Activated Immune T-Cells Infiltrate the Brain and Promote Neurodegeneration in Primate Models of Parkinson’s

Activated Immune T-Cells

Activated immune T-cells can infiltrate the brain and promote neurodegeneration in non-human primate models of Parkinson’s during the chronic stages of the disease, a study has found.

Results of the study, “Chronic infiltration of T lymphocytes into the brain in a non-human primate model of Parkinson’s disease,” were published in the journal Neuroscience.

Parkinson’s disease is a neurodegenerative disorder characterized by the gradual loss of dopaminergic neurons in the substantia nigra — a region of the brain responsible for movement control — together with brain inflammation.

Recent studies have suggested that activated T-cells, which are immune cells that are responsible for destroying other cells or microbes seen as a threat by the immune system, also can play a key role in Parkinson’s neurodegeneration.

Studies in non-human primate models of induced-Parkinson’s have reported the infiltration of these activated T-cells in the brain’s substantia nigra a month after treatment with MPTP during the acute phase of the disease. (MPTP is a neurotoxin that induces brain inflammation and often is used to trigger the onset of Parkinson’s in different animal models.)

“[H]owever, T lymphocyte infiltration into the brain during the chronic phase after MPTP injection in NHP [non-human primate] models remains unclear. We believe that a better understanding of this phenomenon will help identify the neuropathological mechanisms underlying PD [Parkinson’s disease] in humans,” the researchers wrote.

In mice models of the disease, the chemokine RANTES also has been associated with the infiltration of activated T-cells into the brain and with the development of Parkinson’s. (Chemokines are small molecules that mediate and regulate immune and inflammatory responses.)

A team of Korean researchers investigated the mechanisms underlying the infiltration of activated T-cells during the chronic stage of the disease in non-human primate models of induced-Parkinson’s.

In addition to evaluating the infiltration of T-cells in the brain 48 weeks after animals received an injection of MPTP, investigators also assessed changes in the levels of RANTES in the animals’ blood, and assessed microglia activation. (Microglia activation refers to the process by which microglia — nerve cells that support and protect neurons — become overactive, triggering brain inflammation.)

A total of five animals were injected with MPTP and three received a saline injection (controls).

Compared to saline-treated animals, those treated with MPTP showed signs of local chronic infiltration of activated T-cells in different regions of the brain’s striatum — a brain region responsible for controlling body movements — and substantia nigra.

Moreover, in animals treated with MPTP, this was accompanied by the loss of dopaminergic neurons, abnormal microglia morphology, and chronic normalization of the levels of RANTES in the blood 24–48 weeks post-injection, indicative of inflammation.

“This study confirms the involvement of [T-cell] infiltration in MPTP-induced NHP [non-human primates] models of PD. Further, these findings reinforce those of previous studies that identified the mechanisms involved in [T-cell]-induced neurodegeneration,” the researchers wrote.

“The findings of chronic infiltration of T lymphocytes in our NHP model of PD provide novel insights into PD pathogenesis and the development of preventive and therapeutic agents,” they stated.

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First Patient Dosed in Phase 2 Trial of Oral Treatment to Ease Inflammation in Parkinson’s

AKST4290 Phase 2 trial

Alkahest announced the dosing of a first patient in the Phase 2 trial for its Parkinson’s therapy AKST4290, an oral tablet aiming to ease the inflammation that can aggravate disease symptoms.

The efficacy and safety trial, called AKST4290-211 or TEAL (2019-001657-42), will measure AKST4290’s benefits in motor function and activities relevant to daily life in treated patients relative to those given a placebo, the company said in a press release.

AKST4290 is designed to block the protein eotaxin. Eotaxin accumulates in the bloodstream as we age, and is believed to cause increased inflammation.

Inflammation has long been observed in the brains of people with Parkinson’s, but only recently has the idea that it drives disease progression gained traction. Scientists now speculate that the alpha-synuclein clumps that accumulate inside neurons and are a hallmark of the disease, trigger the body’s inflammatory response.

An inflammatory response is a vital part of the immune system. But a prolonged response, as occurs in Parkinson’s, damages cells to promote progression.

