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NLX-112 Eases L-dopa Dyskinesia in Marmosets With Parkinson’s, Study Says

dyskinesia

An investigational therapy known as NLX-112 (befiradol) may hold promise to treat levodopa-induced dyskinesia, a complication of long-term levodopa therapy that affects people with Parkinson’s disease, a study found.

The study, “The selective 5-HT1A receptor agonist, NLX-112, exerts anti-dyskinetic and anti-parkinsonian-like effects in MPTP-treated marmosets,” was published in Neuropharmacology.

Motor symptoms of Parkinson’s disease include tremor; slow movement (bradykinesia); stiffness (rigidity); uncontrolled, involuntary movements that can affect the arms, legs, head, or the whole body (dyskinesia); and poor balance.

As the disease progresses, patients typically need to gradually increase treatment doses for maximum benefit. Even after that, symptoms sometimes reappear or worsen due to the dopaminergic therapy’s gradual loss of efficiency.

Dyskinesia is one of the complications of long-term levodopa therapy that affects many patients with advanced Parkinson’s disease. Currently, the main medication available to manage dyskinesia is amantadine. However, it can have side effects and may not be effective for every patient.

Studies indicate that Parkinson’s progression and symptoms may be associated with impaired signals from another important brain chemical, serotonin. Serotonin is involved in smooth muscle contraction, and serves as the “feel-good” chemical in the brain, influencing one’s sense of well-being and happiness.

Serotonin-producing neurons have an enzyme that is crucial to producing dopamine. This enzyme can be stored in vesicles and released as a “false neurotransmitter.” This results in excessive and inappropriate dopamine release, which generates dyskinesia.

NLX-112 (also known as befiradol or F13640) is an experimental medicine being developed by Neurolixis that activates a type of serotonin receptor called 5-HT1A. This investigational therapy has been shown to inhibit the “false neurotransmitter” release, thereby minimizing or even abolishing dyskinesia in rodent models of Parkinson’s disease.

In a study funded by Parkinson’s Virtual Biotech, the drug development arm of Parkinson’s UK, researchers tested NLX-112 in a marmoset model of levodopa-induced dyskinesia.

Animals were treated with 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin that induces the death of dopamine-producing neurons and mimics Parkinson’s symptoms. Dyskinesia was then induced by chronic levodopa/benserazide combination therapy administered up to twice daily for up to a month.

NLX-112 treatment was administered alone or in combination with levodopa twice a week. Scientists also tested levodopa therapy combined with (+)8-OH-DPAT, another compound that activates the serotonin receptor 5-HT1A.

When administered together with levodopa at three different doses (0.025, 0.1 and 0.4 mg/kg ), NLX-112 reduced dyskinesia in a time and dose-dependent manner. The most prominent effects were at a dosage of 0,4 mg/kg.

In addition, NLX-112 was found to marginally interfere with the anti-parkinsonian effects of levodopa, unlike (+)8-OH-DPAT, which lessened levodopa-induced dyskinesia but also eliminated levodopa’s therapeutic efficacy.

When given alone (not combined with dopaminergic therapy), NLX-112 elicited anti-parkinsonian-like activity, easing disease-related motor disability in marmosets modeling Parkinson’s.

“Interestingly, the higher dose of NLX-112 (0.4 mg/kg) appeared less active than the lower doses, only reducing disability at a single, early time-point, suggesting an inverted dose-response relationship,” the researchers wrote.

Both NLX-112 and (+)8-OH-DPAT produced dose-dependent unusual behavior in marmosets, including sedation, scratching, wet-dog shakes, and sustained muscle contractions in the tail. These manifestations are all consistent with serotonin syndrome, a disorder that can occur when taking serotonin-boosting medications, and manifests itself with both behavioral and other general symptoms such as sweating and diarrhea.

Despite its effects, NLX-112 was not kept in animals’ blood circulation for long, which may limit its pharmacological effects in this particular species.

“This promising research on NLX-112 offers hope that we can find a treatment that can tackle dyskinesia, which can make everyday tasks, such as eating, writing, and walking, extremely difficult,” Arthur Roach, PhD, director of research at Parkinson’s UK, said in a press release.

“People with Parkinson’s tell us it is one of the most critical issues that impacts quality of life, so we’re delighted that this project is progressing so positively,” Roach said. “With 145,000 people living with Parkinson’s in the UK, we are desperately in need of a breakthrough treatment, and we’re committed to delivering one by 2024.”

“It is vital we continue to work with biotech companies like Neurolixis to drive forward new treatments that may slow, stop, or reverse Parkinson’s, and also those, like NLX-112, that could bring relief from symptoms or side effects,” said Roach.

