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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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Oral Treatment in Phase 2 Trial, NYX-458, Seen to Aid Cognition in Primate Model Study

NYX-458 and cognition

Aptinyx‘s investigational oral compound NYX-458 was able to ease cognitive difficulties in a non-human primate model of Parkinson’s disease, including attention, working memory and executive thinking, a study reports.

Its findings also suggest that NYX-458 — now in a Phase 2 clinical trial (NCT04148391) enrolling patients across the U.S. — does not interfere with levodopa treatment.

The study, “NYX‐458 improves cognitive performance in a primate Parkinson’s disease model,” was published in Movement Disorders.

Although Parkinson’s is often classified as a movement disorder, non-motor symptoms of the disease can have a major impact. For instance, as many as a quarter of people with Parkinson’s meet the criteria for at least mild cognitive impairment when they are diagnosed, and this frequency increases to around 80% after years with the disease.

Parkinson’s is characterized by a loss of dopamine-producing neurons in the brain. One of dopamine’s many functions is to regulate a protein called N-methyl-D-aspartate receptor (NMDAR). It is believed that dysregulation of NMDAR, as a result of dopamine’s lack, contributes to cognitive impairment in Parkinson’s disease.

NYX-458 was designed to modulate NMDAR activity to correct this problem.

Researchers evaluated NYX-458 in a non-human primate (macaque) model of Parkinson’s disease. In this model, cognitive defects are induced with low doses of the neurotoxin MPTP, which selectively damages the same kind of dopamine-producing neurons that are lost in Parkinson’s.

Notably, this model has “a minimal impact on motor function,” the researchers wrote. This is important because of how cognitive impairment was measured in the study: the animals were trained to complete learning/memory tasks to get a food reward, and the researchers measured things like how quickly the animals learned and how often they completed the tasks correctly. These tasks invariably involve movement (like having a monkey point at a particular image). So, the MPTP model allowed assessment of cognitive impairment with minimal motor interference.

The researchers first confirmed that MPTP was inducing cognitive impairment as expected. Then, the animals were given a single oral dose (0.03 mg/kg) of NYX-458.

Significant improvements in scores on the cognitive tasks (“across the domains of attention, working memory, and executive function”) were seen, and “occurred as early as 24 hours postdosing and continued for at least 3 weeks after a single dose,” the researchers wrote.

Subsequent doses of NYX-458 (0.03 mg/kg for 26 days following the first dose, and 0.1 mg/kg for 39 days following the first dose) resulted in further improvement over time.

The monkeys were then re-administered the neurotoxin, which again worsened their cognitive abilities. Subsequent NYX-458 treatment at a higher dose (0.1 mg/kg after MPTP reuse, and 1.0 mg/kg two weeks later), again eased evident impairment.

Animals that showed consistent improvements in the previous experiments next underwent a ‘washout’ period, allowing their cognitive scores to drop back to near pre-NYX-458 levels. They were then given NYX-458 daily (1.0 mg/kg) for 10 consecutive days. Cognitive improvements were seen as long as three months following this treatment round.

Such long-term effects “cannot be explained by continued drug action, as the half-life of NYX-458 in primate plasma is short,” the researchers wrote. Instead, these data suggest that NYX-458 treatment leads to changes in the biochemistry of the affected brain cells, with long-lasting consequences. Further studies, however, are needed to directly confirm this idea.

In a separate experiment, animals were given MPTP at much higher doses, such that motor impairments were induced. NYX-458 treatment did not significantly lessen these motor symptoms.

Levodopa (L-dopa), a mainstay of Parkinson’s treatment, did significantly improve motor symptoms in this model. This effect was also seen when L-dopa and NYX-458 were given simultaneously. These result suggest that NYX-458 does not interfere with the action of L-dopa, supporting the use of the two therapies in combination.

“[T]he cognitive improvement seen in this small primate study and the lack of drug-induced motor impairment or dyskinesia seen in the primate motor study support the continued development of NYX-458 as a potential therapeutic for [cognitive impairment] in early PD,” the researchers wrote.

“Cognitive impairment is increasingly recognized as a burdensome component of Parkinson’s and the few available therapies are inadequate,” Norbert Riedel, PhD, president and chief executive officer at Aptinyx, said in a press release. “In a highly translatable model, these data indicate that the novel mechanism of NYX-458 can address aberrant glutamatergic signaling underlying cognitive impairment in Parkinson’s disease.”

NYX-458 was recently assessed in a Phase 1 clinical trial done in healthy volunteers. Results reported by Aptinyx showed a good safety profile, with no treatment-related adverse events reported.

The ongoing Phase 2 clinical trial (NCT04148391) is evaluating NYX-458 in up to 135 people with Parkinson’s disease who have mild cognitive impairment. Recruitment is underway at multiple locations in the United States; additional information can be found here.

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CYP2D6 Enzyme Could Be Therapeutic Target in Parkinson’s, Study Suggests

CYP2D6

Blocking an enzyme that converts compounds derived from certain foods and tobacco in the brain may become a therapeutic target for people with Parkinson’s, according to a new study of mice.