Because the way in which AKST4290 modulates inflammation is not unique to Parkinson’s, it holds the potential to reduce inflammation associated with other age-related diseases. It is also being tested in a Phase 2 trial (2019-002821-31) for age-related macular degeneration.

The TEAL trial is the first testing AKST4290 as a potential Parkinson’s treatment.

The randomized and double-blind trial, taking place in Europe, will enroll about 120 patients on a stable dopamine-based medication like levodopa. All will be randomly assigned to either 400 mg of AKST4290 (200 mg twice a day) or a placebo for 12 weeks, then followed for another 30 days.

The primary endpoint, or the main result to be measured at the end of the trial, will be changes in motor function during off periods at week 12. These are periods characterized by the reappearance or worsening of symptoms due to a gradual decline or waning in a dopamine medication’s effectiveness. Motor function will be measured using the Movement Disorder Society’s Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part 3.

Other endpoints include the compound’s safety and tolerability, as well as various clinical and functional features of an on-medication state.

Requests for more information about the trial, which may open test sites in the U.S., can be sent to Alkahest using this email address.

Few new treatment options for Parkinson’s have been approved since the introduction of dopamine promoters.

The trial is funded in part by the Michael J. Fox Foundation for Parkinson’s Research (MJFF), which has also supported trials into several of Alkahest’s other Parkinson’s therapy candidates.

“Patients’ greatest unmet need is a therapy that prevents, slows or halts the progression of Parkinson’s disease. AKST4290 presents a novel approach toward that goal, and we’re keen to better understand its potential impact for the millions living with this disease and their loved ones,” Todd Sherer, chief executive officer of The Michael J. Fox Foundation, said in the release.

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LRRK2 Gene Mutation Protects Against Infection But Increases Parkinson’s Risk Via Inflammation, Study Suggests

LRRK2, inflammation

Although it may be protective against infections, a specific mutation in the LRRK2 gene — the gene linked to most inheritable mutations that can cause Parkinson’s disease — may increase Parkinson’s risk by promoting inflammation in the brain, according to new research.

The study, “Lrrk2 alleles modulate inflammation during microbial infection of mice in a sex-dependent manner,” appeared in the journal Science Translational Medicine.

Mutations in the LRRK2 gene are found in about 2% of people with Parkinson’s, with different studies reporting a greater frequency in women. But a mutated LRRK2 also has been associated with greater risk for two other disorders in which inflammation is a key component: Crohn’s disease (CD), which targets the gut, and leprosy, which affects the peripheral nervous system.

LRRK2 is highly expressed in several types of immune cells, including macrophages and natural killer cells. This suggests it plays a role in innate immunity — nonspecific defense mechanisms prompted by any given microbe.

To test this hypothesis, a team from Canada assessed LRRK2 expression in human white blood cells and tissues during inflammation, and studied viral and bacterial infections in Lrrk2 mutant animals.

First, the team found that neutrophils — immune cells that travel to the site of an infection — were the cell type with the highest expression of LRRK2 in healthy participants. Immune–related tissues, such as the bone marrow and lymph nodes, showed abundant RNA levels of LRRK2. RNA is the genetic template that gives origin to proteins.

Then, the investigators found significant protein production in gut samples of patients with Crohn’s disease, and in brain tissue of people infected by HIV, rabies virus, or virally infected peripheral nerve roots. All of these are characterized by inflammation.

Taking this data together with findings in Parkinson’s patients, which showed strong LRRK2 production in brain white blood cells, the team “concluded that LRRK2 appears to be abundant in infiltrating leukocytes of human tissues during acute or chronic inflammation.”

In mice, the researchers used a sepsis model — inoculation with Salmonella typhimurium — and an encephalitis model, induced by infection with reovirus, to assess the role of LRRK2 in acute bacterial and viral infection.

They found that, in both models, normal (wild-type) Lrrk2 expression was protective compared with complete Lrrk2 absence or production from only one gene copy. Female mice lacking Lrrk2 showed a stronger inflammatory response than male animals that lacked the gene, the researchers noted.

