation, among other processes.

The investigators also confirmed that the effects of emapunil were mediated through TSPO, as genetic manipulation to lower TSPO levels impaired emapunil’s benefits.

“This drug acts on the microglia and dampens inflammatory reactions. Basically, this was already known. However, we now discovered that the compound also affects neurons directly,” said Tiago Outeiro, a co-author in the study.

“Our data suggest that Emapunil may be a promising approach in the treatment of Parkinson’s,” researchers wrote. “We thus propose to further validate Emapunil in other Parkinson’s disease mouse models and subsequently in clinical trials.”

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CXCL12/CXCR4 Blood Levels Can Help Diagnose Inflammation Linked to Parkinson’s, Study Suggests

CXCL12 CXCR4 biomarkers

Measuring blood levels of the signaling molecule CXCL12 and its receptor CXCR4 may help identify active inflammation in Parkinson’s disease patients, a study suggests.

The study, “CXCL12 and CXCR4 in the Peripheral Blood of Patients with Parkinson’s Disease,” was published in Neuroimmunomodulation.

CXCL12 is a small protein called a chemokine that triggers immune cells to the site of inflammation where they can exert their pro-inflammatory activity.

Previous studies have shown that CXCL12 proteins are increased in inflammatory diseases including inflammatory bowel disease and rheumatoid arthritis, and inhibiting its receptor, CXCR4, may hold therapeutic potential for these diseases.

In addition, CXCL12 has also been shown to contribute to the development of neurodegenerative disorders, such as multiple sclerosis. Preventing the migration of immune cells to lesion sites in the brain could block the progression of such damaging disorders.

“These observations reinforce the significant role of the CXCL12/CXCR4 axis in inflammatory responses,” the researchers wrote.

Parkinson’s disease is characterized by reduced levels of dopamine in the brain caused by the death of dopamine-producing nerve cells. Although it is not fully understood what promotes the death of this particular subset of brain cells, several studies have demonstrated that oxidative stress — cellular damage as a consequence of high levels of oxidant molecules — and increased inflammation are critical players.

Iranian researchers have now investigated the role of CXCL12 and its receptor in Parkinson’s disease.

They evaluated blood samples collected from 30 patients with confirmed Parkinson’s disease and 40 age- and sex-matched healthy volunteers. The patients had the disease for a mean duration of 4.17 years.

The analysis revealed that levels of CXCL12 were 2.4 times higher in Parkinson’s patients over the control group. In addition, CXCR4 levels in peripheral blood mononuclear cells (PBMC, consisting of major immune cells, like T- and B-cells) were found to be approximately three times higher in Parkinson’s patients.

Based on these findings, the researchers believe that CXCL12 signals mediated by CXCR4 could contribute to the activation of immune cells, inflammation, and neurotoxicity linked to Parkinson’s disease.

Importantly, “CXCR4 expression in PBMC or CXCL12 serum levels may be potential biomarkers of inflammation in PD [Parkinson’s disease] patients,” the researchers wrote.

However, the team notes that some studies have found contrasting results, suggesting that CXCL12 signals could be protective for the central nervous system. This highlights the need for further studies to clarify the exact role of CXCL12/CXCR4 signals in the progression of Parkinson’s disease.

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Herantis Creates Video to Show How Its Parkinson’s Therapy Works

Parkinson's therapy video

Herantis Pharma has created an educational video about the way its Parkinson’s treatment CDNF works.

The explainer comes as the company has begun recruiting patients for a Phase 1/2 clinical trial (NCT03295786) of the potential therapy.

Hallmarks of Parkinson’s include damage to dopamine-producing nerve cells in a brain area called the substantia nigra, toxic accumulation of alpha-synuclein protein clumps in nerve cells, and chronic brain inflammation.

Dopamine is a neurotransmitter, or chemical that facilitates communication between nerve cells. This means it’s involved in controlling movement, cognition, learning, memory, and mood.

Alpha-synuclein clumps impair the release of neurotransmitters. Growing evidence indicates that brain inflammation also plays a key role in the development of the disease.

There are no approved therapies to prevent the progression of Parkinson’s. Treatments have focused on alleviating the disease’s movement symptoms. The more damage to dopamine-producing nerve cells, the less effective these therapies are, however.

The treatment of non-movement symptoms — including depression, anxiety, sleep disturbance, and cognitive dysfunction — remains an unmet need for Parkinson’s patients.

CDNF is a synthetic neurotrophic factor, or protein that helps nerve cells survive. The factor occurs naturally in blood and cerebrospinal fluid.

CDNF protected and regenerated nerve cells in studies involving animal models of Parkinson’s disease. It stopped, and to some extent reversed, the progression of the disease.

The video that Herantis produced explains CDNF’s modes of action and advantages. “This video briefly explains the disease and shows how our CDNF aims to protect the dopamine-producing nerve cells from degeneration. This could slow down or even stop disease progression,” Pekka Simula, Herantis’ CEO, said in a press release.

Researchers have found that CDNF can repair nerve cells to the point that they can produce dopamine again. It also reduces alpha-synuclein clumping and nerve cell inflammation.

In addition, CDNF can protect and repair nerve cells from endoplasmic reticulum stress. The reticulum is a large organelle that takes part in a number of cell functions, including protein production. Abnormal protein production can cause the endoplasmic reticulum  stress associated with neurodegenerative diseases such as Parkinson’s.

Preclinical-trial research has also shown signs that CDNF can improve Parkinson’s patients’ non-movement symptoms, Herantis reported.

The clinical trial that Herantis has started will evaluate CDNF’s safety and preliminary ability to improve Parkinson’s symptoms. It hopes to enroll 18 patients in the study.

The participants will receive CDNF directly into theirs brain through an implanted drug delivery system for six months. Simula said the company is working on a non-invasive delivery method for CNDF — a breakthrough in Parkinson’s treatment.

Results of the trial are expected by the end of 2019.

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Source: Parkinson's News Today