The research, “Mitochondria-targeted cytochrome P450 CYP2D6 is involved in monomethylamine-induced neuronal damage in mouse models,” was published in the Journal of Biological Chemistry.

Prior research has shown that a synthetic opioid known as MPTP and related compounds can induce alterations similar to Parkinson’s in rodents and primates. It is thought that an enzyme called monoamine oxidase B (MAO-B), present in the nervous system’s glial cells, oxidizes MPTP into a toxic metabolite called MPP+. This metabolite is then transferred by dopamine transporter proteins to dopamine-producing neurons, which are typically affected in people with Parkinson’s disease.

Scientists at University of Pennsylvania had already found that the CYP2D6 enzyme, present in mitochondria — the cells’ power plants — also could be involved in transforming MPTP to MPP+.

“CYP2D6 is known to play a role in influencing the activity of a number of drugs,” Narayan Avadhani, PhD, the study’s senior author, said in a press release. These include antidepressants, antihypertensive medications, opioids, selective estrogen receptor modulators, and antidiabetic therapies, among other types of treatments.

The researchers focused on toxins called beta-carbolines and isoquinolines, which resemble MPTP and are produced by the body from compounds found in tobacco smoke, alcohol, and some foods. Prior studies indicated these toxins may induce Parkinson’s-related changes in rodents, but the mechanisms remained unclear.

Using a mouse model, the results showed that CYP2D6 activates beta-carbolines and isoquinolines inside dopamine-producing nerve cells, leading to cell damage, oxidative stress (cellular damage as a consequence of high levels of oxidant molecules) and impaired mitochondrial function, as occurs in Parkinson’s disease.

Then, the team observed that mice lacking CYP2D6 did not show the same disease-related alterations and that administering CYP2D6 blockers — quinidine or ajmalicine — could prevent neuronal damage.

Experiments in a type of cells that mimic human dopaminergic neurons, called Neuro2a, revealed that cells mainly producing mitochondria-targeted CYP2D6 were more sensitive to toxin-mediated respiratory impairment than those predominantly expressing endoplasmic reticulum-targeted CYP2D6. Of note, the endoplasmic reticulum is a key cellular structure in the production, folding, modification, and transport of proteins.

Upon exposure to the toxins, nerve cells expressing mitochondrial CYP2D6 also showed production of Parkin and Drp1, protein markers of autophagy — a cellular process in the removal of aggregated and toxic proteins, as well as other components — and mitochondrial fission.

The findings also suggest that targeting CYP2D6 may be a better approach than targeting MAO-B, which has led to mixed success in previous work. “We believe that mitochondrial CYP2D6 is the more direct drug target, which might prove better in treating idiopathic Parkinson’s,” Avadhani said.

Avadhani also said that ajmalicine, found in the medicinal plant Rauwolfia serpentine long had been used in India for treating mental disorders such as paranoia and schizophrenia.

“Mitochondrial targeting of such compounds is likely to be effective in treating Parkinson’s patients, and pursuing that is our future strategy,” he said.

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Plant Compound, Arbutin, Eases Some Symptoms in Parkinson’s Mouse Model, Study Shows

arbutin plant compound

Arbutin, a natural compound found in plants such as bearberry leaves and pear trees, was able to protect dopaminergic neurons and reduce behavioral deficits and oxidative stress in an animal model of Parkinson’s disease, a study reports.

The study, “Arbutin attenuates behavioral impairment and oxidative stress in an animal model of Parkinson’s disease,” was published in the Avicenna Journal of Phytomedicine.

Parkinson’s disease is characterized by the progressive deterioration and death of a specific subset of brain cells called dopaminergic neurons. The loss of these nerve cells causes the disease’s neurological symptoms such as tremors, muscle rigidity, slow movements, and postural instability.

However, the molecular mechanisms by which these dopaminergic neurons are selectively affected and degenerate over time remains unknown.

Increasing evidence shows that oxidative stress is an important factor that contributes to disease progression.

Oxidative stress is caused by an imbalance between the body’s production of potentially harmful reactive oxygen species and the ability of cells to detoxify them. These reactive oxygen species can damage crucial molecules in cells including DNA and proteins, hampering their function and ultimately their ability to survive.

Current treatment options for Parkinson’s are still limited, losing effectiveness over time and often associated with side effects including nausea, fatigue, fainting, and increased tremors. Therefore, new therapeutics are urgently needed.

In this study, researchers investigated the effectiveness of a new compound — arbutin — in the treatment of Parkinson’s disease. Arbutin is naturally found in various plants, such as bearberry leaves and pear trees.

The team used a mouse model that mimics the symptoms and molecular alterations of the human disease. Mice were injected with 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine (MPTP), known for inducing Parkinson’s symptoms similar to those observed in human patients.

Animals were divided into three groups — a control group injected with a saline (innocuous) solution; a second group treated with a saline solution for seven days, followed by MPTP, injected into the abdomen; and a third group receiving arbutin (50 mg/kg) injected into the abdomen, before receiving MPTP injections.

On the 14th day of the experiment, researchers evaluated behavioral deficits using a locomotion test, hanging wire test, and forepaw stride length. They also analyzed the animals’ blood and brain tissue.