Then, the scientists studied the p.G2019S mutation — the most common mutation in LRRK2 — which increases the activity of the LRRK2 protein. Carrying this mutation enhanced inflammation and boosted the protective effect of normal Lrrk2, with reduced bacterial growth and longer survival during sepsis. This greater protection was mediated by the higher number of myeloid cells — monocytes, macrophages and neutrophils — in the spleen.

In mice with sepsis and with the Lrrk2 mutation, the scientists also observed increased oxidative damage in the spleen and the brain.

“When mice with the Parkinson’s-linked mutation were infected with Salmonella bacteria, we saw very high levels of  in the brain, almost twice as high as in normal mice,” Bojan Shutinoski, PhD, the study’s first author, said in a press release. “This was particularly surprising because the bacteria never even entered their nervous system!”

Mouse pups with encephalitis and no Lrrk2 had increased mortality — especially females — and increased activation of microglia, the resident immune cells of the brain. Animals with the p.G2019S mutation showed reduced survival despite lower viral levels. These mice also exhibited greater brain infiltration of white blood cells, and higher concentrations of the alpha-synuclein protein — the main component of Parkinson’s hallmark Lewy bodies.

The higher mortality in mice with the p.G2019S mutation was likely due to increased enzymatic activity of Lrrk2, as animals with a mutation (p.D1994S) that suppresses this activity showed greater survival.

“Our findings support a growing body of evidence that the LRRK2 protein functions in immune cells both within the brain … and the periphery,” the investigators said.

“Everyone thought that LRRK2’s primary role was in the brain, because of its association with Parkinson’s disease. But our research shows for the first time that its primary role is probably in the immune system,” said Michael Schlossmacher, MD, the study’s senior author and a neurologist at The Ottawa Hospital.

“Our research suggests that certain mutations in LRRK2 enhance inflammation and help the body to defend itself better against viruses and bacteria, but this enhanced inflammation could also increase the risk of Parkinson’s and other brain diseases,” added Schlossmacher, also a professor at the University of Ottawa Brain and Mind Research Institute.

The findings are in line with other additional studies suggesting that Parkinson’s may start outside the brain, and showing a link with Crohn’s disease.

“If this theory about LRRK2 is correct, it could open the door for the monitoring of infections as a key risk element for prediction, early detection and prevention of Parkinson’s, and importantly, for new treatment approaches in general,” Schlossmacher said.

The results also may have implications for the clinical development of therapies that block LRRK2 activity.

“Our research suggests that these drugs may well succeed in safely reducing excessive inflammation,” Shutinoski said. “However, we should be careful not to abolish LRRK2 function altogether, as this could make people more susceptible to infections, in particular when being treated potentially for years.”

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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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High Levels of Inflammatory Biomarker Evident in Patients, Study Says, But Cause-Effect Unknown

c-reactive protein inflammation

Parkinson’s disease patients have “significantly elevated” levels of c-reactive protein, an acute-phase biomarker for inflammation in the body, according to a recent literature review.

It remains to be understood, however, if c-reactive protein is a risk factor for this neurodegenerative disorder, or if the disease itself triggers an inflammatory response.

The study, “C-reactive Protein and Risk of Parkinson’s Disease: A Systematic Review and Meta-analysis” was published in Frontiers in Neurology.

Chronic neuroinflammation is a hallmark of Parkinson’s disease (PD). Studies have suggested that inflammatory processes may contribute to disease risk and progression, although this biological response is unlikely to be the primary cause of neuronal death.

Evidence indicates that high c-reactive protein (CRP) levels are strongly correlated with the inflammatory process. Indeed, some studies suggest a link between CRP and chronic inflammatory and neurodegenerative disorders, such as cardiovascular disease, Alzheimer’s disease, or Parkinson’s.

Although some population-based studies have explored the relationship between c-reactive protein levels and Parkinson’s risk, results so far have been contradictory.

That led researchers at the First Affiliated Hospital of Guangxi Medical University, in China, to analyze all available studies regarding c-reactive protein levels in the serum, plasma, blood, and cerebrospinal fluid — the liquid that surrounds the brain and spinal cord — in Parkinson’s patients.

Investigators searched the records of seven life sciences, biomedical or medical databases — three of them Chinese — up through October 2018, examining associations between c-reactive protein levels and Parkinson’s risk.