“We are excited that NLX-112 has shown such positive results in reducing dyskinesia in marmosets,” said Adrian Newman-Tancredi, PhD, co-founder and CEO of Neurolixis. “If the striking preclinical data are reproduced in clinical trials, NLX-112 could significantly alleviate the troubling dyskinesia that prevent many Parkinson’s patients from performing routine daily tasks, thereby improving their quality of life.”

“We are currently making plans and seeking funding to take NLX-112 into clinical trials, and hope to be able to initiate these before the end of 2020,” Newman-Tancredi said.

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Brain Serotonin Changes May Be Early Warning Sign of Parkinson’s, Study Suggests

serotonin early warning

Changes to the serotonin system in the brain occur years before the development of motor symptoms in Parkinson’s — and may be an important early warning signal for the disease, a study suggests.

“Therefore, brain imaging of the serotonin system could become a valuable tool to detect individuals at risk for Parkinson’s disease, monitor their progression and help with the development of new treatments,” Heather Wilson, research associate at King’s College London and the study’s first author, said in a press release.

The study, “Serotonergic pathology and disease burden in the premotor and motor phase of A53T α-synuclein parkinsonism: a cross-sectional study,” was published in The Lancet Neurology.

Parkinson’s is characterized by the progressive death of brain cells that are responsible for producing dopamine, which eventually leads to the development of motor symptoms associated with the disease, including involuntary tremors or muscle contraction.

Studies have suggested that, in addition to changes in the dopaminergic system, Parkinson’s progression and symptoms may be associated with impaired signals from another important neurotransmitter, called serotonin. Serotonin transmits messages between nerve cells, and is thought to be active in constricting smooth muscles.

To further explore the role of serotonin in Parkinson’s progression, a team led by researchers from King’s College evaluated non-symptomatic carriers of an alpha-synuclein (SNCA) gene variant. That variant is an extremely rare mutation, but a well-known cause for hereditary Parkinson’s disease.

Individuals with mutations in the alpha-synuclein gene are almost certain to develop Parkinson’s during their lifetime, which makes them invaluable candidates to study the biological events that result in the development of the disease.

The study recruited 14 individuals who were carriers of the A53T variant in the SNCA gene, as well as 25 patients with idiopathic (of unknown cause) Parkinson’s disease, and 25 healthy matched volunteers who had no history of neurological or psychiatric disorders.

All participants were evaluated by positron emission tomography (PET) scans. PET scans use a specific dye that binds to the serotonin transporter, and evaluates serotonin metabolism in the brain. Participants also underwent several clinical assessments to determine motor and non-motor symptoms. They were evaluated for cognitive status, dopamine metabolism, and brain structural changes.

Among individuals who were SNCA mutation carriers, 50% were still asymptomatic —  at the premotor stage of the disease — and had dopaminergic deficits.

Compared with healthy controls, the premotor SNCA carriers showed reduced serotonin signals in several brain areas. SNCA carriers who still had normal dopamine transporters already showed “an average of 34% loss of serotonin transporters in raphe nuclei and 22% loss in the striatum compared with healthy controls,” the researchers said.

As the name indicates, a serotonin transporter is a protein that binds to and transports serotonin to different areas of the brain. Raphe nuclei are a type of brain receptor that decrease the release of serotonin. The striatum is a critical brain region involved in voluntary movement.

“Parkinson’s disease has traditionally been thought of as occurring due to damage in the dopamine system, but we show that changes to the serotonin system come first, occurring many years before patients begin to show symptoms,” said Marios Politis, MD, PhD, professor at the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) and senior author of the study.

Those who were SNCA carriers but had already been diagnosed with Parkinson’s disease showed more extensive deficits in the serotonin system, affecting even more areas of the brain. There was 48% serotonin transporter loss in the raphe nuclei, and 57%  loss in the striatum areas.

Further analysis revealed that low serotonin signals in the brainstem were associated with increased total scores on the Movement Disorder Score-Unified Parkinson’s Disease Rating Scale (MDS-UPSRS) — indicating higher disease burden. This occurred in all SNCA carriers, and in those with idiopathic Parkinson’s.

“Our findings provide evidence that molecular imaging of serotonin transporters could be used to visualize premotor pathology of Parkinson’s disease in vivo [in the body],” the researchers said.

Future studies should focus on implementing serotonin transporter imaging as “an adjunctive tool for screening and monitoring progression” for those at risk for, or who already have Parkinson’s.

“This is one of the first studies to suggest that changes in serotonin signaling may be an early consequence of Parkinson’s,” said Beckie Port, PhD, research manager at Parkinson’s UK. “Picking up on the condition earlier and being able to monitor its progression would aid the discovery of new and better treatments that could slow the loss of brain cells in Parkinson’s.”

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