Arbutin-treated animals improved their locomotor activity and increased their forepaw step distance over the controls. Treated animals were also able to hand upside down (hanging wire test) for longer periods of time than the controls.

Arbutin also reduced blood and brain levels of specific molecules associated with oxidative stress, such as nitric oxide, previously shown to promote the death of dopaminergic neurons. The expression of thiobarbituric acid reactive substance (TBARS), a marker of oxidative stress whose levels were reported to be higher in the brains of Parkinson’s patients, was also reduced, both in the brain and blood of arbutin-treated animals.

These findings suggest that “arbutin can effectively attenuate behavioral deficits and reduce oxidative and nitrosative stress in MPTP- induced PD [Parkinson’s] model,” the researchers wrote.

They are now interested in clarifying “the exact molecular mechanisms by which arbutin can protect dopaminergic neurons.”

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Parkinson’s Monkey Model May Help Scientists Explore Non-Motor Symptoms, Study Reports

Parkinson's monkey model

A well-known monkey model for Parkinson’s disease — used mainly for its ability to mimic human motor symptoms — can also reflect the disease’s non-motor symptoms, including sleep disturbances, changes in the body’s natural clock, and cognitive impairment, a study shows.

These results highlight the usefulness of this model to explore other, lesser known aspects of Parkinson’s disease.

The study, “Charting the onset of Parkinson-like motor and non-motor symptoms in nonhuman primate model of Parkinson’s disease” was published in the journal Plos One.

Animals are at the cornerstone of human disease research, including Parkinson’s, where reliable animal models that can imitate disease features are used to understand disease mechanisms and develop therapies.

Common models used in research include simpler, multicellular organisms — a worm known as Caenorhabditis elegans, the fruit fly and zebra fish. For therapeutic design, more complex organisms are used, such as mice and even nonhuman primates.

The most common Parkinson’s monkey model was developed using small, New World monkeys called marmosets and injecting them with a toxin called 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, or MPTP.

“Most of the early studies in Parkinson’s have been conducted with rodents, but there are some complex aspects of this disease you simply cannot investigate using rodents in a way that is relevant to human patients,” Marcel Daadi, PhD, the study’s lead author and leader of the Regenerative Medicine and Aging Unit at the Southwest National Primate Research Center in Texas, said in a press release.

“Nonhuman primates are critical in [this] aspect because we can see these symptoms clearly whether it is the dyskinesia (abnormality or impairment of voluntary movements), or the sleep disturbances that you can monitor or the fine motors skills,” Daadi said.

The toxin induces the hallmark parkinsonian symptoms in the monkey that characterize human Parkinson’s — tremor, rigidity, bradykinesia (slowness of movement), postural instability, and freezing.

The symptoms arise due to the specific toxin-induced death of dopaminergic neurons — a class of neurons that produce the neurotransmitter dopamine — and whose loss triggers Parkinson’s disease motor disturbances.

Increasing research, however, shows that Parkinson’s is a multisystem disease that affects other nerve cells besides dopaminergic neurons, triggering non-motor symptoms, such as cognitive impairment, sleep disturbances, depression, and sensory impairments. These symptoms, however, are barely used as endpoints in clinical trials for Parkinson’s.

In this study, Texas Biomedical Research Institute researchers wanted to see if the marmoset MPTP model could be used to characterize both motor and non-motor Parkinson’s symptoms. The team tracked marmosets using devices around their necks similar to Fitbits people use to track their activity and sleep.

Prior to MPTP injection, the marmosets were regularly observed and displayed no abnormal behavior. One month after the MPTP injection though, they developed severe Parkinson’s disease-like symptoms, including tremors, bradykinesia, abnormal posture and decreased activity. The marmosets continued to exhibit these symptoms at six months, although with decreased severity.

Researchers then tested the animals’ motor and cognitive impairments before and after the induction of Parkinson’s disease using the object retrieval task with barrier detour — a reward-based behavioral test.

“Briefly, the task requires the test subject to retrieve a reward (marshmallow) fastened to a tray from the open side (bypassing the barrier) of a transparent box,” the researchers said in the study.

Whereas before the injection the animals showed no signs of difficulty in retrieving the reward from the box,  after Parkinson’s onset, they showed severe action tremor that led to freezing. The progressive nature of the disease was also shown by their worse performance at six months after disease onset compared with one month.

After six months, the animals also showed significant cognitive impairments.

Parkinson’s progression also affected the marmosets’ activity: They fell asleep during the day while in action, and experienced abnormal, irregular sleep. In accordance with these sleep disturbances, they also showed changes in their circadian rhythm, the natural “body-clock” that regulates functions such as sleep and metabolism.

Treatment with levopoda, the gold standard therapy for Parkinson’s disease, alleviated the motor features of the disease and lessened some of the non-motor dysfunctions.

“This study is a great first step,” Daadi said. “More studies are needed to expand on these non-motor symptoms in marmosets in the longer-term, and perhaps, include other nonhuman primates at the SNPRC like macaques and baboons.”

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Source: Parkinson's News Today