The team analyzed a total of 23 case-control studies published between 2009 and 2018, which involved 2,646 Parkinson’s patients (mean age 63.6–73.2) and 1,932 controls. Disease duration ranged from 3 months to 9.8 years.

Whether studies used standard or more sensitive immunoassays — a procedure used to measure certain immune-related proteins or substances — c-reactive protein concentration in whole blood, serum, and cerebrospinal fluid was found to be significantly, and consistently, higher in Parkinson’s patients than in healthy controls.

Other factors, such as the patient’s medication use or other accompanying diseases, also may affect c-reactive protein levels, the researchers said.

Although the findings indicate a link between c-reactive protein levels and Parkinson’s, it is still unknown whether this “measurable” biochemical inflammation contributes to, or is a consequence of, Parkinson’s-related neurodegenerative mechanisms.

“[T]here is growing evidence that support an association between neuroinflammation and the initiation and progression of PD pathophysiology,” the researchers wrote.

“The results of this review only suggested a correlation between CRP levels and PD, but could not completely delineate whether inflammation plays a causal role in PD, or if PD leads to inflammatory processes,” they concluded.

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Study Uncovers Molecular Mechanism of Protein Linked to Early-onset Parkinson’s

Parkin protein

A protein called Parkin, which is absent or faulty in many patients with early-onset Parkinson’s disease, helps keep cells alive and reduces the risk of inflammation, according to a recent study.

These results suggest that the protein may be implicated in the development of Parkinson’s, specifically the brain inflammation and loss of neurons associated with the disease. This discovery may support the development of treatments that slow Parkinson’s progression by helping rescue neurons that would otherwise die.

The study, “Parkin inhibits BAK and BAX apoptotic function by distinct mechanisms during mitophagy” was published in the EMBO Journal.

Lack of the PRKN gene, which codes for the Parkin protein, or mutations that result in faulty Parkin protein are known drivers of early-onset Parkinson’s disease.  Understanding how this protein influences cell survival can provide insight on how it works and why its deficiency promotes neurodegenerative conditions such as Parkinson’s.

Now, a team led by researchers at the Walter and Eliza Hall Institute of Medical Research and the University of Melbourne, Australia, investigated the cell-protective role of Parkin and conducted experiments in different cell types grown in the laboratory, engineered to express a normal and functional Parkin protein or mutant versions associated with Parkinson’s disease.

The results showed that Parkin was able to block cell death by inhibiting a protein called BAK.

BAK and a related protein, called BAX, are activated in response to cellular damage, setting up a programmed cellular death cascade referred to as apoptosis.

An important part of this process is the dismantling of mitochondria, structures that supply energy to cells. Damage to mitochondria may itself trigger apoptosis and inflammation, warning neighboring cells of a potential danger.

In these conditions, Parkin tags BAK with a small protein called ubiquitin that signals cells to limit BAK’s activity. Ubiquitin is part of a “quality control” system by which cells dispose of damaged, misshapen, or excess proteins.

By suppressing BAK,  Parkin halts cell death and promotes clearance of damaged mitochondria, limiting their potential for inducing inflammation.

“Parkin ‘buys time’ for the cell, allowing the cell’s innate repair mechanisms to respond to the damage,” Grant Dewson, Ph.D., associate professor at the Walter and Eliza Hall Institute and senior author of the study, said in a press release.

“In a healthy brain, Parkin helps keep cells alive, and decreases the risk of harmful inflammation by repairing damage to mitochondria,” said study author Jonathan Bernardini.

The data showed that without Parkin or with faulty variants of it, BAK is not tagged and excessive cell death can occur. This may contribute to nerve cell loss typical of Parkinson’s disease, researchers said.

“Drugs that can stifle BAK, mimicking the effect of Parkin, may have the potential to reduce harmful cell death in the brain,” Dewson said. 

These insights expanded on the knowledge of how neuron death and brain inflammation may occur in Parkinson’s disease. This might help foster new therapies to slow the progression of the disease.

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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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IRAK4 Protein Inhibitor Could Lead to Treatment for Parkinson’s, Other Neuroinflammatory Diseases

A newly discovered inhibitor of the immune protein IRAK4, known as the “master switch” in the development of several diseases, could lead to treatments for autoimmune diseases and neuroinflammatory disorders such as Parkinson’s, according to developer Noxopharm and its majority-owned subsidiary Nyrada.
Pre-clinical studies are ongoing to find the most appropriate therapeutic indications for this discovery. Clinical studies are expected in 2020.
Recent evidence has shown that IRAK4 is a crucial regulator in the body’s innate immune response — the body’s first line of defense — against foreign pathogens and leads to the production of pro-inflammatory molecules called cytokines.
As its abnormal function in innate immune cells is implicated in the development of chronic inflammatory and autoimmune diseases, IRAK4 inhibitors have been regarded as the next generation of anti-inflammatory treatments for autoimmune conditions, including rheumatoid arthritis, inflammatory bowel disease, psoriasis, and lupus.
The new compound leads to potent inhibition of IRAK4 and is able to cross the blood-brain barrier and blood-nerve barriers. According to Australia-based Noxopharm, this suggests the new compound could be used to target neuroinflammatory diseases of the central nervous system — such as Parkinson’s, Alzheimer’s, multiple sclerosis, amyotrophic lateral sclerosis — and the body’s peripheral nerves, in particular diabetic peripheral neuropathy.
The blood brain barrier is a semipermeable membrane that protects the brain against the external environment, and is a major barrier for the efficient delivery of certain therapeutics that need to reach the brain and central nervous system.
“We see our discovery as a breakthrough in providing the tools needed to address inflammatory and autoimmune diseases of the nervous system,” James Bonnar, Nyrada’s vice-president, research & development, said in a press release. Bonnar noted that the development of IRAK4 inhibitors is being pursued in rheumatoid arthritis, gouty arthritis and lupus.
“I see this as a major development,” said Graham Kelly, Noxopharm’s CEO. While noting that it helps Noxopharm evolve into a global biotech company, Kelly added that “at the patient level, it represents a realistic prospect for finally being able to provide treatment for a number of insidious diseases affecting the nervous system, which have defied successful management to date.”
Besides Alzheimer’s, Parkinson’s and multiple sclerosis, Kelly said that neuroinflammation is “associated even with psychiatric conditions such as depression, bipolar disorder and schizophrenia.”
“Having a drug that blocks IRAK4 and all its downstream pro-inflammatory cytokine [signaling] effects, combined with its ability to reach the brain in sufficient levels, is an exciting breakthrough that has resulted from a lot of hard work by a team of Australian chemists and scientists,” Kelly added.
U.S. company Nyrada is two-thirds owned by Noxopharm and is responsible for the non-oncology drug development programs, including an anti-inflammatory, a neuroprotectant and a PCSK9 inhibitor compound. Of note, PCSK9 is a protein involved in regulating the amount of cholesterol in the blood.
Noxopharm recently secured a U.S. provisional patent application and a Patent Cooperative Treaty (PCT) patent application.
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Identifying Biomarkers of Inflammation Among Goals of Parkinson’s Study by Longevity Biotech and Veterans’ Center

Longevity Biotech study

Longevity Biotech announced plans for a clinical study aiming to identify potential blood-based markers of inflammation that originates in the immune system, biomarkers that may work to better diagnose Parkinson’s and recognize the disease’s different stages.

The study, being run with the support of The Michael J. Fox Foundation for Parkinson’s Research, will also advance early evaluations of the company’s therapeutic candidate LBT-3627.

The two-year study will launch at the Corporal Michael J. Crescenz Veterans Affairs Medical Center,  part of the Philadelphia Parkinson’s Disease Research, Education and Clinical Centers.

The immune system plays a critical role in neurodegenerative diseases, including Parkinson’s. The study will use machine learning techniques to identify immune-based inflammatory biomarkers “that could provide clinically relevant diagnostic information,” Scott Shandler, PhD, co-founder and CEO of Longevity Biotech, said in a press release.

“The identification of these [immune-based inflammatory] markers would have a tremendous impact on the pace of disease modifying therapeutic development for Parkinson’s disease patients by providing a new metric to track disease progression while possibly identifying new disease targets as well,” he added.

Study researchers will be looking not only to expand knowledge into the underlying mechanisms of Parkinson’s, but also to correlate new and existing blood-based markers, such as the protein alpha-synuclein, with standard clinical scores from the Unified Parkinson’s Disease Rating Scale (UPDRS). This scale uses questions to assess both motor and non-motor symptoms associated with Parkinson’s.

In a preclinical setting — ex vivo, meaning outside a living organism — researchers will also examine the potential efficacy of LBT-3627 using human immune cells. The investigative compound is a small protein designed to mimic naturally occurring molecules that activate a family of receptors known for their neuroprotective and anti-inflammatory activities. As such, LBT-3627 is expected to work to balance immune responses and reduce inflammatory damage done to the brain by immune cells.

Previous studies in mice disease models found evidence that LBT-3627 can protect dopaminergic neurons from degeneration, one of the hallmarks of Parkinson’s disease.

“The goal is to convert T cells, which are key actors in the adaptive immune system, from an inflamed, neurodegenerative state to a more healthy, neuroprotective one,” said Jenell Smith, PhD, a lead scientist at Longevity Biotech.

“LBT-3627 has demonstrated robust neuroprotective results in animal models of Parkinson’s disease to date and we will continue testing the effects of LBT-3627 on human immune cells as part of this study,” Smith concluded.

The release did not specify if this study is already underway.

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Deep Brain Stimulation May Increase Levels of Inflammatory Factors in Parkinson’s, Study Suggests

DBS in Parkinson's patients 

Deep brain stimulation (DBS) may increase the levels of hepcidin — a hormone associated with iron accumulation and inflammation in the brain — in Parkinson’s disease patients, according to a small Polish study.

The study, “Higher serum levels of pro-hepcidin in patients with Parkinson’s disease treated with deep brain stimulation,” was published in the journal Neuroscience Letters.

As people age, iron accumulates in several brain regions and cells, including the microglia (the immune cells of the brain) and the astrocytes (cells that regulate nerve cell communication and survival ).

Increased iron accumulation, as well as brain inflammation, is associated with oxidative stress and cellular damage and is observed in several neurodegenerative disorders such as Parkinson’s and Alzheimer’s disease.

Hepcidin, an iron balance-regulatory hormone, suppresses ferroportin (FPN1) — the protein that transports iron out of cells — and leads to cellular iron accumulation.

Because inflammation can induce the production of hepcidin, this hormone may be a link between brain inflammation and iron-induced oxidative damage, both of which are involved in neurodegeneration in Parkinson’s patients.

Researchers in Poland evaluated the levels of pro-hepcidin — the precursor of hepcidin — in Parkinson’s patients treated only with medication, in those who, in addition to medication, also received DBS, and in healthy people (controls).

DBS — high-frequency stimulation in strategic brain areas through surgically implanted thin wires in the brain — is a treatment strategy for people with advanced Parkinson’s disease whose motor problems do not improve with medication.

Several studies have shown that DBS reduces motor symptoms as well as the necessary daily dose of medication, and improves patients’ quality of life.

Blood samples were collected from 52 people with Parkinson’s disease (25 women and 27 men) with a mean age of 56, and 31 healthy individuals (15 women and 16 men) with no history of neurodegenerative disorders in the family and a mean age of 58.

Among Parkinson’s patients, 37 had been treated only with medication — levodopa (L-DOPA) and/or ropinirole (Requip) — and 15 with additional DBS (with a mean time from implantation of 28.4 months).

Parkinson’s patients had significantly higher levels of pro-hepcidin compared to healthy individuals, supporting the involvement of hepcidin in Parkinson’s disease.

Those treated with medication and deep brain stimulation showed the highest levels of pro-hepcidin. There was no association between hepcidin levels and the duration of DBS, patient’s age, duration of the disease, or medication dose.

Since DBS has been associated with the activation of microglia and astrocytes — which release inflammatory molecules — researchers hypothesized that the overproduction of pro-hepcidin in these patients may be related to DBS and its associated inflammation.

But considering the small group of patients treated with DBS, additional studies are needed to clarify this association and whether it affects the worsening of Parkinson’s disease.

“The results obtained should be interpreted very carefully but are an interesting observation that requires further research, including a larger group of patients,” the researchers wrote.

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